Journal of Alzheimer's Disease Reports - Volume 8, issue 1

Authors: Yeerlan, Jianishaya | He, Binhong | Hu, Xianliang | Zhang, LuShun

Article Type: Review Article

Abstract: Background: Alzheimer’s disease (AD) is a genetically intricate neurodegenerative disorder. Studies on “Ferroptosis in AD”, “Pyroptosis in AD”, and “Necroptosis in AD” are becoming more prevalent and there is increasing evidence that they are closely related to AD. However, there has not yet been a thorough bibliometrics-based investigation on this subject. Objective: This study uses a bibliometric approach to visualize and analyze the literature within the field of three distinct types of cell death in AD and explores the current research hotspots and prospective research directions. Methods: We collected relevant articles from the Web of Science …and used CiteSpace, VOS viewer, and Pajek to perform a visual analysis. Results: A total of 123, 95, and 84 articles were published in “Ferroptosis in AD”, “Pyroptosis in AD”, and “Necroptosis in AD”, respectively. Based on keywords analysis, we can observe that “oxidative stress” and “lipid peroxidation”, “cell death” and “activation”, and “Nlrp3 inflammasome” and “activation” were the three most prominent words in the field of “Ferroptosis in AD”, “Pyroptosis in AD”, and “Necroptosis in AD”, respectively. Focusing on the breakout words in the keyword analysis, we reviewed the mechanisms of ferroptosis, pyroptosis, and necroptosis in AD. By mapping the time zones of the keywords, we speculated on the evolutionary trends of ferroptosis, pyrotosis, and necroptosis in AD. Conclusions: Our findings can help researchers grasp the research status of three types of cell death in AD and determine new directions for future research as soon as possible. Show more

Keywords: Alzheimer’s disease, bibliometric analysis, ferroptosis, necroptosis, pyroptosis

DOI: 10.3233/ADR-230092

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 129-142, 2024

Authors: Sayadnasiri, Mohammad | Darvishskandari, Sahar | Latifian, Maryam | Shariful Islam, Sheikh Mohammed

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of the most debilitating diseases in old age, associated with cognitive decline and behavioral symptoms. Objective: This study aimed to investigate the effect of adding mirtazapine to quetiapine in reducing agitation among patients with AD. Methods: Thirty-seven elderly patients (18 cases and 19 controls) with AD, diagnosed according to National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria, were enrolled at Nezam-Mafi Clinic. Inclusion criteria comprised a minimum of two years post-diagnosis, a Cohen-Mansfield Agitation and Aggression Questionnaire (CMAI) score above 45, and treatment with 100–150 mg of quetiapine. Patients were …randomly assigned to receive mirtazapine (15 mg at night, increased to 30 mg at night after two weeks) or a placebo. Cognitive changes were assessed at weeks 0 and 6 using the Mini-Mental State Examination instrument. Furthermore, symptoms of agitation and aggression were evaluated using the CMAI questionnaire at weeks 4 and 6. Results: In this study, the mean duration of AD in the control group was 4.68 years, and in the case group, it was 5.05 years. Although the total agitation score showed no significant change at the end of the study compared to the control group, the rate of physical non-aggressive behavior showed a significant decrease (p  <  0.05). Conclusions: According to this study, adding mirtazapine to the antipsychotic drug regimen may not be an effective treatment for agitation in AD patients. Show more

Keywords: Agitation, Alzheimer’s disease, mirtazapine, quetiapine

DOI: 10.3233/ADR-230123

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 143-150, 2024

Authors: Takechi, Hajime | Yoshino, Hiroshi | Suzuki, Megumi | Maeda, Akiko | Suzumura, Shota | Kamiya, Eiko

Article Type: Research Article

Abstract: Background: Because dementia is a long-term condition, the appropriate involvement of health-care professionals is considered important. However, little is known about the factors associated with changes in family caregiver burden. Objective: To clarify changes in family caregiver burden and associated factors during follow-up at a memory clinic. Methods: A retrospective cohort study was conducted, enrolling 495 pairs of patients with dementia or mild cognitive impairment and their family caregivers. A total of 120 pairs completed the second evaluation. The caregiver burden was assessed using the Zarit Burden Interview (ZBI). Data at the initial …visit and after an average follow-up of about 2 years were compared and analyzed. Results: At initial visit, the patients’ mean age, Mini-Mental State Examination (MMSE) and ZBI scores were 78.6±5.6 years, 23.3±3.5, and 22.6±16.7, respectively. At follow-up, MMSE scores decreased (21.4±4.5, p  < 0.001), but ZBI scores remained similar (22.5±13.6). When the difference in ZBI scores between the two time points was defined as Δ ZBI, and the related factors were analyzed by multiple regression analysis, ZBI scores at the initial visit, start of psychotropic drug, and decrease of neuropsychiatric symptoms were identified as significant factors (p  < 0.001, p  = 0.003, p  < 0.001, respectively). A significant negative correlation was found between ZBI scores at the initial visit and Δ ZBI (r  = –0.588, p  < 0.001). Conclusions: These findings suggest the importance of assessing changes in the burden experienced by family caregivers during the disease follow-up. Show more

Keywords: Alzheimer’s disease, caregiver burden, dementia, longitudinal, memory clinic, mild cognitive impairment

DOI: 10.3233/ADR-230069

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 151-162, 2024

Authors: Çınar, Nilgün | Aslan Kendirli, Sude | Florentina Ateş, Miruna | Yakupoğlu, Ezgi | Akbuğa, Ebru | Bolu, Naci Emre | Karalı, Fenise Selin | Okluoğlu, Tuğba | Bülbül, Nazlı Gamze | Bayindir, Elif | Atam, Kamil Tolga | Hisarlı, Enis | Akgönül, Sarp | Bagatır, Oğulcan | Sahiner, Emre | Orgen, Bora | Sahiner, Türker Ahmet Hasan

Article Type: Research Article

Abstract: Background: Detecting cognitive impairment such as Alzheimer’s disease early and tracking it over time is essential for individuals at risk of cognitive decline. Objective: This research aimed to validate the Beynex app’s gamified assessment tests and the Beynex Performance Index (BPI) score, which monitor cognitive performance across seven categories, considering age and education data. Methods: Beynex test cut-off scores of participants (n  = 91) were derived from the optimization function and compared to the Montreal Cognitive Assessment (MoCA) test. Validation and reliability analyses were carried out with data collected from an additional 214 participants. …Results: Beynex categorization scores showed a moderate agreement with MoCA ratings (weighted Cohen’s Kappa = 0.48; 95% CI: 0.38–0.60). Calculated Cronbach’s Alpha indicates good internal consistency. Test-retest reliability analysis using a linear regression line fitted to results yielded R∧ 2 of 0.65 with a 95% CI: 0.58, 0.71. Discussion: Beynex’s ability to reliably detect and track cognitive impairment could significantly impact public health, early intervention strategies and improve patient outcomes. Show more

Keywords: Alzheimer’s disease, Beynex, cognitive decline, cognitive impairment, cognitive screening test, computerized cognitive tracking, dementia, early detection, memory, Montreal Cognitive Assessment

DOI: 10.3233/ADR-230117

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 163-171, 2024

Authors: Holmbom Larsen, Axel | Londos, Elisabet

Article Type: Case Report

Abstract: Background: Creativity is a multifaceted, complex, activity, and as such is an overarching function of the brain rather than being confined to a specific structure or region. Alzheimer’s disease effects several cognitive domains involved in the creative process of producing art. Objective: We analyze the art of a well-known Swedish visual artist who suffered from Alzheimer’s disease to determine if, and in what way, his art and creative process might have been influenced by the disease. Methods: We compared his artistic process and artwork along with information from his spouse, medical r ecords, …and cognitive tests as well as reviews of exhibitions written by art critics. Results: We show that not only did the artist continue to produce artwork well into a major decline in cognitive function, according to commonly used tests, but he could continue to do so for even longer with some assistance from his spouse. However, the artwork changed considerably as the disease progressed. We hypothesize that there is a substantial lack of representation of creative ability and function in cognitive tests. Conclusions: Signs of the Alzheimer’s disease can be seen in the early artwork if viewed by critics and those with more specialized knowledge into the artist’s production. Further analysis of the complex interaction between complex neural activities, such as artistic creativity, and cognitive diseases is warranted and might provide insight in the field of neurological degenerative disease. Show more

Keywords: Alzheimer’s disease, art, creativity, cognitive dysfunction, esthetics

DOI: 10.3233/ADR-230134

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 173-187, 2024

Authors: Moore, Arelis | Davis, Nicole J. | Dolins, Madeline | Barkley, Ethan | Reese, Ann | Meggett, Kinsey | Bailey-Taylor, Melissa J.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRD) disproportionately impact Latinx and other communities of color in the United States. The challenges for patients with ADRD and their informal caretakers can be attributed, in part, to the gaps that exist within health care services and systems. Objective: To understand the perspectives of barriers, beliefs, knowledge, and needs for the Latinx informal caregivers that take care of relatives with ADRD in the Upstate of South Carolina, region of Appalachia. Methods: This study was approved by the GHS-Prisma Health and Clemson University IRB, Study #Pro00086707. In-depth …phone interviews were conducted with a sample of Latinx informal caregivers. A descriptive and interpretive phenomenological approach was used for analysis. Participants were recruited through community partnerships with local organizations. Results: Salient themes identified in this study included the relevance of caregiver’s degree of awareness about the disease and a perspective of Alzheimer’s disease as a progressive and degenerative disease. Critical moments identified encompassed challenges related to patient engagement with the outside world, their attitudes, and behaviors, as well as caregiver-related challenges with access to culturally and linguistically relevant resources needed to provide proper care. Caregivers identified several culturally relevant coping strategies used and motivators in providing care for their relatives with ADRD. Conclusions: Linguistically and culturally sensitive programs and resources that account for knowledge, assets, and needs of Latinx informal caregivers of ADRD patients are needed to improve the quality of care and decrease disparities in health outcomes for Latinx older adults. Show more

Keywords: KeywordsAlzheimer’s disease, Alzheimer’s disease and related dementias, assessment of healthcare needs, coping strategies, culturally appropriate services, family caregiver, informal caregiver, Latinx/Latino/Hispanic

DOI: 10.3233/ADR-230108

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 189-202, 2024

Authors: Garcia, Maria João | Leadley, Regina | Ross, Janine | Bozeat, Sasha | Redhead, Gabrielle | Hansson, Oskar | Iwatsubo, Takeshi | Villain, Nicolas | Cummings, Jeffrey

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) causes progressive decline of cognition and function. There is a lack of systematic literature reviews on prognostic and predictive factors in its early clinical stages (eAD), i.e., mild cognitive impairment due to AD and mild AD dementia. Objective: To identify prognostic factors affecting eAD progression and predictive factors for treatment efficacy and safety of approved and/or under late-stage development disease-modifying treatments. Methods: Databases were searched (August 2022) for studies reporting prognostic factors associated with eAD progression and predictive factors for treatment response. The Quality in Prognostic Factor Studies tool …or the Cochrane risk of bias tool were used to assess risk of bias. Two reviewers independently screened the records. A single reviewer performed data extraction and quality assessment. A second performed a 20% check. Content experts reviewed and interpreted the data collected. Results: Sixty-one studies were included. Self-reporting, diagnosis definition, and missing data led to high risk of bias. Population size ranged from 110 to 11,451. Analyses found data indicating that older age was and depression may be associated with progression. Greater baseline cognitive impairment was associated with progression. APOE4 may be a prognostic factor, a predictive factor for treatment efficacy and predicts an adverse response (ARIA). Elevated biomarkers (CSF/plasma p-tau, CSF t-tau, and plasma neurofilament light) were associated with disease progression. Conclusions: Age was the strongest risk factor for progression. Biomarkers were associated with progression, supporting their use in trial selection and aiding diagnosis. Baseline cognitive impairment was a prognostic factor. APOE4 predicted ARIA, aligning with emerging evidence and relevant to treatment initiation/monitoring. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, prognosis, review

DOI: 10.3233/ADR-230045

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 203-240, 2024

Authors: Sleem, Tamara | Decourt, Boris | Sabbagh, Marwan N.

Article Type: Review Article

Abstract:  Huge investments continue to be made in treatment for Alzheimer’s disease (AD), with more than one hundred drugs currently in development. Pharmacological approaches and drug development, particularly those targeting amyloid-β, have dominated the therapeutic landscape. At the same time, there is also a growing interest in devices for treating AD. This review aimed to identify and describe devices under development for AD treatment. In this review, we queried the devices that are in development for the treatment of AD. PubMed was searched through the end of 2021 using the terms “device,” “therapeutics,” and “Alzheimer’s” for articles that report on devices …to treat AD. Ten devices with 31 references were identified as actively being developed for the treatment of AD. Many of these devices are far along in development. Device-based therapies are often overlooked when evaluating treatment approaches to AD. However, many devices for treating AD are in development and some show promising results. Show more

Keywords: Alzheimer’s disease, clinical trials, devices, treatment

DOI: 10.3233/ADR-230115

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 241-255, 2024

Authors: Sun, Wenxian | Wei, Cuibai

Article Type: Research Article

Abstract: Background: Previous observational research has indicated a correlation between ferritin levels and neuropsychiatric disorders, although the causal relationship remains uncertain. Objective: The objective of this study was to investigate the potential causal link between plasma ferritin levels and neuropsychiatric disorders. Methods: A two-sample Mendelian randomization (MR) study was conducted, wherein genetic instruments associated with ferritin were obtained from a previously published genome-wide association study (GWAS). Summary statistics pertaining to neuropsychiatric disorders were derived from five distinct GWAS datasets. The primary MR analysis employed the inverse variance weighted (IVW) method and was corroborated by …additional methods including MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses were employed to identify potential pleiotropy and heterogeneity in the results. Results: The fixed effects IVW method revealed a statistically significant causal relationship between plasma ferritin level and the occurrence of Alzheimer’s disease (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.00–1.12, p  = 0.037), as well as Parkinson’s disease (OR = 1.06, 95% CI: 1.00–1.13, p  = 0.041). Various sensitivity analyses were conducted, which demonstrated no substantial heterogeneity or pleiotropy. Conversely, no compelling evidence was found to support a causal association between ferritin and amyotrophic lateral sclerosis, schizophrenia, or major depressive disorder. Conclusions: This MR study provides evidence at the genetic level for a causal relationship between plasma ferritin and an increased risk of Alzheimer’s disease and Parkinson’s disease. The exact genetic mechanisms underlying this connection necessitate further investigation. Show more

Keywords: Alzheimer’s disease, ferritin, Mendelian randomization, neuropsychiatric disorders, Parkinson’s disease

DOI: 10.3233/ADR-230136

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 257-266, 2024

Authors: Evans, Sarah A. | Paitel, Elizabeth R. | Bhasin, Riya | Nielson, Kristy A.

Article Type: Research Article

Abstract: Background: Subjective cognitive complaints (SCC) may be an early indicator of future cognitive decline. However, findings comparing SCC and objective cognitive performance have varied, particularly in the memory domain. Even less well established is the relationship between subjective and objective complaints in non-amnestic domains, such as in executive functioning, despite evidence indicating very early changes in these domains. Moreover, particularly early changes in both amnestic and non-amnestic domains are apparent in those carrying the Apolipoprotein-E ɛ4 allele, a primary genetic risk for Alzheimer’s disease (AD). Objective: This study investigated the role of the ɛ4 allele in …the consistency between subjective and objective executive functioning in 54 healthy, cognitively intact, middle-aged and older adults. Methods: Participants (M age  = 64.07, SD  = 9.27, range = 48–84; ɛ4+ = 18) completed the Frontal Systems Behavior Scale (FrSBe) Executive Dysfunction Scale (EXECDYS) to measure subjective executive functioning (SEF) and multiple executive functioning tasks, which were condensed into a single factor. Results: After accounting for age, depression, and anxiety, objective executive functioning performance significantly predicted SEF. Importantly, ɛ4 moderated this effect. Specifically, those carrying the ɛ4 allele had significantly less accurate self-awareness of their executive functioning compared to ɛ4 non-carriers. Conclusions: Utilizing an approach that integrates self-evaluation of executive functioning with objective neurocognitive assessment may help identify the earliest signs of impending cognitive decline, particularly in those with genetic risk for AD. Such an approach could sensitively determine those most prone to future cognitive decline prior to symptom onset, when interventions could be most effective. Show more

Keywords: Aging, Alzheimer’s disease, APOE ɛ4, executive function, subjective cognitive complaints

DOI: 10.3233/ADR-230166

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 267-279, 2024

Authors: Lombardi, Gemma | Berti, Valentina | Ginestroni, Andrea | Nacmias, Benedetta | Sorbi, Sandro

Article Type: Case Report

Abstract: Amyloid-β deposition is the pathological hallmark of both cerebral amyloid angiopathy and Alzheimer’s disease dementia, clinical conditions that can share cognitive decline and positive Amyloid-PET scan. A case is reported involving an 82-year-old Italian female who presented initially a memory deficit, later transient focal neurologic episodes, and finally two symptomatic lobar intracerebral hemorrhages. In light of these events, MRI and PET imaging findings, acquired before cerebral hemorrhages, are reconsidered and discussed, highlighting the utility of Amyloid-PET in supporting an in vivo diagnosis of cerebral amyloid angiopathy.

Keywords: Alzheimer’s disease, amyloid PET, cerebral amyloid angiopathy, lobar cerebral hemorrhage, superficial siderosis, FDG-PET

DOI: 10.3233/ADR-230183

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 281-288, 2024

Authors: Chithiramohan, Tamara | Santhosh, Smrithi | Threlfall, Grace | Hull, Louise | Mukaetova-Ladinska, Elizabeta B. | Subramaniam, Hari | Beishon, Lucy

Article Type: Systematic Review

Abstract: Background: Cognitive screening tools are important in the detection of dementia, including Alzheimer’s disease; however, they may contain cultural biases. Objective: This review examines culture-fair cognitive screening tools and evaluates their screening accuracy, strengths, and limitations. Methods: Medline, Embase, PsychINFO and CINAHL were searched. The protocol was registered on PROSPERO (CRD42021288776). Included studies used a culture-fair tool to assess cognition in older adults from varying ethnicities. Narrative synthesis was conducted. Results: 28 studies were included assessing eleven different tools. The Rowland Universal Dementia Assessment Scale (RUDAS) was as accurate as …the Mini-Mental State Examination (MMSE) (AUC 0.62-0.93), with a similar sensitivity (52–94%) and better specificity (70–98%), and the Multicultural Cognitive Examination (MCE) had improved screening accuracy (AUC 0.99) compared to RUDAS (AUC 0.92). The Visual Cognitive Assessment Test (VCAT) was equivalent to MMSE (AUC 0.84–0.91). The Kimberley Indigenous Cognitive Assessment tool (KICA) had AUC of 0.93–0.95; sensitivity of 90.6%, specificity 92.6%. Conclusions: The RUDAS, KICA and VCAT were superior to MMSE for screening dementia in ethnic minorities. Other tools also showed good screening accuracy. Further research should be done to validate tools in different populations. Show more

Keywords: Alzheimer’s disease, culture-fair, cognitive screening, dementia

DOI: 10.3233/ADR-230194

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 289-306, 2024

Authors: Shan, Guogen | Lu, Xinlin | Li, Zhigang | Caldwell, Jessica Z.K. | Bernick, Charles | Cummings, Jeffrey

Article Type: Research Article

Abstract: Background: Composite scores have been increasingly used in trials for Alzheimer’s disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial. Objective: To develop a new composite score to improve the prediction of outcome change. Methods: We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression. Results: The new AD composite S core with variable S election (ADSS) includes 7 …cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs. Conclusions: ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages. Show more

Keywords: ADCOMS, Alzheimer’s disease, cognitive outcome, composite score, mild cognitive impairment, model selection

DOI: 10.3233/ADR-230043

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 307-316, 2024

Authors: Dakdareh, Sara Ghasemi | Abbasian, Karim

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and mild cognitive impairment are common diseases in the elderly, affecting more than 50 million people worldwide in 2020. Early diagnosis is crucial for managing these diseases, but their complexity poses a challenge. Convolutional neural networks have shown promise in accurate diagnosis. Objective: The main objective of this research is to diagnose Alzheimer’s disease and mild cognitive impairment in healthy individuals using convolutional neural networks. Methods: This study utilized three different convolutional neural network models, two of which were pre-trained models, namely AlexNet and DenseNet, while the third model was …a CNN1D-LSTM neural network. Results: Among the neural network models used, the AlexNet demonstrated the highest accuracy, exceeding 98%, in diagnosing mild cognitive impairment and Alzheimer’s disease in healthy individuals. Furthermore, the accuracy of the DenseNet and CNN1D-LSTM models is 88% and 91.89%, respectively. Conclusions: The research highlights the potential of convolutional neural networks in diagnosing mild cognitive impairment and Alzheimer’s disease. The use of pre-trained neural networks and the integration of various patient data contribute to achieving accurate results. The high accuracy achieved by the AlexNet neural network underscores its effectiveness in disease classification. These findings pave the way for future research and improvements in the field of diagnosing these diseases using convolutional neural networks, ultimately aiding in early detection and effective management of mild cognitive impairment and Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, AlexNet convolutional neural network, DenseNet convolutional neural network, mild cognitive impairment

DOI: 10.3233/ADR-230118

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 317-328, 2024

Authors: Pinjala, Poojitha | Tryphena, Kamatham Pushpa | Kulkarni, Amrita | Goswami, Prince Giri | Khatri, Dharmendra Kumar

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial selective autophagy, is critical in maintaining mitochondrial and subsequently neuronal homeostasis. Its impairment is strongly implicated in PD and is associated with accelerated neurodegeneration. Objective: To study the positive effect of dimethyl fumarate (DMF) on mitophagy via the NRF2/BNIP3/PINK1 axis activation in PD disease models. Methods: The neuroprotective effect of DMF was explored in in vitro and in vivo PD models. MTT assay was performed to determine the DMF …dose followed by JC-1 assay to study its mitoprotective effect in MPP+ exposed SHSY5Y cells. For the in vivo study, C57BL/6 mice were divided into six groups: Normal Control (NC), Disease Control (DC), Sham (Saline i.c.v.), Low Dose (MPP+ iodide+DMF 15 mg/kg), Mid Dose (MPP+ iodide+DMF 30 mg/kg), and High Dose (MPP+ iodide+DMF 60 mg/kg). The neuroprotective effect of DMF was assessed by performing rotarod, open field test, and pole test, and biochemical parameter analysis using immunofluorescence, western blot, and RT-PCR. Results: DMF treatment significantly alleviated the loss of TH positive dopaminergic neurons and enhanced mitophagy by increasing PINK1, Parkin, BNIP3, and LC3 levels in the MPP+ iodide-induced PD mice model. DMF treatment groups showed good locomotor activity and rearing time when compared to the DC group. Conclusions: DMF confers neuroprotection by activating the BNIP3/PINK1/Parkin pathway, enhancing the autophagosome formation via LC3, and improving mitophagy in PD models, and could be a potential therapeutic option in PD. Show more

Keywords: Alzheimer’s disease, autophagy, dimethyl fumarate, 1-methyl-4-phenyl pyridinium iodide, nuclear factor E2-related factor 2, Parkinson’s disease

DOI: 10.3233/ADR-230128

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 329-344, 2024

Authors: Teng, Zenghui

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease with cognitive decline and behavioral dysfunction. AD will become a global public health concern due to its increasing prevalence brought on by the severity of global aging. It is critical to understand the pathogenic mechanisms of AD and investigate or pursue a viable therapy strategy in clinic. Amyloid-β (Aβ) accumulation and abnormally hyperphosphorylated tau protein are the main regulating variables in the pathological phase of AD. And neuroinflammation brought on by activated microglia was found to be one risk factor contributing to changes in Aβ and tau pathology. It is important …to investigate the unique biomarkers of early diagnosis and advanced stage, which may help to elucidate the specific pathological process of AD and provide potential novel therapeutic targets or preventative measures. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, neuroinflammation, tau

DOI: 10.3233/ADR-230130

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 345-354, 2024

Authors: Ozsahin, Ilker | Zhou, Liangdong | Wang, Xiuyuan | Garetti, Jacob | Jamison, Keith | Xi, Ke | Tanzi, Emily | Jaywant, Abhishek | Patchell, Abigail | Maloney, Thomas | de Leon, Mony J. | Kuceyeski, Amy | Shah, Sudhin A. | Li, Yi | Butler, Tracy A.

Article Type: Short Communication

Abstract: Diffusion tensor imaging along perivascular spaces (DTI-ALPS) is a novel MRI method for assessing brain interstitial fluid dynamics, potentially indexing glymphatic function. Failed glymphatic clearance is implicated in Alzheimer’s disease (AD) pathophysiology. We assessed the contribution of age and female sex (strong AD risk factors) to DTI-ALPS index in healthy subjects. We also for the first time assessed the effect of head size. In accord with prior studies, we show reduced DTI-ALPS index with aging, and in men compared to women. However, head size may be a major contributing factor to this counterintuitive sex difference.

Keywords: Aging, Alzheimer’s disease, DTI-ALPS, glymphatic system, interstitial fluid dynamics, sex difference

DOI: 10.3233/ADR-230143

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 355-361, 2024

Authors: Perini, Giulia | Cotta Ramusino, Matteo | Conca, Francesca | Cosentino, Giuseppe | Farina, Lisa Maria | Costa, Alfredo | Farina, Elisabetta

Article Type: Case Report

Abstract: The prodromal stage of Lewy body dementia includes a mild cognitive impairment with visual processing and/or attention-executive deficits. A clinical presentation with progressive visual loss is indeed seldom reported and can be misleading with a posterior cortical atrophy disease. While the neurodegeneration at the occipital cortex can only partially explain the visual disturbances of Lewy body dementia, more recently a retinal dysfunction has been suggested by preliminary optical coherence tomography and autoptic findings. Herein, we present a case of a mild cognitive impairment with Lewy bodies, who presented initially with visual disturbances and signs of both retinal and cortical visual …processing dysfunction. A complete neuropsychological, neurophysiological and brain imaging assessment highlighted a prominent ventral visual pathway involvement. This report provides first that the prodromal stage of Lewy body dementia can manifest as a primarily progressive visual loss, second that the involvement of visual pathway, particularly the ventral stream, can be detectable from the retinal to the cortical level. Show more

Keywords: Alzheimer’s disease, Lewy body dementia, parvicellular system, prodromal stage, retinal involvement, visual perception deficits

DOI: 10.3233/ADR-230176

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 363-369, 2024

Authors: Singh, Anita | Maker, Matthew | Prakash, Jayant | Tandon, Raghav | Mitchell, Cassie S.

Article Type: Research Article

Abstract: Background: Amyloid-β plaques (Aβ) are associated with Alzheimer’s disease (AD). Pooled assessment of amyloid reduction in transgenic AD mice is critical for expediting anti-amyloid AD therapeutic research. Objective: The mean threshold of Aβ reduction necessary to achieve cognitive improvement was measured via pooled assessment (n  = 594 mice) of Morris water maze (MWM) escape latency of transgenic AD mice treated with substances intended to reduce Aβ via reduction of beta-secretase cleaving enzyme (BACE). Methods: Machine learning and statistical methods identified necessary amyloid reduction levels using mouse data (e.g., APP/PS1, LPS, Tg2576, 3xTg-AD, control, wild type, treated, untreated) …curated from 22 published studies. Results: K-means clustering identified 4 clusters that primarily corresponded with level of Aβ: untreated transgenic AD control mice, wild type mice, and two clusters of transgenic AD mice treated with BACE inhibitors that had either an average 25% “medium reduction” of Aβ or 50% “high reduction” of Aβ compared to untreated control. A 25% Aβ reduction achieved a 28% cognitive improvement, and a 50% Aβ reduction resulted in a significant 32% improvement compared to untreated transgenic mice (p  < 0.05). Comparatively, wild type mice had a mean 41% MWM latency improvement over untreated transgenic mice (p  < 0.05). BACE reduction had a lesser impact on the ratio of Aβ42 to Aβ40 . Supervised learning with an 80% –20% train-test split confirmed Aβ reduction was a key feature for predicting MWM escape latency (R2  = 0.8 to 0.95). Conclusions: Results suggest a 25% reduction in Aβ as a meaningful treatment threshold for improving transgenic AD mouse cognition. Show more

Keywords: Alzheimer’s disease, anti-amyloid therapy, artificial intelligence, BACE inhibitor, effect size, machine learning, transgenic mice

DOI: 10.3233/ADR-230174

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 371-385, 2024

Authors: Xia, Xuefei | Yuan, Pingqiao | Zhao, Xue | Jia, Fang Rong | Li, Bangyang | Cai, Peng

Article Type: Research Article

Abstract: Background: The development and popularization of the Internet provides an important opportunity to advance national strategies for healthy aging, particularly the impact of the Internet on cognitive function in middle-aged and older adults. Objective: This study aimed to quantify the impact of Internet use on the cognitive health of middle-aged and older adults (aged≥45 years). Methods: We used data from the Chinese Family Panel Study (CFPS) survey, tested the robustness of the baseline findings by variable substitution and instrumental variables methods, and analyzed heterogeneity. Subsequently, five purposes of Internet use that affect cognitive function were analyzed …in depth. Results: Internet use may improve cognitive function in middle-aged and older adults. The effect of Internet use on cognitive function was more pronounced in the lower age group (45–59 years), among males, in rural areas, and among middle-aged and older adults with higher levels of education. Cognitive functioning of middle-aged and older adults varied according to how often they used the Internet for entertainment, socialization, study, work, and business activities. Conclusions: The use of the Internet may be considered a practical non-pharmacological intervention to slow cognitive decline in middle-aged and older adults. Show more

Keywords: Alzheimer’s disease, cognitive function, Internet use, heterogeneity analysis, instrumental variable

DOI: 10.3233/ADR-230137

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 387-397, 2024

Authors: Lacerda, Isabel Barbeito | Baptista, Maria Alice Tourinho | Belfort, Tatiana | Mograbi, Daniel | Dourado, Marcia Cristina Nascimento

Article Type: Research Article

Abstract: Background: Awareness is a heterogeneous construct that requires accurate assessment. There is no consensus on the best methodology for capturing the phenomenon, thus leading to inconsistent results in this area. Objective: We aim to evaluate the reliability of clinicians’ ratings and a discrepancy assessment method, examining groups of people with Alzheimer’s disease (PwAD) according to their degree of awareness and demographic and clinical aspects. Methods: We cross-sectionally assessed 134 PwAD and their caregivers. Individuals’ level of awareness was assessed with two methods: clinicians’ ratings identified three groups (preserved awareness, impaired awareness, and absent awareness), while discrepancy …assessment identified four groups (preserved awareness, mildly impaired awareness, moderately impaired awareness, and absent awareness). Results: Clinicians’ ratings showed significant differences between PwAD with preserved, impaired, and absent awareness groups in cognition, functionality, and neuropsychiatric symptoms. There was a significant difference in caregivers’ anxiety between the impaired and absent awareness groups. Discrepancy assessment showed no clinical differences between the preserved and mildly impaired awareness groups or between the absent and moderately impaired awareness groups. A significant difference in functionality was observed between the other groups. Conclusions: Clinical aspects of each measure tended to differ between the chosen methods. Impairments in awareness fluctuate despite disease progression. Cognition and severity of disease cannot explain deficits in awareness. Show more

Keywords: Alzheimer’s disease, awareness, dementia, measures

DOI: 10.3233/ADR-230090

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 399-410, 2024

Authors: Liu, Jiahao | Roccati, Eddy | Chen, Yutong | Zhu, Zhuoting | Wang, Wei | He, Mingguang | Shang, Xianwen

Article Type: Research Article

Abstract: Background: Limited knowledge exists regarding the association between dementia incidence and vitamin D insufficiency/deficiency across seasons. Objective: This study aimed to evaluate the impact of seasonal serum vitamin D (25(OH)D) levels on dementia and its subtypes, considering potential modifiers. Methods: We analyzed 193,003 individuals aged 60–73 at baseline (2006–2010) from the UK Biobank cohort, with follow-up until 2018. 25(OH)D were measured at baseline, and incident dementia cases were identified through hospital records, death certificates, and self-reports. Results: Out of 1,874 documented all-cause dementia cases, the median follow-up duration was 8.9 years. Linear and nonlinear …associations between 25(OH)D and dementia incidence across seasons were observed. In multivariable-adjusted analysis, 25(OH)D deficiency was associated with a 1.5-fold (95% CIs: 1.2–2.0), 2.2-fold (1.5–3.0), 2.0-fold (1.5–2.7), and 1.7-fold (1.3–2.3) increased incidence of all-cause dementia in spring, summer, autumn, and winter, respectively. Adjusting for seasonal variations, 25(OH)D insufficiency and deficiency were associated with a 1.3-fold (1.1–1.4) and 1.8-fold (1.6–2.2) increased dementia incidence, respectively. This association remained significant across subgroups, including baseline age, gender, and education levels. Furthermore, 25(OH)D deficiency was associated with a 1.4-fold (1.1–1.8) and 1.5-fold (1.1–2.0) higher incidence of Alzheimer’s disease and vascular dementia, respectively. These associations remained significant across all subgroups. Conclusions: 25(OH)D deficiency is associated with an increased incidence of dementia and its subtypes throughout the year. Show more

Keywords: Alzheimer’s disease, dementia, moderation analysis, season, vitamin D

DOI: 10.3233/ADR-230077

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 411-422, 2024

Authors: Seifallahi, Mahmoud | Galvin, James E. | Ghoraani, Behnaz

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) can be an early sign of Alzheimer’s disease and other types of dementia detectable through gait analysis. Curve walking, which demands greater cognitive and motor skills, may be more sensitive in MCI detection than straight walking. However, few studies have compared gait performance in older adults with and without MCI in these conditions. Objective: To compare the capability of curve and straight walking tests for the detection of MCI among older adults. Methods: We employed a Kinect v.2 camera to record the gait of 55 older adults (30 healthy controls, 25 …with MCI) during single-task straight and curve walking tests. We examined 50 gait markers and conducted statistical analyses to compare groups and conditions. The trail was approved with protocol No. IR.SEMUMS.REC.1398.237 by the ethics committee of Semnan University of Medical Sciences in Iran. Results: Older adults with MCI exhibited more compromised gait performance, particularly during curve walking. Curve walking outperformed straight walking in MCI detection, with several gait markers showing significant differences between healthy controls and MCI patients. These markers encompass average velocity, cadence, temporal markers (e.g., gait cycle subphase durations), spatial markers (e.g., foot position changes during gait subphases), and spatiotemporal markers (e.g., step and stride velocities). Conclusions: Our study suggests curve walking as a more informative and challenging test for MCI detection among older adults, facilitating early diagnosis using non-invasive, cost-effective tools like the Kinect v.2 camera, complementing cognitive assessments in early diagnosis, and tracking MCI progression to dementia. Show more

Keywords: Alzheimer’s disease, curve walking, gait analysis, Kinect v.2 camera, mild cognitive impairment, straight walking

DOI: 10.3233/ADR-230149

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 423-435, 2024

Authors: Wang, Hao | Shi, Lin | Luo, Shimei | Luo, Yishan | Xu, Chunyan | Qiu, Guozhen | Guo, Qiwen | Chen, Chunchun | Lu, Taikun | Liu, Kangding | Zhu, Feiqi

Article Type: Research Article

Abstract: Background: Increasing evidence suggests that both amyloid-β metabolism disorders in the liver and cerebral hypoperfusion play an important role in the pathogenesis of Alzheimer’s disease (AD). However, the relevance of liver function alterations to cerebral blood flow (CBF) of patients with AD remains unclear. Objective: We aimed to investigate the associations between liver function changes and CBF of patients with AD. Methods: We recruited 17 patients with sporadic AD. In addition to physical and neurological examinations, detection of AD biomarkers in cerebrospinal fluid by enzyme-linked immunosorbent assay and CBF assessment by arterial spin labeling sequence of …magnetic resonance image scans as well as measure of liver function markers in serum by routine laboratory testing were conducted. Neuropsychological tests were evaluated, including Mini-Mental State Examination and Montreal Cognitive Assessment. Linear and rank correlations were performed to test the associations of liver function alterations with regional CBF of AD. Results: We found that liver function markers, especially total protein, the ratio of albumin to globin, globin, alkaline phosphatase, and aspartate aminotransferase were significantly associated with regional CBF of AD patients. Conclusions: These findings demonstrated significant associations between perfusion in certain brain regions of AD and alterations of liver function markers, particularly proteins and liver enzymes, which might provide implications to the pathogenesis and treatment of AD. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, cerebral blood flow, liver function markers

DOI: 10.3233/ADR-230102

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 437-445, 2024

Authors: Padala, Akshay P. | Ramakrishnan, Parameshwaran | Crawford, Christina G.

Article Type: Case Report

Abstract: Background: Social isolation is very common and has increased during the COVID-19 pandemic. Objective: To study if spiritual reconnection as part of a multi-component intervention can reduce social isolation in older adults with cognitive impairment. Methods: A longitudinal case study framework was used. A 68-year-old female with mild cognitive impairment presented with social isolation exacerbated by the COVID-19 pandemic. She participated in a telephone-based psychosocial intervention program called Connection Plans for 8 weeks. Motivational interviewing techniques were used to encourage the patient to pick goals to improve the mind, body, and connections. In her connections goal, …the patient expressed a desire to make spiritual reconnection. Connecting back to her spirituality was one of the key interventions in this patient. Social isolation, resilience, self-efficacy, and cognition were assessed using standardized rating scales before and after the intervention. Results: The patient was able to identify goals to enhance connections and physical and mental well-being. She successfully reconnected with her spirituality while maintaining COVID prevention measures. At an 8-week follow-up, compared to the baseline visit there was an improvement in measures of social isolation (22/30 to 14/30, a 36% reduction), resilience (12/20 to 20/20, a 67% improvement), and confidence (4/20 to 16/20, a 300% improvement). No improvement was noted in cognition. Conclusions: Spiritual reconnection as part of a multi-component intervention may protect against social isolation in older adults with cognitive impairment. Caution must be exercised in reaching this conclusion as this is a report of a single patient. Systematic studies are needed. Show more

Keywords: COVID pandemic, resilience, social isolation, spirituality

DOI: 10.3233/ADR-220028

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 447-452, 2024

Authors: Rohini, M. | Oswalt Manoj, S. | Surendran, D.

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) is an illness that affects the nervous system, leading to a loss in cognitive and logical abilities. Gene regulatory expressions, which are the complex language exhibited by DNA, serve several functionalities, including the physical and biological life cycle processes in the human body. The gene expression sequence affects the pathology experienced by an individual, its longevity, and potential for a cure. The transcription factors, from DNA to RNA conversion, and the binding process determine the gene expression, which varies for every human organ and disease. This study proposes Deep convolutional neural network model that reads the gene …regulatory expression sequence through various convolutional layers encoded to detect positive spikes in transcription factors. This results in the prediction of disease conversion probability from mild cognitive impairment to AD which is the key-requisite for affected geriatric cohorts. Show more

Keywords: Alzheimer’s disease, APOE, DNA, gene regulatory mechanism, rs429358, rs7412

DOI: 10.3233/ADR-230083

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 453-460, 2024

Authors: Ding, Yu | He, Jinrong | Kong, Fanli | Sun, Dongsheng | Chen, Weiqun | Luo, Bo | Wu, Jia | Zhang, Shaoying | Zhan, Peiyan | Peng, Caixia

Article Type: Research Article

Abstract: Background: Neuronal loss occurs early and is recognized as a hallmark of Alzheimer’s disease (AD). Promoting neurogenesis is an effective treatment strategy for neurodegenerative diseases. Traditional Chinese herbal medicines serve as a rich pharmaceutical source for modulating hippocampal neurogenesis. Objective: Gallic acid (GA), a phenolic acid extracted from herbs, possesses anti-inflammatory and antioxidant properties. Therefore, we aimed to explore whether GA can promote neurogenesis and alleviate AD symptoms. Methods: Memory in mice was assessed using the Morris water maze, and protein levels were examined via western blotting and immunohistochemistry. GA’s binding site in the promoter region …of transcription regulator nuclear factor erythroid 2-related factor 2 (Nrf2) was calculated using AutoDock Vina and confirmed by a dual luciferase reporter assay. Results: We found that GA improved spatial memory by promoting neurogenesis in the hippocampal dentate gyrus zone. It also improved synaptic plasticity, reduced tau phosphorylation and amyloid-β concentration, and increased levels of synaptic proteins in APP/PS1 mice. Furthermore, GA inhibited the activity of glycogen synthase kinase-3β (GSK-3β). Bioinformatics tools revealed that GA interacts with several amino acid sites on GSK-3β. Overexpression of GSK-3β was observed to block the protective effects of GA against AD-like symptoms, while GA promoted neurogenesis via the GSK-3β-Nrf2 signaling pathway in APP/PS1 mice. Conclusions: Based on our collective findings, we hypothesize that GA is a potential pharmaceutical agent for alleviating the pathological symptoms of AD. Show more

Keywords: Alzheimer’s disease, gallic acid, GSK-3β , neurogenesis, Nrf2, spatial memory

DOI: 10.3233/ADR-230171

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 461-477, 2024

Authors: Mondal, Tanmoy | Noreen, Zarish | Loffredo, Christopher A. | Johnson, Jheannelle | Bhatti, Attya | Nunlee-Bland, Gail | Quartey, Ruth | Howell, Charles D. | Moses, Gemeyel | Nnanabu, Thomas | Cotin, Sharleine T. | Clark, Marika | Chandra, Vijay | Jana, Siddhartha S. | Kwabi-Addo, Bernard | Korba, Brent E. | Shahzad, Sharoon | Bhatti, Muhammad Farrukh | Ghosh, Somiranjan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that is most prevalent in elderly individuals, especially in developed countries, and its prevalence is now increasing in developing countries like Pakistan. Objective: Our goal was to characterize key genes and their levels of expression and related molecular transcriptome networks associated with AD pathogenesis in a pilot case-control study in a Pakistani population. Methods: To obtain the spectrum of molecular networks associated with pathogenesis in AD patients in Pakistan (comparing cases and controls), we used high-throughput qRT-PCR (TaqMan Low-Density Array; n  = 33 subjects) coupled with Affymetrix Arrays …(n  = 8) and Ingenuity Pathway Analysis (IPA) to identify signature genes associated with Amyloid processing and disease pathways. Results: We confirmed 16 differentially expressed AD-related genes, including maximum fold changes observed in CAPNS2 and CAPN1 . The global gene expression study observed that 61% and 39% of genes were significantly (p -value 0.05) up- and downregulated, respectively, in AD patients compared to healthy controls. The key pathways include, e.g., Amyloid Processing , Neuroinflammation Signaling , and ErbB4 Signaling . The top-scoring networks in Diseases and Disorders Development were Neurological Disease , Organismal Injury and Abnormalities , and Psychological Disorders . Conclusions: Our pilot study offers a non-invasive and efficient way of investigating gene expression patterns by combining TLDA and global gene expression method in AD patients by utilizing whole blood. This provides valuable insights into the expression status of genes related to Amyloid Processing , which could play potential role in future studies to identify sensitive, early biomarkers of AD in general. Show more

Keywords: Alzheimer’s disease, amyloid processing, gene expression, pathogenesis, transcriptomic

DOI: 10.3233/ADR-230146

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 479-493, 2024

Authors: El Haj, Mohamad | Boutoleau-Bretonnière, Claire | Gallouj, Karim | Wagemann, Nathalie | Antoine, Pascal | Kapogiannis, Dimitrios | Chapelet, Guillaume

Article Type: Research Article

Abstract: Background: The potential of ChatGPT in medical diagnosis has been explored in various medical conditions. Objective: We assessed whether ChatGPT can contribute to the diagnosis of Alzheimer’s disease (AD). Methods: We provided ChatGPT with four generated cases (mild, moderate, or advanced stage AD dementia, or mild cognitive impairment), including descriptions of their complaints, physical examinations, as well as biomarker, neuroimaging, and neuropsychological data. Results: ChatGPT accurately diagnosed the test cases similarly to two blinded specialists. Conclusions: While the use of generated cases can be a limitation to our study, our findings demonstrate …that ChatGPT can be a useful tool for symptom assessment and the diagnosis of AD. However, while the use of ChatGPT in AD diagnosis is promising, it should be seen as an adjunct to clinical judgment rather than a replacement. Show more

Keywords: Alzheimer’s disease, artificial intelligence, ChatGPT, diagnosis, mild cognitive impairment

DOI: 10.3233/ADR-230191

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 495-500, 2024

Authors: Turner, Michael | Belli, Antonio | Castellani, Rudolph J.

Article Type: Research Article

Abstract: Background: Cumulative effects of traumatic brain injury is of increasing concern, especially with respect to its role in the etiology and pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Objective: Compare regional brain volume and connectivity between athletes with a history of concussion and controls. Methods: We evaluated whole-brain volumetric effects with Bayesian regression models and functional connectivity with network-based statistics, in 125 retired athletes (a mean of 11 reported concussions) and 36 matched controls. Results: Brain regions significantly lower in volume in the concussed group included the …middle frontal gyrus, hippocampus, supramarginal gyrus, temporal pole, and inferior frontal gyrus. Conversely, brain regions significantly larger included the hippocampal and collateral sulcus, middle occipital gyrus, medial orbital gyrus, caudate nucleus, lateral orbital gyrus, and medial postcentral gyrus. Functional connectivity analyses revealed increased edge strength, most marked in motor domains. Numerous edges of this network strengthened in athletes were significantly weakened with concussion. Aligned to meta-analytic neuroimaging data, the observed changes suggest functional enhancement within the motor, sensory, coordination, balance, and visual processing domains in athletes, attenuated by concussive head injury with a negative impact on memory and language. Conclusions: These findings suggest that engagement in sport may benefit the brain across numerous domains, but also highlights the potentially damaging effects of concussive head injury. Future studies with longitudinal cohorts including autopsy examination are needed to determine whether the latter reflects tissue loss from brain shearing, or the onset of a progressive Alzheimer’s disease like proteinopathy. Show more

Keywords: Alzheimer’s disease, brain imaging, brain structure and function, concussion, neurodegeneration, sport, traumatic brain injury

DOI: 10.3233/ADR-240021

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 501-516, 2024

Authors: Moon, Sung Seek | Anderson, Lindsey | Liu, Jinyu | Lee, Jinwon | Moon, Youngkwang

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) poses a growing public health challenge, particularly with an aging population. While extensive research has explored the relationships between AD, socio-demographic factors, and cardiovascular risk factors, a notable gap exists in understanding these connections within the Asian American elderly population. Objective: This study aims to address this gap by employing the Classification and Regression Tree (CART) approach to investigate the intricate interplay of socio-demographic variables, cardiovascular risk factors, sleep patterns, prior antidepressant use, and AD among Asian American elders. Methods: Data from the 2017 Uniform Data Set, provided by the National Alzheimer’s …Coordinating Center, were analyzed, focusing on a sample of Asian American elders (n  = 4,343). The analysis utilized the Classification and Regression Tree (CART) approach. Results: CART analysis identified critical factors, including levels of independence, specific age thresholds (73.5 and 84.5 years), apnea, antidepressant use, and body mass index, as significantly associated with AD risk. Conclusions: These findings have far-reaching implications for future research, particularly in examining the roles of gender, cultural nuances, socio-demographic factors, and cardiovascular risk elements in AD within the Asian American elderly population. Such insights can inform tailored interventions, improved healthcare access, and culturally sensitive policies to address the complex challenges posed by AD in this community. Show more

Keywords: Alzheimer’s disease, Asian American, classification and regression tree, National Alzheimer’s Coordinating Center

DOI: 10.3233/ADR-230162

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 517-530, 2024

Authors: Pruitt, Patrick J. | Damoiseaux, Jessica S. | Hampstead, Benjamin M. | Peltier, Scott J. | Bhaumik, Arijit K. | Albin, Roger L. | Dodge, Hiroko H.

Article Type: Research Article

Abstract: Background: Social engagement has beneficial effects during cognitive aging. Large-scale cognitive brain network functions are implicated in both social behaviors and cognition. Objective: We evaluated associations between functional connectivity (FC) of large-scale brain cognitive networks and social engagement, characterized by self-reported social network size and contact frequency. We subsequently tested large-scale brain network FC as a potential mediator of the beneficial relationship between social engagement and cognitive performance. Methods: 112 older adults (70.7±7.3 years, range 54.6–89.7; 84 women) completed the Lubben Social Network Scale 6 (LSNS-6), National Alzheimer’s Coordinating Center (NACC) Uniform Data Set 3 (UDS-3) …cognitive battery, and resting state fMRI. We completed seed-based correlational analysis in the default mode and salience networks. Significant associations between social engagement scores and cognitive performance, as well as between social engagement and FC of brain networks, informed the construction of mediation models. Results: Social engagement was significantly associated with executive function and global cognition, with greater social engagement associated with better cognitive performance. Social engagement was significantly associated with salience network FC, with greater social engagement associated with higher connectivity. Salience network FC partially mediated associations between social engagement and both executive function and global cognition. Conclusions: Our results suggest that the salience network is a key mediator of the beneficial relationship between social engagement and cognition in older adults. Show more

Keywords: Alzheimer’s disease, cognitive aging, functional connectivity, older adults, salience network, social engagement

DOI: 10.3233/ADR-220082

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 531-542, 2024

Authors: Tsatali, Marianna | Moraitou, Despina | Gialaouzidis, Moses | Bakoglidou, Evaggelia | Psaltis, Vasilis | Bertzes, Natalia | Hassanin, Hany Ibrahim | Emmanouilidou, Eudokia | Totonidis, Michael | Frantzi, Nikoleta | Avdikou, Konstantina | Gavra, Andromachi | Diamantidou, Alexandra | Kapsali, Nikolina | Kouroundi, Eleni | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) is a widely used screening tool for detecting older adults with Alzheimer’s disease among their cognitively healthy peers. A previous study in Greek population showed that ADAS-Cog-Greek (G) is a valid tool and can identify people with Alzheimer’s disease from older adult control group; however, there is no current data about whether ADAS-Cog can differentiate older adults with mild cognitive impairment (MCI) from those who have subjective cognitive decline (SCD). Objective: The current study aimed to examine the discriminant potential of ADAS-Cog-G in Greek older adults who meet the criteria …for SCD or MCI. Methods: Four hundred eighty-two community-dwelling older adults, visitors of the Greek Alzheimer Association and Related Disorders, were enrolled in the current study. One hundred seventy-six of them met the criteria for SCD and three hundred six had MCI. Results: Path analysis applied to the data showed that age, as well as educational level affected ADAS-Cog-G performance. Results showed that the cut-off scores, which better discriminate people with SCD from MCI as well as their sensitivity and specificity values, were extracted in participants with high educational level (13 educational years<) and mainly under the age of 75 years. Conclusions: The current study provided evidence concerning the discriminant potential of ADAS-Cog-G to differentiate older adults with SCD from those with MCI in the Greek population, and therefore contributes to the relevant literature on the field. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-Greek), cutoff scores, discriminant validity, mild cognitive impairment, validation

DOI: 10.3233/ADR-230151

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 543-554, 2024

Authors: Brownell, Malcolm | Sehar, Ujala | Kshirsagar, Sudhir | Reddy, P. Hemachandra

Article Type: Article Commentary

Abstract: Our commentary aims to elucidate the importance of participant recruitment strategy in healthy brain aging study, particularly in rural West Texas, where more than 50% of the population are Hispanics and Latinos. The objective of our health aging study is to investigate the possible influence of biological, sociodemographic, and lifestyle factors on the occurrence of chronic diseases and dementia in the aging populations of West Texas. The success of this initiative is, in large part, reliant on high-quality, effective recruitment of participants. To that end, we propose an increase in our strategic recruitment efforts for both healthy, cognitively superior agers …as well as those with mild cognitive impairment and patients with Alzheimer’s disease in rural west Texas. We discussed, multi-advertising approaches, including ads in the local newspapers, local TV Channels and poster boards in senior centers. Show more

Keywords: Alzheimer’s disease, dementia, healthy aging, mild cognitive impairment, recruitment strategies, rural elderly

DOI: 10.3233/ADR-240009

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 555-559, 2024

Authors: Jiang, Jing | Wang, Zidong | Yu, Ruxia | Yang, Jiayi | Wang, Qiucheng | Wu, Guoqing | Tao, Yilin | Zhao, Xiaoyue | Wang, Yue | Li, Zhigang | Qin, Xiaoqian

Article Type: Research Article

Abstract: Background: Alzheimer’s disease may be effectively treated with acupoint-based acupuncture, which is acknowledged globally. However, more research is needed to understand the alterations in acupoints that occur throughout the illness and acupuncture treatment. Objective: This research investigated the differences in acupoint microcirculation between normal mice and AD animals in vivo . This research also examined how acupuncture affected AD animal models and acupoint microcirculation. Methods: 6-month-old SAMP8 mice were divided into two groups: the AD group and the acupuncture group. Additionally, SAMR1 mice of the same month were included as the normal group. The study involved …subjecting a group of mice to 28 consecutive days of acupuncture at the ST36 (Zusanli ) and CV12 (Zhongwan ) acupoints. Following this treatment, the Morris water maze test was conducted to assess the mice’s learning and memory abilities; the acoustic-resolution photoacoustic microscope (AR-PAM) imaging system was utilized to observe the microcirculation in CV12 acupoint region and head-specific region of each group of mice. Results: In comparison to the control group, the mice in the AD group exhibited a considerable decline in their learning and memory capabilities (p  < 0.01). In comparison to the control group, the vascular in the CV12 region and head-specific region in mice from the AD group exhibited a considerable reduction in length, distance, and diameter r (p  < 0.01). The implementation of acupuncture treatment had the potential to enhance the aforementioned condition to a certain degree. Conclusions: These findings offered tangible visual evidence that supports the ongoing investigation into the underlying mechanisms of acupuncture’s therapeutic effects. Show more

Keywords: Acupuncture, Alzheimer’s disease, microcirculation, photoacoustic microscope, senescence-accelerated mouse prone 8

DOI: 10.3233/ADR-230193

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 561-574, 2024

Authors: Zhu, Congcong | Tong, Tong | Farrell, John J. | Martin, Eden R. | Bush, William S. | Pericak-Vance, Margaret A. | Wang, Li-San | Schellenberg, Gerard D. | Haines, Jonathan L. | Lunetta, Kathryn L. | Farrer, Lindsay A. | Zhang, Xiaoling

Article Type: Research Article

Abstract: Background: Mitochondrial DNA (mtDNA) is a double-stranded circular DNA and has multiple copies in each cell. Excess heteroplasmy, the coexistence of distinct variants in copies of mtDNA within a cell, may lead to mitochondrial impairments. Accurate determination of heteroplasmy in whole-genome sequencing (WGS) data has posed a significant challenge because mitochondria carrying heteroplasmic variants cannot be distinguished during library preparation. Moreover, sequencing errors, contamination, and nuclear mtDNA segments can reduce the accuracy of heteroplasmic variant calling. Objective: To efficiently and accurately call mtDNA homoplasmic and heteroplasmic variants from the large-scale WGS data generated from the Alzheimer’s Disease Sequencing …Project (ADSP), and test their association with Alzheimer’s disease (AD). Methods: In this study, we present MitoH3—a comprehensive computational pipeline for calling mtDNA homoplasmic and heteroplasmic variants and inferring haplogroups in the ADSP WGS data. We first applied MitoH3 to 45 technical replicates from 6 subjects to define a threshold for detecting heteroplasmic variants. Then using the threshold of 5% ≤variant allele fraction≤95%, we further applied MitoH3 to call heteroplasmic variants from a total of 16,113 DNA samples with 6,742 samples from cognitively normal controls and 6,183 from AD cases. Results: This pipeline is available through the Singularity container engine. For 4,311 heteroplasmic variants identified from 16,113 samples, no significant variant count difference was observed between AD cases and controls. Conclusions: Our streamlined pipeline, MitoH3, enables computationally efficient and accurate analysis of a large number of samples. Show more

Keywords: Alzheimer’s disease, haplogroup, homoplasmic and heteroplasmic variant calling, mitochondrial DNA, whole genome sequencing

DOI: 10.3233/ADR-230120

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 575-587, 2024

Authors: Yu, Xianfeng | Deng, Shuqing | Liu, Junxin | Zhang, Mingkai | Zhang, Liang | Li, Ruixian | Zhang, Wei | Han, Ying

Article Type: Research Article

Abstract: Background: Sleep disturbances frequently affect Alzheimer’s disease (AD), with up to 65% patients reporting sleep-related issues that may manifest up to a decade before AD symptoms. Objective: To construct a nomogram that synthesizes sleep quality and cognitive performance for predicting cognitive impairment (CI) conversion outcomes. Methods: Using scores from three well-established sleep assessment tools, Pittsburg Sleep Quality Index, REM Sleep Behavior Disorder Screening Questionnaire, and Epworth Sleepiness Scale, we created the Sleep Composite Index (SCI), providing a comprehensive snapshot of an individual’s sleep status. Initially, a CI conversion prediction model was formed via COX regression, fine-tuned …by bidirectional elimination. Subsequently, an optimized prediction model through COX regression, depicted as a nomogram, offering predictions for CI development in 5, 8, and 12 years among cognitively unimpaired (CU) individuals. Results: After excluding CI patients at baseline, our study included 816 participants with complete baseline and follow-up data. The CU group had a mean age of 66.1±6.7 years, with 36.37% males, while the CI group had an average age of 70.3±9.0 years, with 39.20% males. The final model incorporated glial fibrillary acidic protein, Verbal Fluency Test and SCI, and an AUC of 0.8773 (0.792–0.963). Conclusions: In conclusion, the sleep-cognition nomogram we developed could successfully predict the risk of converting to CI in elderly participants and could potentially guide the design of interventions for rehabilitation and/or cognitive enhancement to improve the living quality for healthy older adults, detect at-risk individuals, and even slow down the progression of AD. Show more

Keywords: Alzheimer’s disease, biomarkers, prediction, sleep

DOI: 10.3233/ADR-240001

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 589-600, 2024

Authors: Batesole, Joshua | Tomkinson, Grant R. | Erickson, Kirk I. | Jurivich, Donald | Lang, Justin J. | McGrath, Brenda M. | Robinson-Lane, Sheria G. | Smith, Ashleigh E. | McGrath, Ryan

Article Type: Research Article

Abstract: Background: Weakness can be operationalized with several thresholds, which in turn, could impact associations with cognitive impairment when considering obesity status. Objective: We examined the associations of absolute, normalized, and collective weakness thresholds on future cognitive impairment by obesity status in older adults. Methods: We performed a secondary data analysis on the 2006–2018 waves of the Health and Retirement Study. A spring-type dynamometer collected handgrip strength (HGS). Males were categorized weak if their HGS was <35.5-kg (absolute), <0.45-kg/kg (body mass normalized), or <1.05-kg/kg/m2 (body mass index (BMI) normalized), while females were defined as weak if …their HGS was <20.0-kg, <0.337-kg/kg, or <0.79-kg/kg/m2 . The modified Telephone Interview of Cognitive Status examined cognitive function. Persons scoring ≤10 had a cognitive impairment. Obesity was categorized as BMI ≥30 kg/m2 . Results: We included 7,532 and 3,584 persons aged ≥65-years living without and with obesity, respectively. Those without obesity but beneath the absolute weakness threshold had 1.54 (95% confidence interval (CI): 1.24–1.91) greater odds for future cognitive impairment. Persons with obesity and beneath each threshold also had greater odds for future cognitive impairment: 1.89 (95% CI: 1.28–2.78) for absolute, 2.17 (95% CI: 1.02–4.62) for body mass normalized, and 1.75 (95% CI: 1.10–2.80) for BMI normalized. Older Americans without obesity but underneath all the weakness thresholds had 1.32 (95% CI: 1.00–1.74) greater odds for impairment in cognitive function, while persons with obesity had 2.76 (95% CI: 1.29–5.93) greater odds. Conclusions: There should be consideration for how body size and different weakness thresholds may influence future cognitive outcomes. Show more

Keywords: Aging, Alzheimer’s disease, body composition, body mass index, cognition, dementia, functional status, geriatrics, muscle strength, muscle strength dynamometer

DOI: 10.3233/ADR-230190

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 601-608, 2024

Authors: Hashiguchi, Kenichi | Kobayashi, Ryota | Morioka, Daichi | Kawakatsu, Shinobu | Sakamoto, Kazutaka | Matsuda, Hiroshi | Suzuki, Akihito

Article Type: Short Communication

Abstract: Identifying the coexistence of Lewy body (LB) pathology with Alzheimer’s disease (AD) in clinical practice is important in the era of anti-amyloid-β antibody therapy. However, few studies have predicted the presence of comorbid LB pathology with AD using indicative biomarkers of dementia with Lewy bodies or by collecting detailed clinical symptoms. We report the clinical progression of a 67-year-old patient diagnosed with AD who developed rapid eye movement sleep disorder-like symptoms and transient visual hallucinations 10 years after AD onset and was considered to have comorbid LB pathology based on imaging indicative biomarkers of dementia with Lewy bodies.

Keywords: Alzheimer’s disease, dementia, dopamine transporter, Lewy bodies, myocardial scintigraphy, rapid eye movement sleep behavior disorder, visual hallucinations

DOI: 10.3233/ADR-240019

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 609-614, 2024

Authors: Basurto-Islas, Gustavo | Tung, Yunn Chyn | Dai, Chun-ling | Iqbal, Khalid | Gong, Cheng-Xin

Article Type: Research Article

Abstract: Background: Diabetes mellitus (DM) increases the risk for cognitive impairment and Alzheimer’s disease (AD). Diabetic ketoacidosis (DKA), a serious complication of DM, may also cause brain damage and further AD, but the underlying molecular mechanisms remain unclear. Objective: Our objective was to understand how DKA can promote neurodegeneration in AD. Methods: We induced DKA in rats through intraperitoneal injection of streptozotocin, followed by starvation for 48 hours and investigated AD-related brain alterations focusing on tau phosphorylation. Results: We found that DKA induced hyperphosphorylation of tau protein at multiple sites associated with AD. Studies of …tau kinases and phosphatases suggest that the DKA-induced hyperphosphorylation of tau was mainly mediated through activation of c-Jun N-terminal kinase and downregulation of protein phosphatase 2A. Disruption of the mTOR-AKT (the mechanistic target of rapamycin−protein kinase B) signaling pathway and increased levels of synaptic proteins were also observed in the brains of rats with DKA. Conclusions: These results shed some light on the mechanisms by which DKA may increase the risk for AD. Show more

Keywords: Dementia, diabetic ketoacidosis, protein kinases, protein phosphatases, tau

DOI: 10.3233/ADR-240040

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 615-626, 2024

Authors: Nguyen, Michelle | Wood, Colby | Rios, Andres | Salter, Zach | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is characterized by memory loss and multiple cognitive impairments. AD is pathologically characterized by age-dependent accumulation of amyloid-β protein and the phosphorylation of tau protein in the brains of patients with AD. Clinically, manifestations of AD include cognitive decline, dementia, alterations of high-order brain functions, and movement disorders. Double-stranded DNA breaks are a lethal form of DNA damage and are typically repaired via non-homologous end joining and homologous recombination. However, in AD brain, repair mechanism is disrupted, leading to a cascade of events, cognitive dysfunction, organ failure and reduced lifespan. Increased …circulating cell-free DNA in the blood, cerebrospinal fluid, and urine in patients with AD, can be used as early detectable biomarkers for AD. The purpose of our article is to explore the potential uses of cell-free DNA and double-stranded DNA breaks as prognostic markers for AD and examine the recent research on the application of these markers in studies. Show more

Keywords: Alzheimer’s disease, cell-free DNA, dementia, double-stranded DNA breaks

DOI: 10.3233/ADR-240012

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 627-635, 2024

Authors: Besser, Lilah M. | Edwards, Kyle | Lobban, Nina-Simone | Tolea, Magdalena I. | Galvin, James E.

Article Type: Research Article

Abstract: Background: Few studies have investigated associations between perceived social determinants of health (SDOH) and Alzheimer’s disease and related dementia (ADRD) biomarkers or between SDOH and resilience against ADRD. Objective: To examine associations between perceived and objective SDOH and ADRD-related outcomes. Methods: We used cross-sectional data on≥50-year-olds without dementia in the Healthy Brain Initiative (n = 162). Questionnaires captured trust in neighbors and indices of perceived neighborhood greenspace access, time spent in neighborhood greenspaces, and interpersonal discrimination. Residential addresses were linked to 2021 Area Deprivation Index scores. The Vulnerability Index (VI) is based on 12 dementia risk factors (e.g., …age, race/ethnicity, diabetes) and Resilience Index (RI) is based on 6 protective factors (e.g., diet, mindfulness, physical activity). Cognitive measured included number symbol coding task and Montreal Cognitive Assessment. Biomarkers included Aβ42/40 and pTau-217/npTau-217, hippocampal and white matter hyperintensity volume, lipoprotein A, and high-sensitivity c-reactive protein. Results: Perceived greater access to greenspaces (estimate = 2.83, 95% CI = 1.40–4.26) and greater time in neighborhood greenspaces were associated with greater RI scores (estimate = 2.30, 95% CI = 1.24–3.35). Reporting greater discrimination (estimate = 0.10, 95% CI = 0.04–0.16) and living in higher deprivation neighborhoods were associated with greater VI scores (estimate = 0.017, 95% CI = 0.003–0.032). Greater discrimination was associated with greater white matter hyperintensity volume (estimate = 0.27, 95% CI = 0.04–0.51). Conclusions: Perceived greenspace access and time spent in greenspaces were associated with resilience against ADRD, and interpersonal discrimination was associated with vulnerability to ADRD. Future work needs to validate perceived SDOH measures, examine associations in racially/ethnic diverse populations, and investigate longitudinal associations between SDOH and ADRD-related biomarkers. Show more

Keywords: Alzheimer’s disease, biomarkers, built environment, dementia, green space, neighborhood resilience, social determinants of health, socioeconomic status, structural determinants of health

DOI: 10.3233/ADR-230155

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 637-646, 2024

Authors: Wang, Weiye | Cui, Ruxin | Leng, Luming | Wang, Gang | Peng, Guoping

Article Type: Review Article

Abstract: Cognitive impairment is a primary manifestation of neurological symptoms associated with COVID-19 and may occur after disease resolution. Although cognitive impairment has been extensively reported in the literature, its duration and rate of remission remain controversial. This study discusses the various factors that influence cognitive impairment, including demographic characteristics, genetics, as well as disease course and severity. Furthermore, imaging and laboratory data have suggested various associations with cognitive impairment, most notably changes in EEG patterns, PET imaging, and serum markers. Some findings suggest similarities and potential links between COVID-related cognitive impairment and Alzheimer’s disease. Moreover, this study reviews the various …mechanisms proposed to explain the development of cognitive impairment in COVID-19, including cytokine storm, damage to the blood-brain barrier, compromise of small vessel integrity, hypoxic conditions, and immune dysregulation. Show more

Keywords: Alzheimer’s disease, cognitive impairment, COVID-19, mechanism, nervous system, SARS-CoV-2

DOI: 10.3233/ADR-230172

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 647-658, 2024

Authors: Czerwinski-Alley, Natasha C. | Chithiramohan, Tamara | Subramaniam, Hari | Beishon, Lucy | Mukaetova-Ladinska, Elizabeta B.

Article Type: Systematic Review

Abstract: Background: The current cognitive tests have been developed based on and standardized against Western constructs and normative data. With older people of minority ethnic background increasing across Western countries, there is a need for cognitive screening tests to address factors which influence performance bias and timely diagnostic dementia accuracy. The diagnostic accuracy in translated and culturally adapted cognitive screening tests and their impact on test performance in diverse populations have not been well addressed to date. Objective: This review aims to highlight considerations relating to the adaptation processes, language, cultural influences, impact of immigration, and level of education …to assess for dementia in non-Western and/or non-English speaking populations. Methods: We conducted a systematic search for studies addressing the effects of translation and cultural adaptations of cognitive screening tests (developed in a Western context) upon their diagnostic accuracy and test performance across diverse populations. Four electronic databases and manual searches were conducted, using a predefined search strategy. A narrative synthesis of findings was conducted. Results: Search strategy yielded 2,890 articles, and seventeen studies (4,463 participants) met the inclusion criteria. There was variability in the sensitivity and specificity of cognitive tests, irrespective of whether they were translated only, culturally adapted only, or both. Cognitive test performance was affected by education, linguistic ability, and aspects of acculturation. Conclusions: We highlight the importance of translating and culturally adapting tests that have been developed in the Western context. However, these findings should be interpreted with caution as results varied due to the broad selection of included cognitive tests. Show more

Keywords: Alzheimer’s disease, cognitive test, dementia, ethnic minority, mild cognitive impairment, translation

DOI: 10.3233/ADR-230198

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 659-675, 2024

Authors: Jamshidi-Naeini, Yasaman | Escobar Velasquez, Nicolas | Golzarri-Arroyo, Lilian | Ali, Sumayyah | Howard, Luke R. | Dickinson, Stephanie | Allison, David B.

Article Type: Article Commentary

DOI: 10.3233/ADR-240006

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 677-679, 2024

Authors: Hedayatjoo, Mohammad | Tehrani-Doost, Mehdi | Vahabi, Zahra | Akbarfahimi, Malahat | Khosrowabadi, Reza

Article Type: Research Article

Abstract: Background: Some pathological changes occur in patients with Alzheimer’s disease (AD) prior to the onset of clinical symptoms. Objective: In the present study, we aimed to investigate the potential of event-related potential (ERP) components in error processing performance as a neuromarker of mild cognitive impairment (MCI) and transition to AD and their relation with cognitive functions. Methods: We conducted an evaluation of 16 patients diagnosed with AD, 16 patients with MCI, and 15 normal controls using three subtests from the Cambridge Neuropsychological Testing Automated Battery (CANTAB). The ERP components of error processing were extracted and compared …among the three groups using a modified version of the Eriksen flanker task. Additionally, we assessed the correlation between the cognitive results and the ERP components. Results: Significant differences were observed among the three groups in terms of providing correct responses following errors and the amplitude of error-related negativity (ERN). These differences were also significant between all paired groups. Regarding other ERP components of error processing and the peak latency of ERN, no significant differences were observed among the three groups. The findings revealed that the spatial working memory and new learning were correlated with the amplitude of ERN. Conclusions: In the context of error processing performance, both the accuracy of responses following an error and the amplitude of ERN can be considered as indicators of MCI and its progression to AD. The present findings do not support the use of other error processing components as differential markers in the three groups. Show more

Keywords: Alzheimer’s disease, brain mapping, error processing, event-related potential, mild cognitive impairment

DOI: 10.3233/ADR-230104

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 681-696, 2024

Authors: Amos, Jessica G. | Zheng, Lidan | Eramudugolla, Ranmalee | Andrews, Sophie C. | Anstey, Kaarin J.

Article Type: Research Article

Abstract: Background: Digital dementia risk reduction interventions are cost-effective and scalable. However, it is unknown how they are perceived by people already experiencing cognitive concerns or decline. Objective: To understand the current use, interest, and preferences for online learning courses and interest in learning about factors influencing brain health and dementia risk among adults ≥45. To explore potential differences between individuals experiencing cognitive concerns and those without. Methods: Adults aged 45 and older completed a survey on technology use and healthy ageing (n  = 249, Mean age = 65.6, 76.3% female). The Memory Assessment Clinic-Questionnaire was used to assess subjective …memory decline, and 153 participants met the study criteria for cognitive concerns (≥25). Results: Almost all participants (98.4%) reported using two or more digital devices, and 51.8% reported increasing device usage following COVID-19. Most (92.1%) were interested in learning about healthy living and memory within an online course, and over 80% indicated a high interest in learning about dementia risk factors. People with cognitive concerns were more likely to report using a ‘routine or system’ to aid memory than people without (82.4% versus 62.9%, p  = 0.001). However, no significant difference was found in technology use, course preferences, or interest in learning about different risk factors. Conclusions: We conclude that adults 45 years and over are interested in online methods for learning about brain health and offer unique insights into adapting dementia prevention programs for cognitive concerns. Show more

Keywords: Alzheimer’s disease, cognition, dementia, prevention and control, technology

DOI: 10.3233/ADR-230160

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 697-708, 2024

Authors: García-Roldán, Ernesto | Tsai, Richard | Berger, Amy | Franco-Macías, Emilio

Article Type: Case Report

Abstract: A 60-year-old man presented to a Neurology Clinic specialized in cognitive disorders to evaluate memory complaints. A comprehensive neuropsychological examination detected an isolated and severe hippocampal memory deficit. Laboratory tests, brain magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) tests, including Alzheimer’s disease (AD) biomarkers, did not show remarkable results. Due to family history of cognitive impairment, we extended the study to non-Alzheimer monogenic mutations (Next Generation Sequencing) detecting a pathogenic variant of the progranulin (PGRN) gene (c.1414-1 G > T) which has been previously associated with the same phenotype. These results should be considered in patients with an Alzheimer-like presentation, negative AD …biomarkers’ results, and family history of dementia. Show more

Keywords: Alzheimer’s disease, dementia, human GRN protein, limbic-predominant age-related TDP-43 encephalopathy, neurocognitive disorder

DOI: 10.3233/ADR-240014

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 709-713, 2024

Authors: Lehrer, Steven | Rheinstein, Peter H.

Article Type: Research Article

Abstract: Background: In comparison to persons who did not have viral encephalitis, people with viral encephalitis had a later-life risk of Alzheimer’s disease (AD) that was 31 times higher. In a previous study, we were able to confirm the association of viral encephalitis with AD and suggest that West Nile Virus infection is a significant AD risk factor. A genome wide association study (GWAS) with UK Biobank data revealed that the gene RAR Related Orphan Receptor B (RORB) is significantly associated with viral encephalitis. Objective: To use data from the 8 PheWeb datasets to try to identify genes other …than RORB that might be involved in both infectious encephalitis and AD. Methods: PheWeb includes data from UKBB and 5 other databanks. We used UK Biobank data to examine gene expression and phenotypic expression. Results: PheWeb identified additional genes associated with both infectious encephalitis and AD. RPTOR, a gene associated with the mTOR pathway, emerges as significant. Analyses of UK Biobank data reveal the impact of RPTOR on AD risk, with carriers of the minor allele A exhibiting decreased prevalence in subjects under age 55. Further analysis demonstrates that RPTOR genotypes influence body mass index (BMI) in subjects of all ages, with carriers of the minor allele A having lower BMI. Logistic regression analyses confirm the association between reduced BMI and increased AD risk, along with the established factor of age. Conclusions: RPTOR may represent an AD gene, though mTOR’s role in AD and BMI is complex. Nevertheless, RPTOR and mTOR could represent potential therapeutic targets for AD. Show more

Keywords: Alzheimer’s disease, body mass index, encephalitis, mTOR, neurodegeneration

DOI: 10.3233/ADR-230185

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 715-721, 2024

Authors: Makri, Marina | Despoti, Akyllina | Teichmann, Birgit | Gkioka, Mara | Moraitou, Despina | Fidani, Liana | Tegos, Thomas | Tsolaki, Magdalini

Article Type: Research Article

Abstract: Background: In recent years, studies have examined the acceptability and attitudes that influence the intention to early screen for Alzheimer’s disease (AD) in the general population, older people, carers, and asymptomatic individuals who report a family history of AD. However, it remains unclear what specific factors promote or reduce the acceptability of pre-symptomatic screening. Objective: The aim of this study is to explore the attitudes of family and non-family members as well as caregivers and non-caregivers toward the pre-symptomatic screening of AD. Methods: A total of 213 participants completed the Perceptions regarding pRE-symptomatic Alzheimer’s Disease Screening …(PRE-ADS) Questionnaire. Group comparisons using t-test and one-way ANOVA were used to examine differences in attitudes toward pre-symptomatic screening regarding age, family history, knowing someone with AD, influence of depression, and feelings of anxiety. The subscale “Acceptability of Screening” was developed to investigate the willingness to undergo pre-symptomatic screening. Results: Participants with a family history showed greater acceptance of pre-symptomatic screening while both caregivers and non-caregivers had similar attitudes. People with a family history as well as those with personal connections to dementia indicate a greater need for knowledge. The findings suggest that younger adults appear to perceive less harm from testing, whereas those who experience higher levels of anxiety and depression seem to perceive more testing harms. Conclusions: Comparing the attitudes of people with and without a family history as well as caregivers and non-caregivers toward pre-symptomatic screening of AD is critical to understand the differences between these groups and develop comprehensive screening programs. Show more

Keywords: Acceptance, Alzheimer’s disease, attitudes, caregivers, family history, screening

DOI: 10.3233/ADR-230145

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 723-735, 2024

Authors: Cubas Guillen, Jonathan | Rojas, Galeno | Demey, Ignacio | Sarasola, Diego | Merchán del Hierro, Xavier | Persi, Gabriel | Aldinio, Victoria | Pereira de Silva, Nahuel | Fernández Boccazzi, Julián | Seguí, Josefina | Muniagurria, Santiago | Gilbert, Afra | Gatto, Emilia

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) presents a significant global health challenge. Understanding the current and upcoming treatment landscape is crucial for effectively managing patients. Objective: The aim of this study was to assess the pattern of prescription and knowledge about new therapies by physicians who treat AD patients in Argentina. Methods: A cross- sectional and analytic study was conducted. A survey was elaborated about pharmacological treatment in AD. Statistical analysis of answers of specialists in cognitive disorders (SCD), non-specialists in cognitive disorders (NSCD), recommended treatment, non-recommended treatment (NRT), and off-label treatment was performed. Results: …155 physicians answered the survey. A 19.35%prescribed at least one NRT for dementia. 78.06%prescribed at least an off-label treatment or an NRT for mild cognitive impairment (MCI). 31%would prescribe monoclonal antibodies (MABs) against cerebral amyloid-β (Aβ) to AD patients, and 42.6%responded that they were not aware of any adverse effect of these. Quetiapine was the most frequent treatment for psychotic symptoms (88.4%) and escitalopram (32.3%) for apathy. A 70%of potential prescribers of MABs (n  = 100) would request biomarkers of cerebral Aβ in the initial assessment. There were significant differences between the responses of SCD and NSCD regarding the prescription of MABs (52.17%versus 23.08, respectively) and knowledge about adverse events (76.09%versus 38.46%, respectively). Conclusions: A considerable percentage of physicians indicated NRT and off-label medication in MCI and dementia. In Argentina, there are many physicians who would indicate a MABs for AD, but many are not completely aware of its safety profile. Show more

Keywords: Alzheimer’s disease, drug therapy, epidemiology, health policy, monoclonal antibodies

DOI: 10.3233/ADR-240018

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 737-746, 2024

Authors: Brownell, Malcolm | Sehar, Ujala | Mukherjee, Upasana | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Dementia is a major health concern in society, particularly in the aging population. It is alarmingly increasing in ethnic minorities such as Native Americans, African Americans, Hispanics/Latinos, and to some extent Asians. With increasing comorbidities of dementia such as diabetes, obesity, and hypertension, dementia rates are expected to increase in the next decade and beyond. Understanding and treating dementia, as well as determining how to prevent it, has become a healthcare priority across the globe for all races and genders. Awareness about dementia and its consequences such as healthcare costs, and caregiver burden are immediate needs to be addressed. Therefore, …it is high time for all of us to create awareness about dementia in society, particularly among Hispanics/Latinos, Native Americans, and African Americans. In the current article, we discuss the status of dementia, cultural, and racial impacts on dementia diagnosis and care, particularly in Hispanic populations, and possible steps to increase dementia awareness. We also discussed factors that need to be paid attention to, including, cultural & language barriers, low socioeconomic status, limited knowledge/education, religious/spiritual beliefs and not accepting modern medicine/healthcare facilities. Our article also covers both mental & physical health issues of caregivers who are living with patients with dementia, Alzheimer’s disease, and Alzheimer’s disease-related dementias. Most importantly, we discussed possible measures to create awareness about dementia, including empowering community advocacy, promoting healthy lifestyle choices, education on the impact of nutrition, encouraging community participation, and continued collaboration and evaluation of the success of dementia awareness. Show more

Keywords: Alzheimer’s disease, community participation, comorbidities, dementia, healthy brain aging, Hispanics, lifestyle choices

DOI: 10.3233/ADR-240043

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 747-764, 2024

Authors: Bai, Yamei | Tian, Meng | Chen, Yuqing | Song, Yulei | Zhang, Xueqing | Yin, Haiyan | Luo, Dan | Xu, Guihua

Article Type: Research Article

Abstract: Background: Individuals with mild cognitive impairment (MCI) frequently experience sleep disorders, which may elevate the risk of developing Alzheimer’s disease. Yet, sleep types in MCI patients and the factors influencing them have not been sufficiently investigated. Objective: The objective of this study was to explore potential sleep typing and its influencing factors in patients with MCI using latent class analysis. Methods: A cross-sectional survey was conducted in Jiangsu Province, China. Cognitive function in older adults was assessed using neuropsychological tests, including the Montreal Cognitive Assessment Scale-Beijing version (MoCA), the Mini-Mental State Examination (MMSE), the Activities of …Daily Living Scale (ADL), and the Clinical Dementia Rating Scale (CDR). Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Latent class analysis based on PSQI scores and multinomial logistic regression analyses were employed to explore the influencing factors of sleep typing. Results: The study included a total of 611 patients with MCI. Latent class analysis identified three latent classes to categorize the sleep patterns of MCI patients: the good sleep type (56.6%), the insufficient sleep type (29.6%), and the difficulty falling asleep type (13.7%). Potential sleep typing is influenced by gender, chronic disease, physical exercise, social activity, brain exercise, smoking, frailty, subjective cognitive status, and global cognitive function. Conclusions: The findings of this study underscore the notable heterogeneity in the sleep patterns of patients with MCI. Future research may provide targeted prevention and interventions to address the characteristics and influencing factors of patients with different subtypes of sleep MCI. Show more

Keywords: Alzheimer’s disease, latent class analysis, mild cognitive impairment, risk factors, sleep

DOI: 10.3233/ADR-230192

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 765-776, 2024

Authors: Liang, Yulin | Doré, Vincent | Rowe, Christopher C. | Krishnadas, Natasha

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. While preclinical studies have shown benefits of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in targeting core AD pathology, clinical studies are limited. Objective: A systematic review was performed to evaluate GLP-1 RAs in AD for their potential to target core AD pathology and improve cognition. Methods: Searches were conducted via three different databases (PubMed, Embase, and Cochrane Library). Search terms included Medical Subject Headings (MeSH) terms: ‘glucagon-like peptide 1 receptor agonist’ and ‘Alzheimer’s disease’, as well as entry terms ‘GLP-1 RA’, ‘AD’, and three …types of GLP-1 RA: ‘liraglutide’, ‘exenatide’, and ‘lixisenatide’. Results: A total of 1,444 studies were screened. Six articles that met criteria were included (four randomized control trials [RCTs] and two protocol studies). Two RCTs with amyloid-β and tau biomarker endpoints did not observe an end of treatment difference between the placebo and treated groups. In three RCTs with cognitive endpoints, there was no end of treatment difference between placebo and treated groups. GLP-1 RA showed metabolic benefits, such as lower body mass index and improved glucose levels on oral glucose tolerance tests in treated groups. GLP-1 RA may mitigate the decline in cerebral glucose metabolism and show enhanced blood-brain glucose transport capacity using 18 F-FDG PET, however, more data is needed. Conclusions: GLP-1 RA therapy did not alter amyloid-β and tau biomarkers nor show improvements in cognition but showed potential metabolic and neuroprotective benefits. Show more

Keywords: Alzheimer’s disease, amyloid, cognition, glucagon-like peptide 1, tau protein

DOI: 10.3233/ADR-230181

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 777-789, 2024

Article Type: Correction

DOI: 10.3233/ADR-249002

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 791-792, 2024

Authors: Adhikari, Alisa | Nwosu, Adaora | Qian, Min | Hellegers, Caroline | Devanand, Davangere P. | Doraiswamy, P. Murali

Article Type: Research Article

Abstract: Background: There is a need for integration and comprehensive characterization of environmental determinants of Alzheimer’s disease. The Environmental Justice Index (EJI) is a new measure that consolidates multiple environmental health hazards. Objective: This analysis aims to explore how environmental vulnerabilities vary by race/ethnicity and whether they predict cognitive outcomes in a clinical trial of mild cognitive impairment (MCI). Methods: We used data from a clinical trial of 107 MCI participants (28% minorities). Using the EJI, we extracted 40 measures of neighborhood environmental and social vulnerability including air and water pollution, access to recreational …spaces, exposure to coal and lead mines, and area poverty. We also examined the relationship of the EJI to the Area Deprivation Index (ADI). Data was analyzed using regressions, correlations, and t -tests. Results: Environmental Burden Rank (EBR) across the sample (0.53±0.32) was near the 50th percentile nationally. When divided by race/ethnicity, environmental (p  = 0.025) and social (p  < 0.0001) vulnerabilities were significantly elevated for minorities, specifically for exposure to ozone, diesel particulate matter, carcinogenic air toxins, and proximity to treatment storage and disposal sites. ADI state decile was not correlated with the EBR. Neither EBR nor ADI were a significant predictor of cognitive decline. Conclusions: To our knowledge, this is the first study to link the EJI to an MCI trial. Despite limitations of a relatively small sample size, the study illustrates the potential of the EJI to provide deeper phenotyping of the exposome and diversity in clinical trial subjects. Show more

Keywords: Alzheimer’s disease, climate medicine, cognition, disparities, diversity, environment global warming, neurodegeneration, ozone, particulate matter

DOI: 10.3233/ADR-240020

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 793-804, 2024

Authors: Ho, Duc Sy Minh | Zaitsu, Takashi | Ihira, Hikaru | Iwasaki, Masanori | Yoshihara, Akihiro | Suzuki, Seitaro | Inoue, Manami | Yamagishi, Kazumasa | Yasuda, Nobufumi | Aida, Jun | Shinozaki, Tomohiro | Goto, Atsuhi | Tsugane, Shoichiro | Sawada, Norie

Article Type: Research Article

Abstract: Background: As infrequent social interaction is a potential risk of dementia, oral malodor may increase the risk of dementia, including Alzheimer’s disease. Objective: This study investigated the association between malodor and dementia. Methods: We used the Japan Public Health Center-based Prospective Study data obtained at Yokote City. A total of 1,493 individuals aged 56 to 75 years underwent a dental examination and self-reported survey from May 2005 to January 2006. Follow-up for the onset of dementia was conducted using long-term care insurance data from 2006 to 2016. Hazard ratios of oral malodor on …dementia were estimated by the Cox proportional hazards model. The inverse probability-weighted Cox model was used as a sensitivity analysis. Results: The study comprised 1493 participants (53.6% women) with a mean age of 65.6 (SD = 5.8) years old; at the end of the follow-up, 6.4% (n  = 96) developed dementia, and the percentage was 20.7 in severe malodor group. Throughout 15274.133 person-years of follow-up, the average incidence rate for the onset of dementia per 1000 person-years was 6.29. The highest incidence rate was seen in participants with severe malodor (22.4 per 1000 person-years). After adjusting for confounders, compared to those with no malodor, there was a 3.8 (95% confidence interval: 1.5 to 9.4) times greater hazard of developing dementia in participants with severe malodor. The inverse probability weighted Cox model confirmed the same trend with an adjusted marginal hazard ratio of 4.4 (1.2 to 16.4). CONCLUSIONS: A significant association between oral malodor and the onset of dementia exists. Show more

Keywords: Alzheimer’s disease, dementia, oral health, oral malodor

DOI: 10.3233/ADR-240015

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 805-816, 2024

Authors: Stein, Ryan G. | Ten Brinke, Lisanne F. | Boa Sorte Silva, Nárlon C. | Hsu, Chun Liang | Handy, Todd C. | Hsiung, Ging-Yuek R. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Slower walking is associated with changes in cortical volume and thickness. Computerized cognitive training (CCT) and exercise improve cortical volume and thickness and thus, may promote gait speed. Slowing of gait is predictive of Alzheimer’s disease. Objective: To examine: 1) the effect of CCT, with or without physical exercise, on cortical volume and thickness and; 2) the association of changes in cortical volume and thickness with changes in gait speed. Methods: A subset of 124 adults (n  = 53), aged 65–85 years, enrolled in an 8-week randomized controlled trial and completed T1-weighted MRI …and 4-meter walk at baseline and 8 weeks. Participants were randomized to: 1) active control (BAT; n  = 19); 2) CCT (n  = 17); or 3) CCT preceded by exercise (Ex-CCT; n  = 17). Change in cortical volume and thickness were assessed and compared across all groups using Freesurfer. RESULTS: BAT versus CCT increased left rostral middle frontal gyrus volume (p   = 0.027) and superior temporal gyrus thickness (p  = 0.039). Ex-CCT versus CCT increased left cuneus thickness (p  < 0.001) and right post central gyrus thickness (p  = 0.005), and volume (p  < 0.001). Ex-CCT versus BAT increased left (p  = 0.001) and right (p  = 0.020) superior parietal gyri thickness. There were no significant between-group differences in gait speed (p  > 0.175). Increased left superior parietal volume (p  = 0.036, r  = 0.340) and thickness (p  = 0.002, r  = 0.348), right post central volume (p  = .017, r  = 0.341) and thickness (p  = 0.001, r  = 0.348), left banks of superior temporal sulcus thickness (p  = 0.002, r  = 0.356), and left precuneus thickness (p  < 0.001, r  = 0.346) were associated with increased gait speed. CONCLUSIONS: CCT with physical exercise, but not CCT alone, improves cortical volume and thickness in older adults. These changes may contribute to the maintenance of gait speed in aging. Show more

Keywords: Alzheimer’s disease, clinical trial, cognitive training, exercise, gait, magnetic resonance imaging

DOI: 10.3233/ADR-230206

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 817-831, 2024

Authors: Ben Ayed, Ines | Ammar, Achraf | Aouichaoui, Chirine | Naija, Salma | Ben Amor, Sana | Glenn, Jordan M. | Chtourou, Hamdi | Jahrami, Haitham | Trabelsi, Khaled | Trabelsi, Yassine | El Massioui, Farid

Article Type: Research Article

Abstract: Background: The evidence supporting the effectiveness of combined interventions in Alzheimer’s disease (AD) patients remains inconclusive. Objective: The aim of this study was to evaluate the mid- and long-term effectiveness of physical training, alone or combined with cognitive games, on cognitive performance in patients with moderate AD. Methods: Seventy-nine AD patients (≈73% females, age of ≈70±1 years) were randomly divided into three groups: aerobic-based training (AT-group, n  = 27), aerobic-based training plus cognitive games (ACT-group, n  = 25), and a control group engaged in reading (CG, n  = 26), two sessions per week. Cognitive performance was evaluated at the …start, 4th week (W4), end of the 8th week (W8), and after a 4-week detraining period (W12), using problem-solving (Tower-of-Hanoi), selective attention (Stroop-test), and working memory (Digit-Span-test) assessments. Stress levels and quality of life were also evaluated. Results: Aerobic and combined training induced a positive effect on all cognitive functions tested at W4 (except problem-solving) and W8 (all p  < 0.001) with greater improvements in working-memory and problem-solving in ACT-group (p  < 0.05). Depression levels also decreased significantly, and quality of life improved at W8 (p  < 0.001) in both groups. After 4 weeks of detraining, the beneficial effect of AT and ACT was still observed. The CG did not show any significant improvements at all time points. Conclusions: Physical and cognitive interventions appear effective for improving cognitive-functions, quality-of-life, and reducing depression in AD patients. Combined training emerges as a more effective strategy to mitigate AD progression. Further research is necessary to validate these results and explore their potential for preventing early cognitive decline. Results: Aerobic and combined training induced a positive effect on all cognitive functions tested at W4 (except problem-solving) and W8 (all p  < 0.001) with greater improvements in working-memory and problem-solving in ACT-group (p  < 0.05). Depression levels also decreased significantly, and quality of life improved at W8 (p  < 0.001) in both groups. After 4 weeks of detraining, the beneficial effect of AT and ACT was still observed. The CG did not show any significant improvements at all time points. Conclusions: Physical and cognitive interventions appear effective for improving cognitive-functions, quality-of-life, and reducing depression in AD patients. Combined training emerges as a more effective strategy to mitigate AD progression. Further research is necessary to validate these results and explore their potential for preventing early cognitive decline. Show more

Keywords: Alzheimer’s disease, cognitive decline, combined intervention, dementia, low-cost intervention, problem-solving, selective attention, working memory

DOI: 10.3233/ADR-249003

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 833-845, 2024

Article Type: Correction

DOI: 10.3233/ADR-249000

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 847-848, 2024

Article Type: Correction

DOI: 10.3233/ADR-249001

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 849-850, 2024

Authors: Jang, Hyemin | Na, Duk L. | Kwon, Jay Cheol | Jung, Na-Yeon | Moon, Yeonsil | Lee, Jung Seok | Park, Kyung-Won | Lee, Ae Young | Cho, Hanna | Lee, Jae-Hong | Kim, Byeong C. | Park, Kee Hyung | Lee, Byung-Chul | Choi, Hojin | Kim, Jieun | Park, Mee Young

Article Type: Research Article

Abstract: Background: Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI. Objective: To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram. Methods: This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion …rate to probable AD and brain structure changes between the two groups. Results: In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001). Conclusions: The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making. Trial Registration: ClinicalTrials.gov (NCT03448445) Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, conversion rate, neurodegeneration, neuropsychometry, nomogram

DOI: 10.3233/ADR-230189

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 851-862, 2024

Authors: Choe, Yeong Sim | Kim, Regina E.Y. | Kim, Hye Weon | Kim, JeeYoung | Lee, Hyunji | Lee, Min Kyoung | Lee, Minho | Kim, Keun You | Kim, Se-Hong | Kim, Ji-hoon | Lee, Jun-Young | Kim, Eosu | Kim, Donghyeon | Lim, Hyun Kook

Article Type: Research Article

Abstract: Background: Application of visual scoring scales for regional atrophy in Alzheimer’s disease (AD) in clinical settings is limited by their high time cost and low intra/inter-rater agreement. Objective: To provide automated atrophy scoring using objective volume driven from deep-learning segmentation methods for AD subtype classification using magnetic resonance imaging (MRI). Methods: We enrolled 3,959 participants (1,732 cognitively normal [CN], 1594 with mild cognitive impairment [MCI], and 633 with AD). The occupancy indices for each regional volume were calculated by dividing each volume by the size of the lateral and inferior ventricular volumes. MR images …from 355 participants (119 CN, 119 MCI, and 117 AD) from three different centers were used for validation. Two neuroradiologists performed visual assessments of the medial temporal, posterior, and global cortical atrophy scores in the frontal lobe using T1-weighted MR images. Images were also analyzed using the deep learning-based segmentation software, Neurophet AQUA. Cutoff values for the three scores were determined using the data distribution according to age. The scoring results were compared for consistency and reliability. Results: Four volumetric-driven scoring results showed a high correlation with the visual scoring results for AD, MCI, and CN. The overall agreement with human raters was weak-to-moderate for atrophy scoring in CN participants, and good-to-almost perfect in AD and MCI participants. AD subtyping by automated scores also showed usefulness as a research tool. Conclusions: Determining AD subtypes using automated atrophy scoring for late-MCI and AD could be useful in clinical settings or multicenter studies with large datasets. Show more

Keywords: Alzheimer’s disease, atrophy, cognitive dysfunction, magnetic resonance imaging, visual scoring

DOI: 10.3233/ADR-230105

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 863-876, 2024

Authors: Garcia, Ricardo Isaiah | Khemka, Sachi | Roghani, Aryan Kia | Reddy, Ruhananhad P. | Pattoor, Vasanthkumar | Jacob, Michael | Reddy, Aananya | Sehar, Ujala | Reddy, P. Hemachandra

Article Type: Review Article

Abstract:  A caregiver is a constantly evolving role that an individual most likely undertakes at some point in their lifetime. With discoveries and research in increasing life expectancy, the prevalence of neurological-related diseases, such as Alzheimer’s disease (AD) and dementia, is certainly likely to require more caregivers. The demand for AD caregivers is escalating as the prevalence of the disease continues to rise. The projected rise in AD within the Hispanic population in the United States over the next few decades is expected to be the most significant among all ethnic groups. The Hispanic population faces unique dementia risks due to …cultural factors like language barriers, lower education, and limited healthcare access. Higher rates of conditions such as diabetes and cardiovascular disease further elevate dementia risk. Family dynamics and caregiving responsibilities also differ, affecting dementia management within Hispanic households. Addressing these distinct challenges requires culturally sensitive approaches to diagnosis, treatment, and support for Hispanic individuals and their family’s facing dementia. With AD and other dementia becoming more prevalent, this article will attempt to expand upon the status of caregivers concerning their economic, health, and cultural statuses. We will attempt to focus on the Hispanic caregivers that live in Texas and more specifically, West Texas due to the lack of current literature that applies to this area of Texas. Lastly, we discuss the ramifications of a multitude of factors that affect caregivers in Texas and attempt to provide tools that can be readily available for Hispanics and others alike. Show more

Keywords: Alzheimer’s Association, Alzheimer’s disease, caregivers, culture, dementia, disparities, Hispanics, non-Hispanic whites, West Texas

DOI: 10.3233/ADR-240035

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 877-902, 2024

Authors: McKay, Mary | Gorai, Sukhamoy | Paidi, Ramesh K. | Mondal, Susanta | Pahan, Kalipada

Article Type: Research Article

Abstract: Background: Despite intense investigations, no effective treatment is yet available to reduce plaques and protect memory and learning in patients with Alzheimer’s disease (AD), the most common neurodegenerative disorder. Therefore, it is important to identify a non-toxic, but effective, treatment option for AD. Objective: Cinnamein, a nontoxic compound, is naturally available in Balsam of Peru and Tolu Balsam. We examined whether cinnamein treatment could decrease plaques and improve cognitive functions in 5XFAD mouse model of AD. Methods: We employed in silico analysis, time-resolved fluorescence energy transfer assay, thermal shift assay, primary neuron isolation, western …blot, immunostaining, immunohistochemistry, Barnes maze, T maze, and open field behavior. Results: Oral administration of cinnamein led to significant reduction in amyloid-β plaque deposits in the brain and protection of spatial learning and memory in 5XFAD mice. Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, is involved in plaque lowering and increase in hippocampal plasticity. While investigating underlying mechanisms, we found that cinnamein served as a ligand of PPARα. Accordingly, oral cinnamein upregulated the level of PPARα, but not PPARβ, in the hippocampus, and remained unable to decrease plaques from the hippocampus and improve memory and learning in 5XFAD mice lacking PPARα. While A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is one of the drivers of nonamyloidogenic pathway, transcription factor EB (TFEB) is considered as the master regulator of autophagy. Cinnamein treatment was found to upregulate both ADAM10 and TFEB in the brain of 5XFAD mice via PPARα. Conclusions: Our results suggest that this balsam component may have therapeutic importance in AD. Show more

Keywords: ADAM10, Alzheimer’s disease, cinnamein, cognitive function, plaque, PPARα , TFEB

DOI: 10.3233/ADR-230179

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 903-922, 2024

Authors: MohanaSundaram, ArunSundar | Patil, Bhushan | Praticò, Domenico

Article Type: Article Commentary

Abstract:  A recent article by El Haj et al. provided evidence that ChatGPT could be a potential tool that complements the clinical diagnosis of various stages of Alzheimer’s Disease (AD) as well as mild cognitive impairment (MCI). To reassess the accuracy and reproducibility of ChatGPT in the diagnosis of AD and MCI, we used the same prompt used by the authors. Surprisingly, we found that some of the responses of ChatGPT in the diagnoses of various stages of AD and MCI were different. In this commentary we discuss the possible reasons for these different results and propose strategies for future studies.

Keywords: Alzheimer’s disease, mild cognitive impairment, brain aging, diagnosis, artificial intelligence, ChatGPT

DOI: 10.3233/ADR-240069

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 923-925, 2024

Authors: Basta, Maria | Bouloukaki, Izolde | Skourti, Eleni | Zampetakis, Alexandros | Alexopoulou, Christina | Ganiaris, Andronikos | Aligizaki, Marina | Zaganas, Ioannis | Simos, ‘Panagiotis | Vgontzas, Alexandros

Article Type: Short Communication

Abstract:  We examined associations between objective sleep duration and cognitive status in older adults initially categorized as cognitively non-impaired (CNI, n  = 57) or diagnosed with mild cognitive impairment (MCI, n  = 53). On follow-up, 8 years later, all participants underwent neuropsychiatric/neuropsychological evaluation and 7-day 24-h actigraphy. On re-assessment 62.7% of participants were cognitively declined. Patients who developed dementia had significantly longer night total sleep time (TST) than persons with MCI who, in turn, had longer night TST than CNI participants. Objective long sleep duration is a marker of worse cognitive status in elderly with MCI/dementia and this association is very strong in …older adults. Show more

Keywords: Alzheimer’s disease, cognitive performance, dementia, long sleep duration, mild cognitive impairment, older adults

DOI: 10.3233/ADR-230203

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 927-934, 2024

Authors: Feng, Ziqian | Wang, Jiayu | Xu, Lisi | Wu, Jiajing | Li, Hongyi | Wang, Ziqi | Duan, Mingjun

Article Type: Research Article

Abstract: Background: Excessive daytime sleepiness (EDS) and caudate nucleus volume alterations have been linked to Alzheimer’s disease (AD), but their relationship remains unclear under the context of subjective cognitive decline (SCD). Objective: This study aimed to investigate the relationship between EDS and caudate nucleus volume in patients with SCD. Methods: The volume of entire brain was measured in 170 patients with SCD, including 37 patients with EDS and 133 non-EDS, from the Sino Longitudinal Study on Cognitive Decline (SILCODE). Participants underwent a comprehensive assessment battery, including neuropsychological and clinical evaluations, blood tests, genetic analysis for APOE …ɛ 4, and structural MRI scans analyzed using the fully automated segmentation tool, volBrain. Results: Patients with EDS had significantly increased volume in the total and left caudate nucleus compared to non-EDS. The most significant cognitive behavioral factor associated with caudate nucleus volume in the EDS was the Auditory Verbal Learning Test-recognition. Conclusions: These findings suggest that EDS may be associated with alterations in caudate nucleus volume, particularly in the left hemisphere, in the context of SCD. Further research is necessary to understand the underlying mechanisms of this relationship and its implications for clinical management. Show more

Keywords: Alzheimer’s disease, caudate nucleus, excessive daytime sleepiness, memory, subjective cognitive decline, volume

DOI: 10.3233/ADR-230101

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 935-944, 2024

Authors: Li, Cong | Qian, Haifeng | Feng, Lina | Li, Mingquan

Article Type: Research Article

Abstract: Background: There is now increasing evidence that type 2 diabetes mellitus (T2DM) is associated with Alzheimer’s disease (AD). However, it is unclear whether the two are causally related. Objective: To reveal the causal association between T2DM and AD, we performed a bidirectional Mendelian randomization (MR) analysis. Methods: Genetic instrumental variables were systematically screened, and inverse-variance weighting, MR—Egger regression, weighted median, simple mode, and weighted mode were applied to assess the pathogenic associations between the two diseases, and sensitivity analyses were used to further validate the robustness of the results. Results: The results of forward …MR analysis with T2DM as the exposure were [OR = 0.998, 95% CI (0.975∼1.021), p  = 0.857], and the results of reverse MR analysis with AD as the exposure were [OR = 0.966, 95% CI (0.934∼0.999), p  = 0.043]. The results showed no significant association between T2DM and AD at the gene level (p  < 0.025). Sensitivity analyses were consistent with the results of the main analysis, confirming the robustness of the study. Conclusions: T2DM and AD may not be genetically causally associated. Show more

Keywords: Alzheimer’s disease, causal association, Mendelian randomization, type 2 diabetes mellitus

DOI: 10.3233/ADR-240053

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 945-957, 2024

Authors: Abbate, Carlo | Gallucci, Alessia | Trimarchi, Pietro Davide | Piacquadio, Emanuela | Caramanti, Giulia | Parma, Anna | Fumagalli, Giorgio Giulio | Inglese, Silvia | Parisi, Paola Maria Rita | Tartarone, Federica | Giunco, Fabrizio

Article Type: Review Article

Abstract: We rediscovered a phenotype of AD known in the early 1900s as presbyophrenia, but then forgotten, and renamed as confabulation-misidentification phenotype. The phenotype includes diencephalic amnesia whose prototype is Korsakoff syndrome. The main features are anterograde and retrograde amnesia with marked disorientation and confabulation, executive impairments, reduced insight and attention deficits, misidentification, minor hallucination and other delusions, behavioral disturbances, and early anxiety. In this article, we summarize what we have discovered about the new phenotype and what is still missing to confirm this diencephalic variant of AD.

Keywords: Alzheimer’s disease, confabulation, diencephalic amnesia, Korsakoff syndrome, misidentification, presbyophrenia

DOI: 10.3233/ADR-230196

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 959-969, 2024

Authors: O’Caoimh, Rónán | Foley, Mary J. | Timmons, Suzanne | Molloy, D. William

Article Type: Research Article

Abstract: Background: The Montreal Cognitive Assessment (MoCA) is recommended by the Movement Disorder Society for cognitive testing in movement disorders including Parkinson’s disease (PD) and lewy body dementia. Few studies have compared cognitive screening instruments in these diseases, which overlap clinically. Objective: To compare the MoCA and Quick Mild Cognitive Impairment (Qmci) screen in this population. Methods: Patients attending memory and movement disorder clinics associated with a university hospital had the MoCA and Qmci screen performed and diagnostic accuracy compared with the area under the receiver operating characteristic curve (AUC). Duration and severity of movement …disorders was assessed using the Unified PD Rating Scale (UPDRS). Results: In total, 133 assessments were available, median age 74±5. Median education was 11±4 years and 65% were male. Median total UPDRS score was 37±26. Median Qmci screen was 51±27, median MoCA was 19±10. There were statistically significant differences in test scores between those with subjective symptoms but normal cognition, mild cognitive impairment (MCI) and dementia (p  < 0.001). The Qmci screen had significantly greater accuracy differentiating normal cognition from MCI versus the MoCA (AUC 0.90 versus 0.72, p  = 0.01). Both instruments had similar accuracy in identifying cognitive impairment and separating MCI from dementia. The median administration time for the Qmci screen and MoCA were 5.19 and 9.24 minutes (p  < 0.001), respectively. Conclusions: Both the MoCA and Qmci screen have good to excellent accuracy in a population with movement disorders experiencing cognitive symptoms. The Qmci screen was significantly more accurate for those with early symptoms and had a shorter administration time. Show more

Keywords: Alzheimer’s disease, cognitive assessment screening instrument, lewy body disease, Montreal Cognitive Assessment, movement disorders, Parkinson’s disease

DOI: 10.3233/ADR-230207

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 971-980, 2024

Authors: Chittimalli, Kishore | Adkins, Stephen | Arora, Sanjay | Singh, Jagdish | Jarajapu, Yagna P.R.

Article Type: Research Article

Abstract: Background: The APP/PS1 mouse model recapitulates pathology of human Alzheimer’s disease (AD). While amyloid-β peptide deposition and neurodegeneration are features of AD, the pathology may involve inflammation and impaired vascular regeneration. Objective: This study evaluated inflammatory environments in the brain and bone marrow (BM), and the impact on brain microvascular density. Methods: BM and frontal cortex from male nine-month-old APP/PS1 or the control C57Bl6/j mice were studied. Vascular density and inflammatory cells were evaluated in the sections of frontal cortex by immunohistochemistry. Different subsets of hematopoietic stem/progenitor cells (BM) and monocyte-macrophages were characterized by flow cytometry …and by clonogenic assays. Myelopoietic or inflammatory factors were evaluated by real-time RT-PCR or by western blotting. Results: CD34+ or CD31+ vascular structures were lower (p  < 0.01, n  = 6) in the frontal cortex that was associated with decreased number of Lin− Sca-1+ cKit+ vasculogenic progenitor cells in the BM and circulation (p  < 0.02, n  = 6) compared to the control. Multipotent progenitor cells MPP4, common lymphoid, common myeloid and myeloid progenitor cells were higher in the APP/PS1-BM compared to the control, which agreed with increased numbers of monocytes and pro-inflammatory macrophages. The expression of pro-myelopoietic factors and alarmins was higher in the APP/PS1 BM-HSPCs or in the BM-supernatants compared to the control. Frontal cortices of APP/PS1 mice showed higher number of pro-inflammatory macrophages (CD11b+ F4/80+ or CD80+ ) and microglia (OX42+ Iba1+ ). Conclusions: These findings show that AD pathology in APP/PS1 mice is associated with upregulated myelopoiesis, which contributes to the brain inflammation and decreased vascularity. Show more

Keywords: Alarmins, Alzheimer’s disease, APP/PS1 mice, bone marrow, frontal cortex, inflammation, myelopoiesis

DOI: 10.3233/ADR-240024

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 981-998, 2024

Authors: Zhang, Weiyi | Fu, Weilun | Zhang, Yumei

Article Type: Research Article

Abstract: Background: Effect of stenosis of vertebrobasilar artery (VBA) on cognitive function is elusive. Objective: To investigate association of cerebral hypoperfusion and poor collaterals with vascular cognitive impairment (VCI) in severe VBA stenosis patients. Methods: We consecutively enrolled patients with severe VBA stenosis confirmed by digital subtraction angiography who underwent computed tomographic perfusion (CTP) and cognitive assessments. Patients were divided into poor or good collaterals groups according to the collateral circulation status, and were grouped into different perfusion groups according to CTP. Cognitive function was measured by Montreal Cognitive Assessment (MoCA), Clock Drawing Test, Stroop Color Word …Test, Trail Making Test, Digital Span Test, Auditory Verbal Learning Test, and Boston Naming Test scales. The association of cerebral perfusion and collaterals with VCI were explored. Results: Among 88 eligible patients, VCI occurred in 51 (57.9%) patients experienced. Poor collateral was present in 73 (83.0%) patients, and hypoperfusion in 64 (72.7%). Compared with normal perfusion patients, the odds ratio with 95% confidence interval for VCI was 12.5 (3.7–42.4) for overall hypoperfusion, 31.0 (7.1–135.5) for multiple site hypoperfusion, 3.3 (1.0–10.5) for poor collaterals, and 0.1 (0–0.6) for presence of posterior communicating artery (PcoA) compensated for posterior cerebral artery (PCA) and basilar artery (BA). Additionally, decreased scores of cognitive function tests occurred in patients with decompensated perfusion or poor collaterals. Conclusions: Hypoperfusion and poor collaterals were positively associated with cognitive impairment in patients with severe VBA. However, PcoA compensated for the PCA and BA had a protective role in cognitive impairment development. Show more

Keywords: Alzheimer’s disease, cerebral perfusion, collateral circulation, vascular cognitive impairment, vertebrobasilar artery stenosis

DOI: 10.3233/ADR-240007

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 999-1007, 2024

Authors: De Guia, Isaiah-Lorenzo | Eslick, Shaun | Naismith, Sharon L. | Kanduri, Swathi | Shah, Tejal M. | Martins, Ralph N.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common type of dementia, which is characterised by progressive memory loss and accumulation of hallmark markers amyloid-β (Aβ) and neurofibrillary tangles in the diseased brain. The current gold standard diagnostic methods have limitations of being invasive, costly, and not easily accessible. Thus, there is a need for new avenues, such as imaging the retina for early AD diagnosis. Sleep disruption is symptomatically frequent across preclinical and AD subjects. As circadian activity, such as the sleep-wake cycle, is linked to the retina, analysis of their association may be useful additions for achieving predictive AD diagnosis. …In this narrative review, we provide an overview of human retina studies concerning the deposition of Aβ, the role of the retina in sleep-wake cycle, the disruption of sleep in AD, and to gather evidence for the associations between Aβ, the retina, and sleep. Understanding the mechanisms behind the associations between Aβ, retina, and sleep could assist in the interpretation of retinal changes accurately in AD. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, retina, sleep

DOI: 10.3233/ADR-230150

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1009-1021, 2024

Authors: Caccamo, Martina | Urso, Daniele | Nanni, Alfredo Gabriele | Gnoni, Valentina | Giugno, Alessia | Vitulli, Alessandra | Vilella, Davide | Zecca, Chiara | Dell’Abate, Maria Teresa | Anastasia, Antonio | De Blasi, Roberto | Introna, Alessandro | Logroscino, Giancarlo

Article Type: Case Report

Abstract: The presence of parkinsonism features in primary progressive aphasia (PPA) is a subject of ongoing research. These features are usually more pronounced in the advanced stages of the disease, particularly in the non-fluent/agrammatic subtype, and are exceptionally rare in the logopenic variant (lvPPA). Here we report a case of a 63-year-old man presenting as language impairment, predominantly naming and word-finding difficulties, emerged alongside a left-sided internal tremor. Neurological examination revealed bilateral, left-side predominant rigidity, bradykinesia, and resting tremor. Notably, anosmia and constipation were present. Language assessments showed preserved single-word comprehension, object knowledge, and a minimal apraxia of speech, as well …as sentence repetition issues. Neuroimaging and biomarker analysis supported a diagnosis of primary progressive logopenic aphasia with amyloid pathology co-existing with prominent and early parkinsonism. This case underlines the intricate relationship between language disorders, parkinsonism, and amyloid pathology in lvPPA. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid PET, logopenic variant, parkinsonism, primary progressive aphasia

DOI: 10.3233/ADR-230168

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1023-1030, 2024

Authors: Chen, Anqi | Wang, Yuquan | Hu, Yue-Qing

Article Type: Research Article

Abstract: Background: Many observational studies have investigated the link between the gut microbiota and Alzheimer’s disease (AD), but the causality remains uncertain. Objective: This study aimed to evaluate the causal impact of gut microbiota on AD. Methods: A two-sample Mendelian randomization (MR) study was conducted employing summary data. Summary statistics for AD were from the latest genome-wide association study (cases and proxy cases: 85,934; controls: 401,577). Summary data for gut microbiota were acquired from MiBioGen consortium. Causal effect estimations primarily relied on the inverse variance weighting method along with the sensitivity analyses for testing for pleiotropy and …heterogeneity. Additionally, reverse MR analyses were performed to examine potential reverse causality. Results: Seven gut microbiota were identified as associated with AD risk. Order Selenomonadales (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.03–1.24, p  = 0.01), Family Pasteurellaceae (OR 1.07, 95% CI 1.01–1.13, p  = 0.01), and Genus Methanobrevibacter (OR 1.07, 95% CI 1.00–1.13, p  = 0.04) were correlated with an elevated likelihood of AD, while Class Mollicutes (OR 0.87, 95% CI 0.79–0.95, p  = 0.00), Genus Ruminiclostridium9 (OR 0.87, 95% CI 0.78–0.97, p  = 0.01), Genus Clostridiuminnocuumgroup (OR 0.94, 95% CI 0.89–0.99, p  = 0.03), and Genus Eggerthella (OR 0.94, 95% CI 0.89–1.00, p  = 0.04) exerted beneficial impact in mitigating AD. No statistically significant reverse causality was found between AD and each of these seven specific gut microbiota species. Conclusions: This study unveiled a causal link between certain gut microbiota and AD, offering new insights for advancing clinical treatments. Show more

Keywords: Aging, Alzheimer’s disease, gut microbiota, Mendelian randomization, neuropsychiatric disorder

DOI: 10.3233/ADR-240071

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1031-1040, 2024

Authors: Sharif, Azaz Bin | Jahan, Ishrat | Hasan, A.B.M. Nahid

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a growing public health concern affecting millions of individuals worldwide. This disease burden is exacerbated in countries like Bangladesh, where public awareness and knowledge about the condition remains limited. Objective: This study aimed to assess the level of AD knowledge, awareness, and perceived threat among family caregivers of individuals with chronic physical conditions of Bangladesh. Methods: A descriptive cross-sectional study was conducted among the caregivers of patients selected via convenience sampling in six public hospitals between October 2022 and March 2023. The data was collected via face-to-face interviews employing a semi-structured …questionnaire that contained information about socio-demographic characteristics, personal experiences with AD, knowledge of AD, level of awareness regarding AD, and perceived threat toward AD. Results: The findings revealed a poor knowledge of AD among the study participants. Regarding AD awareness, 52.5% considered memory loss in older individuals abnormal, 26.2% attributed AD to causes like black magic, psychological distress, or bad eyes. Regarding perceived threat, 60.2% wanted to assess their AD risk, while 68.2% disagreed with the likelihood of developing the disease. Multiple linear regression analysis revealed that age, place of residence, education, and employment status significantly contribute to AD knowledge scores. Conclusions: This study highlights the urgent need for public education and awareness campaigns to address the knowledge gap and reduce stigmatization associated with AD in Bangladesh. Targeted efforts, particularly among older age groups and rural communities, can enhance understanding and improve the quality of care and support for AD patients and their caregivers. Show more

Keywords: Alzheimer’s disease, awareness, Bangladesh, knowledge, perceived threat

DOI: 10.3233/ADR-240055

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1041-1054, 2024

Authors: Singhrao, Sim K. | Consoli, Claudia | Dennison, Sarah R. | Kanagasingam, Shalini | Welbury, Richard

Article Type: Research Article

Abstract: Background: Glycogen synthase-3 kinase (GSK3) is one of the major contributors of tau hyperphosphorylation linked to neurofibrillary tangles in Alzheimer’s disease (AD). Objective: To determine a mechanism of GSK-3β activation by two periodontal bacteria consistently confirmed in AD autopsied brains. Methods: Porphyromonas gingivalis FDC381 and Actinomyces naeslundii ATCC10301 conditioned media were collected. IMR-32 cells were challenged for 48 h with the conditioned media alongside P. gingivalis (ATCC33277) ultrapurified lipopolysaccharide (LPS) designated Pg.LPS under established cell culture conditions either alone or combined. Gene expression and protein analyses for GSK-3β were carried out. Results: …qPCR demonstrated that GSK-3β gene was overexpressed in IMR-32 cells treated with Pg.LPS with a 2.09-fold change (p  = 0.0005), while A. naeslundii treated cells demonstrated 1.41-fold change (p  = 0.004). Western blotting of the cells challenged with Pg.LPS (p  = 0.01) and A. naeslundii conditioned medium (p  = 0.001) demonstrated the 37 kDa band for each treatment with variable intensity across the medium control. Immunohistochemistry with the GSK-3β of the IMR-32 cells challenged with Pg.LPS and A. naeslundii alone demonstrated cytoplasmic and nuclear localization. Conclusions: Exposure to various bacterial factors upregulated the gene expression of GSK-3β. Western blotting for GSK-3β confirmed the presence of the cleaved fragment by Pg.LPS (37 kDa band p  = 0.01) and A. naeslundii conditioned medium (37 kDa band p  = 0.001). Immunostaining demonstrated both cytoplasmic and nuclear localization of GSK-3β. Therefore, Pg.LPS and an unknown factor from the A. naeslundii conditioned medium mediated GSK-3β activation via its transcriptionally active, cleaved, fragment. These virulence factors in the body appear to be detrimental to brain health. Show more

Keywords: Actinomyces naeslundii, Alzheimer’s disease, glycogen synthase-3 kinase, inflammation, LPS, Porphyromonas gingivalis

DOI: 10.3233/ADR-240066

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1055-1067, 2024

Authors: Kunkler, Michelle Celine | Falkenreck, Julia Maria | Ophey, Anja | Dencker, Katharina | Friese, Andrea | Jahr, Petra | Kalbe, Elke | Nelles, Gereon | Polidori, M. Cristina

Article Type: Research Article

Abstract: Background: Age-related neuronal changes impact cognitive integrity, which is a major contributor to health and quality of life. The best strategy to prevent cognitive decline and Alzheimer’s disease is still debated. Objective: To investigate the long-term effects of the eight-week multicomponent training program BrainProtect® on cognitive abilities compared to general health counseling (GHC) in cognitively healthy adults in Germany. Methods: Healthy adults (age ≥50 years) previously randomized to either GHC (n  = 72) or BrainProtect (intervention group, IG, n  = 60) for eight-weeks (once weekly, 90 minutes, group-based) underwent a comprehensive neuropsychological test battery and health-related quality …of life (HRQoL) evaluation 3- and 12-months after intervention end. Results: Dropout rates were n  = 8 after 3 months and n  = 19 after 12 months. No significant long-term effect of BrainProtect was observed for the primary endpoint Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-Plus) total score. Logical reasoning was significantly improved (p  = 0.024) 12 months after completion of the training program in IG participants compared to the GHC group independent of sex, age, education, diet, and physical activity. In IG participants, thinking flexibility (p  = 0.019) and confrontational naming (p  = 0.010) were improved 3 months after completing the intervention compared to the GHC group, however, after conservative Bonferroni adjustment, significance was lost. Conclusions: BrainProtect® independently improved logical reasoning compared to GHC up to 12 months after cognitive training’s end in healthy adults. To uncover the long-term clinical significance of multicomponent cognitive training in healthy adults, studies with larger sample size and frequent follow up visits are necessary. Show more

Keywords: Alzheimer’s disease, cognitive integrity, cognitive training, dementia prevention, long-term effects

DOI: 10.3233/ADR-230199

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1069-1087, 2024

Authors: Renard, Dimitri | Sangare, Birama | Youssouf, Ansma | Thouvenot, Eric

Article Type: Short Communication

Abstract:  Alzheimer’s disease and cerebral amyloid angiopathy (CAA) are often associated. Amyloid accumulation within leptomeningeal and small/median-sized cerebral blood vessels in CAA results in vessel fragility, leading to spontaneous leptomeningeal bleeding, lobar intracerebral hemorrhage (ICH) and cerebral microbleeds. CAA is also associated with non-traumatic subdural hematoma. The role of CAA-related vessel fragility in hemorrhagic complications after trauma, brain surgery, and intracranial drain insertion in CAA is unknown. We present two sporadic CAA patients with intracranial drain-related ICH, probably due to different underlying mechanisms, related to indirect and direct CAA-associated vessel fragility.

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, decompressive craniectomy, intracranial drain, intracerebral hemorrhage

DOI: 10.3233/ADR-240086

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1089-1092, 2024

Authors: Hu, Wenyi | Chu, Tiancheng | Liao, Huan | Wang, Wei | Ha, Jason | Kiburg, Katerina | Zhang, Xiayin | Shang, Xianwen | Huang, Yu | Zhang, Xueli | Tang, Shulin | Hu, Yijun | Yu, Honghua | Yang, Xiaohong | He, Mingguang | Zhu, Zhuoting

Article Type: Research Article

Abstract: Background: Previous studies found that visual impairment (VI) is associated with higher risk of cognitive impairment, but the molecular basis of these conditions is unknown. Objective: We aim to compare the metabolite associations of VI and cognitive impairment. Methods: The study population with comprehensive measurements was derived from the UK Biobank study. Visual acuity worse than 0.3 logMAR units were defined as VI. Failure in one or more of the four cognitive tests was defined as cognitive impairment. A panel of 249 metabolites was measured using a nuclear magnetic resonance metabolites profiling platform. Logistic regression models …were applied to compare metabolite associations with VI and cognitive impairment. Results: 23,775 participants with complete data on visual acuity, cognitive tests and metabolomics, and without a history of neurological disorders at baseline were included. After adjusting for confounding factors, VI was significantly associated with cognitive impairment (odds ratio[OR] = 1.49, 95% confidence interval [CI]: 1.27–1.74, p  < 0.001). After multiple testing correction (p  < 9×10–4 ), five metabolites including the ratio of omega-6 to omega-3 fatty acids (FAs) (OR = 1.18[1.10–1.27]), ratio of omega-3 to total FAs (OR = 0.84[0.77–0.91]), ratio of docosahexaenoic acid (DHA) to total FAs (OR = 0.86[0.80–0.94]), DHA (OR = 0.85[0.78–0.92]), and omega-3 FAs (OR = 0.84[0.77–0.91]) were uniquely associated with VI. Glycoprotein acetyls (OR = 1.06[1.03–1.10]) and alanine (OR = 0.95[0.92–0.98]) were exclusively associated with cognitive impairment. Albumin was identified as the common metabolite shared by the two phenotypes (OR = 0.90[0.85–0.95] for VI, and 0.95[0.92–0.98]) for cognitive impairment). Conclusions: We identified distinct and overlapping metabolites associated with VI and cognitive impairment, unveiling their distinct metabolic profiles and potential common pathophysiology. Show more

Keywords: Alzheimer’s disease, cognitive impairment, metabolomics, visual impairment

DOI: 10.3233/ADR-230154

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1093-1104, 2024

Authors: Nanni, Alfredo Gabriele | Urso, Daniele | Caccamo, Martina | Gnoni, Valentina | Giugno, Alessia | Zecca, Chiara | Dell’Abate, Maria Teresa | Vilella, Davide | De Blasi, Roberto | Logroscino, Giancarlo

Article Type: Case Report

Abstract: This report presents a challenging case of Creutzfeldt-Jakob Disease (CJD), a rare and rapidly progressing neurological disorder. The patient exhibited diverse and progressive neuro-psychiatric symptoms, including memory impairment, behavioral changes, and hallucinations associated with cacosmia. The diagnosis of CJD is complicated due to its variable clinical presentation, limited awareness, and the need for tissue pathology confirmation. Diagnostic tests, particularly brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis, played crucial roles in the evaluation. The MRI revealed characteristic cortical ribboning patterns. CSF analysis initially suggested Alzheimer’s disease pathology continuum. Repeated Real-time-quaking-induced assay testing (RT-QuIC) confirmed the diagnosis despite an …initial negative result. This case underscores the significance of contemplating CJD in individuals exhibiting rapidly progressive dementia, even in the presence of atypical clinical features. Furthermore, it emphasizes the importance of recognizing that an initial negative result from the RT-QuIC test should not preclude consideration of CJD, particularly when characteristic MRI findings are present. Show more

Keywords: Alzheimer’s disease, amyloid pathology, cacosmia, Creutzfeldt-Jacob Disease, prion disease, RT-QuIC Test

DOI: 10.3233/ADR-230173

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1105-1110, 2024

Authors: Gordon, Marc L. | Christen, Erica | Keehlisen, Lynda | Gong, Michelle | Lam, Fung | Giliberto, Luca | Gomar, Jesus J. | Koppel, Jeremy

Article Type: Short Communication

Abstract: We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer’s disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures.

Keywords: Alzheimer’s disease, CD38, daratumumab, energy metabolism, NAD, neuroinflammation

DOI: 10.3233/ADR-240089

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1111-1114, 2024

Authors: Kaltsa, Maria | Tsolaki, Anthoula | Lazarou, Ioulietta | Mittas, Ilias | Papageorgiou, Mairi | Papadopoulou, Despina | Tsimpli, Ianthi Maria | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Earlier research focuses primarily on the cognitive changes due to Alzheimer’s disease (AD); however, little is known with regard to changes in language competence across the lifespan. Objective: The present study aims to investigate the decline of language skills at the grammatical and syntactic levels due to changes in cognitive function. Methods: We administered the Litmus Sentence Repetition Task (SRT) to 150 native speakers of Greek who fall into five groups: 1) young healthy speakers, 2) cognitively intact elder healthy speakers, 3) speakers with subjective cognitive impairment (SCI), 4) speakers with mild cognitive impairment (MCI); …and 5) speakers with AD dementia at the mild/moderate stages. All participants underwent a physical and neurological examination and cognitive screening with a standardized neuropsychological battery to assess cognitive status comprehensively and evaluate aspects like working memory, executive function, attention and memory to appropriately classify them. Results: The data analysis revealed that the SRT had high discriminatory value in the development of AD; specifically, both accuracy and grammaticality indices were related to cognitive decline. Additionally, syntax significantly affected the performance of speakers with structures such as clitics being particularly challenging and in most structures the performance of speakers with MCI drops significantly compared to speakers with SCI. Conclusions: Linguistic indices revealed subtle early signs of cognitive decline that can be helpful in the early detection of AD, thus facilitating the clinical process offering support to language-based assessment tools such as sentence repetition, a non-invasive type of assessment to evaluate symptoms of AD. Show more

Keywords: Alzheimer’s disease, grammar, healthy aging, language competence, mild cognitive impairment, sentence repetition, subjective cognitive impairment, syntax

DOI: 10.3233/ADR-230204

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1115-1132, 2024

Authors: Khan, Hafiz | Farhana, Fardous | Mostafa, Fahad | Rafiq, Aamrin | Nizia, Effat Walia | Razzaq, Refaya | Atique, Rumana | Dauenhauer, Megan | Zabin, Zawah | Palle, Komaraiah | Reddy, P. Hemachandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is related to one or more chronic illnesses, which may develop cognitive decline and dementia. Cognitive impairment is increasing, and public health officials must address risk factors for AD to improve the health of rural West Texas communities. Objective: The purpose of this study was to explore the sociodemographic and chronic disease risk factors related to cognitive impairment among elderly adults living in Cochran, Parmer, and Bailey counties in rural West Texas. Methods: Statistical methods such as Pearson’s chi-squared, proportion tests, univariate binary logistic regression, and a multivariable logistic regression were utilized …to analyze data. SPSS software was used to detect the significant relationship between cognitive impairment and risk factors. Results: Summary statistics were obtained for sociodemographic and chronic diseases by using cross-tabulation analysis and comparing the county respondents with proportion tests. A univariate binary logistic regression method was utilized and found that age group 60–69, anxiety, depression, diabetes, hypertension, and cardiovascular disease were significantly associated with cognitive impairment. Using a multivariable logistic regression approach, it was found that Bailey County (age group 60–69) had a higher likelihood (p  = 0.002) of cognitive impairment than Parmer (p  = 0.067) and Cochran counties (p  = 0.064). The risk of females (p  = 0.033) in Parmer County was 78.3% lower compared to males in developing AD. Conclusions: Identifying significant risk factors for cognitive impairment are important in addressing issues of geographic variations and integrating such factors may guide relevant policy interventions to reduce cognitive impairment incidence in rural communities within West Texas. Show more

Keywords: Alzheimer’s disease, chronic diseases, cognitive impairment, FRONTIER database, risk factors, rural West Texas, sociodemographic variables

DOI: 10.3233/ADR-240092

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1133-1151, 2024

Authors: Ehteshamzad, Sharareh

Article Type: Systematic Review

Abstract: Background: As the prevalence of Alzheimer’s disease (AD) grows with an aging population, the need for early diagnosis has led to increased focus on electroencephalography (EEG) as a non-invasive diagnostic tool. Objective: This review assesses advancements in EEG analysis, including the application of machine learning, for detecting AD from 2000 to 2023. Methods: Following PRISMA guidelines, a search across major databases resulted in 25 studies that met the inclusion criteria, focusing on EEG’s application in AD diagnosis and the use of novel signal processing and machine learning techniques. Results: Progress in EEG analysis has …shown promise for early AD identification, with techniques like Hjorth parameters and signal compressibility enhancing detection capabilities. Machine learning has improved the precision of differential diagnosis between AD and mild cognitive impairment. However, challenges in standardizing EEG methodologies and data privacy remain. Conclusions: EEG stands out as a valuable tool for early AD detection, with the potential to integrate into multimodal diagnostic approaches. Future research should aim to standardize EEG procedures and explore collaborative, privacy-preserving research methods. Show more

Keywords: Alzheimer’s disease, cognitive decline, diagnostic advancements, electroencephalography, machine learning, mild cognitive impairment, neurodiagnostic, neurophysiological biomarkers

DOI: 10.3233/ADR-230159

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1153-1169, 2024

Authors: Islam, Md Ariful | Kshirsagar, Sudhir | Reddy, Arubala P. | Sehar, Ujala | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Several decades of research on cell and animal models contributed tremendously to understanding human diseases. Particularly, research on rodents and non-human primates revealed that animal research is a major and important component in biomedical research in learning complex pathophysiological processes. Further, animal research helped us to understand human diseases, such as Alzheimer’s disease. In addition, animal research has also helped us to test hundreds of drugs and develop treatments for human use. Researchers can gain a better understanding of key biological and physiological processes in humans by comparing them to laboratory animals. Based on their relevance and resemblance to people, …or even usual living conditions, scientists rationalize the use of particular animal models in their studies. It is suggested that in the National Institutes of Health and other agencies-funded research, animal models should be carefully selected to study the biology and pathophysiology of human health and diseases such as Alzheimer’s disease and other dementias. However, it is critical to use a minimum number of animals for human research. Further, it is also noted that the use and reuse of behavioral,  molecular, and biochemical data from wild-type (WT) control mice with mutant lines of disease models, as long as the genetic background is the same in both WT and disease mice. On the other hand, anonymous readers have challenged the use and reuse of WT mice data for comparison. In the current article, we discuss the minimum utility of animals, covering the 3Rs, Replacement, Reduction, and Refinement, and also discuss the use and reuse of behavioral, molecular, and biochemical data. Show more

Keywords: Alzheimer’s disease, animal research, replacement, reduction and refinement, wild-type mice

DOI: 10.3233/ADR-240126

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1171-1184, 2024

Authors: Wang, Ying | Song, Xinhua | Wang, Rui | Xu, Xinzi | Du, Yaming | Chen, Guohua | Mei, Junhua

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) currently lacks effective disease-modifying treatments. Recent research suggests that ferroptosis could be a potential therapeutic target. Mendelian randomization (MR) is a widely used method for identifying novel therapeutic targets. Objective: Employ genetic information to evaluate the causal impact of ferroptosis-related genes on the risk of AD. Methods: 564 ferroptosis-related genes were obtained from FerrDb. We derived genetic instrumental variables for these genes using four brain quantitative trait loci (QTL) and two blood QTL datasets. Summary-data-based Mendelian randomization (SMR) and two-sample MR methods were applied to estimate the causal effects of ferroptosis-related genes …on AD. Using extern transcriptomic datasets and triple-transgenic mouse model of AD (3xTg-AD) to further validate the gene targets identified by the MR analysis. Results: We identified 17 potential AD risk gene targets from GTEx, 13 from PsychENCODE, and 22 from BrainMeta (SMR p  < 0.05 and HEIDI test p  > 0.05). Six overlapping ferroptosis-related genes associated with AD were identified, which could serve as potential therapeutic targets (PEX10, CDC25A, EGFR, DLD, LIG3, and TRIB3 ). Additionally, we further pinpointed risk genes or proteins at the blood tissue and pQTL levels. Notably, EGFR demonstrated significant dysregulation in the extern transcriptomic datasets and 3xTg-AD models. Conclusions: This study provides genetic evidence supporting the potential therapeutic benefits of targeting the six druggable genes for AD treatment, especially for EGFR (validated by transcriptome and 3xTg-AD), which could be useful for prioritizing AD drug development in the field of ferroptosis. Show more

Keywords: Alzheimer’s disease, ferroptosis, Mendelian randomization, 3xTg-AD

DOI: 10.3233/ADR-240062

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1185-1197, 2024

Authors: Low, Serena | Moh, Angela | Goh, Kiat Sern | Khoo, Jonathon | Ang, Keven | Liu, Allen Yan Lun | Tang, Wern Ee | Lim, Ziliang | Subramaniam, Tavintharan | Sum, Chee Fang | Lim, Su Chi

Article Type: Research Article

Abstract: Background: Decline in renal function impairs systemic clearance of amyloid-β which characterizes Alzheimer’s disease while albuminuria is associated with blood-brain barrier disruption due to endothelial damage. Arterial stiffness adversely affects the brain with high pulsatile flow damaging cerebral micro-vessels. Objective: To examine association between a novel kidney disease index (KDI), which is a composite index of estimated glomerular filtration (eGFR) and urinary albumin-to-creatinine ratio (uACR), and cognitive function with potential mediation by arterial stiffness. Methods: This was a longitudinal multi-center study of participants with type 2 diabetes (T2D) aged 45 years and above. We assessed cognitive …function with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pulse wave velocity (PWV), an index of arterial stiffness, was measured using applanation tonometry method. KDI was calculated as geometric mean of 1/eGFR and natural logarithmically-transformed (ln)(ACR*100). Results: There were 1,303 participants with mean age 61.3±8.0 years. LnKDI was associated with lower baseline RBANS total score with adjusted coefficient –2.83 (95% CI –4.30 to –1.35; p  < 0.001). 590 participants were followed over up to 8.6 years. LnKDI was associated with lower follow-up RBANS score in total, immediate memory, visuo-spatial/construction and attention domains with corresponding adjusted coefficients –2.35 (95% CI –4.50 to –0.20; p  = 0.032), –2.93 (95% CI –5.84 to –0.02; p  = 0.049), –3.26 (95% CI –6.25 to –0.27; p  = 0.033) and –4.88 (95% CI –7.95 to –1.82; p  = 0.002). PWV accounted for 19.5% of association between and follow-up RBANS total score. Conclusions: KDI was associated with lower cognitive function globally, and in immediate memory, visuo-spatial/construction and attention domains. Arterial stiffness mediated the association between KDI and cognitive decline in patients with T2D. Show more

Keywords: Alzheimer’s disease, cognitive function, kidney disease index, type 2 diabetes

DOI: 10.3233/ADR-240067

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1199-1210, 2024

Authors: Yang, Yiwen | Tong, Ming | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), one of the most prevalent causes of dementia, is mainly sporadic in occurrence but driven by aging and other cofactors. Studies suggest that excessive alcohol consumption may increase AD risk. Objective: Our study examined the degree to which short-term moderate ethanol exposure leads to molecular pathological changes of AD-type neurodegeneration. Methods: Long Evans male and female rats were fed for 2 weeks with isocaloric liquid diets containing 24% or 0% caloric ethanol (n  = 8/group). The frontal lobes were used to measure immunoreactivity to AD biomarkers, insulin-related endocrine metabolic molecules, and proinflammatory cytokines/chemokines …by duplex or multiplex enzyme-linked immunosorbent assays (ELISAs). Results: Ethanol significantly increased frontal lobe levels of phospho-tau, but reduced Aβ, ghrelin, glucagon, leptin, PAI, IL-2, and IFN-γ . Conclusions: Short-term effects of chronic ethanol feeding produced neuroendocrine molecular pathologic changes reflective of metabolic dysregulation, together with abnormalities that likely contribute to impairments in neuroplasticity. The findings suggest that chronic alcohol consumption rapidly establishes a platform for impairments in energy metabolism that occur in both the early stages of AD and alcohol-related brain degeneration. Show more

Keywords: Alzheimer’s disease, alcohol, amyloid, cytokines, metabolism, neurodegeneration, neuroendocrine, rat model, tau

DOI: 10.3233/ADR-240026

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1211-1228, 2024

Authors: Xiong, Min | You, Hongji | Liao, Wang | Mai, Yingren | Luo, Xiaoming | Liu, Yipei | Jiang, Sheng-nan

Article Type: Research Article

Abstract: Background: 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET) is valuable in Alzheimer’s disease (AD) workup. Objective: To explore the effectiveness of 18 F-FDG PET in differentiating and staging AD and associations between brain glucose metabolism and cognitive functions and vascular risk factors. Methods: 107 participates including 19 mild cognitive impairment (MCI), 38 mild AD, 24 moderate AD, 15 moderate-severe AD, and 11 frontotemporal dementia (FTD) were enrolled. Visual and voxel-based analysis procedures were utilized. Cognitive conditions, including 6 cognitive function scores and 7 single-domain cognitive performances, and vascular risk factors linked to hypertension, hyperlipidemia, diabetes, …and obesity were correlated with glucose metabolism in AD dementia using age as a covariate. Results: 18 F-FDG PET effectively differentiated AD from FTD and also differentiated MCI from AD subtypes with significantly different hypometabolism (except for mild AD) (height threshold p  < 0.001, all puncorr  < 0.05, the same below). The cognitive function scores, notably Mini-Mental State Examination and Montreal Cognitive Assessment, correlated significantly with regional glucose metabolism in AD participants (all p  < 0.05), whereas the single-domain cognitive performance and vascular risk factors were significantly associated with regional glucose metabolism in MCI patients (all p  < 0.05). Conclusions: This study underlines the vital role of 18 F-FDG PET in identifying and staging AD. Brain glucose metabolism is associated with cognitive status in AD dementia and vascular risk factors in MCI, indicating that 18 F-FDG PET might be promising for predicting cognitive decline and serve as a visual framework for investigating underlying mechanism of vascular risk factors influencing the conversion from MCI to AD. Show more

Keywords: Alzheimer’s disease, cognitive function, 18Fluorodeoxyglucose, metabolism, mild cognitive impairment, positron emission tomography, risk factor

DOI: 10.3233/ADR-240104

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1229-1240, 2024

Authors: Gohil, Namra Vinay | Gandara, Fabio Fuentes | Gohil, Harshal | Gurajala, Swathi | Innocent, David Chinaecherem | Tesfaye, Tadele | Praticò, Domenico

Article Type: Systematic Review

Abstract: Background: Antibiotic resistance is a global health concern, and its prevalence among older adults and Alzheimer’s disease (AD) patients is gaining attention. Understanding the extent of antibiotic resistance in these populations is critical for designing targeted interventions. Objective: The objective of this systematic review and meta-analysis was to determine the prevalence of antibiotic resistance in older adults and AD patients with a focus on quantitative studies in order to provide comprehensive insights into the current landscape. Methods: To identify relevant studies, we conducted a thorough search of the PubMed, Scopus, CINAHL, and Web of Science databases. …Only studies involving adults and AD patients, published in English, and reporting quantitative data on antibiotic resistance prevalence were considered. The Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool was used to assess quality. The data was summarized by using Revman 5.4.1. Results: A total of six studies met the final criteria for selection and results from the meta-analysis found a pooled prevalence odds ratio of OR = 1.27 (95% CI: [0.99, 1.63], Z  = 1.87, p  = 0.06). The studies showed significant heterogeneity (I2 = 100%, p  < 0.00001), emphasizing the need for cautious interpretation. Conclusions: The findings indicate a potential trend of increased antibiotic resistance in older adults and AD patients, though statistical significance was not achieved for both. The significant heterogeneity highlights the complexity of resistance patterns in these populations, necessitating additional research for tailored interventions. Show more

Keywords: Alzheimer’s disease, antibiotic resistance, meta-analysis, older adults, prevalence, systematic review

DOI: 10.3233/ADR-240057

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1241-1251, 2024

Authors: Coemans, Silke | De Aguiar, Vânia | Paquier, Philippe | Tsapkini, Kyrana | Engelborghs, Sebastiaan | Struys, Esli | Keulen, Stefanie

Article Type: Case Report

Abstract: Background: Primary progressive aphasia (PPA) is a language-based dementia, causing progressive decline of language functions. Transcranial direct current stimulation (tDCS) can augment effects of speech-and language therapy (SLT). However, this has not been investigated in bilingual patients with PPA. Objective: We evaluated the case of Mr. G., a French (native language, L1)/Dutch (second language, L2)-speaking 59-year-old male, with logopenic PPA, associated with Alzheimer’s disease pathology. We aimed to characterize his patterns of language decline and evaluate the effects of tDCS applied to the right posterolateral cerebellum on his language abilities and executive control circuits. Methods: In …a within-subject controlled design, Mr. G received 9 sessions of sham and anodal tDCS combined with semantic and phonological SLT in L2. Changes were evaluated with an oral naming task in L2, the Boston Naming Task and subtests of the Bilingual Aphasia Test in in L2 and L1, the Stroop Test and Attention Network Test, before and after each phase of stimulation (sham/tDCS) and at 2-month follow-up. Results: After anodal tDCS, but not after sham, results improved significantly on oral naming in L2, with generalization to untrained tasks and cross-language transfer (CLT) to L1: picture naming in both languages, syntactic comprehension and repetition in L2, and response times in the incongruent condition of the Attention Network Test, indicating increased inhibitory control. Conclusions: Our preliminary results are the first to indicate that tDCS applied to the cerebellum may be a valuable tool to enhance the effects of SLT in bilingual patients with logopenic PPA. Show more

Keywords: Alzheimer’s disease, bilingualism, cerebellum, executive functions, primary progressive aphasia, transcranial direct current stimulation

DOI: 10.3233/ADR-240034

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1253-1273, 2024

Authors: Fernandes, Mariana | Chiaravalloti, Agostino | Cassetta, Emanuele | Placidi, Fabio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Research Article

Abstract: Background: Although disturbed sleep is frequent in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease (AD), the association between sleep and tau pathology is unclear. Objective: This case series focused on measuring the sleep-wake rhythm over 7 days through actigraphy in patients diagnosed with MCI due to AD. Further, the association between sleep-wake cycle and tau deposition measured through positron emission tomography (PET) was explored. Methods: This case series included 6 MCI due to AD patients (2 women and 4 men, mean age 73.17±5.53 years), who completed neuropsychological testing, 7-day actigraphy, and …tau PET imaging with radiolabeled compounds aimed to estimate the density and distribution of aggregated tau neurofibrillary tangles in the brain. Results: The case series indicated that patients with MCI due to AD who exhibited greater tau deposition in the frontal, parietal, and limbic regions, as well as in the precuneus and olfactory regions, also showed increased sleep fragmentation, as measured through actigraphy. Conclusion: The findings from this case series suggest a potential link between tau deposition in key brain regions associated with AD and both sleep fragmentation and sleep-wake cycle dysregulation in a small sample of patients with MCI due to AD. These preliminary results warrant further investigation in larger, more comprehensive studies to confirm and expand upon these findings. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, positron emission tomography, sleep, sleep-wake cycle, tau

DOI: 10.3233/ADR-230187

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1275-1283, 2024

Authors: Bai, Dong | Fan, Junting | Li, Mengyue | Dong, Cuixia | Gao, Yiming | Fu, Min | Liu, Qianfeng | Liu, Huan

Article Type: Research Article

Abstract: Background: Our previously randomized controlled trial (RCT) showed daily oral folic acid (FA), docosahexaenoic acid (DHA) and their combined treatment for 6 months could significantly improve cognitive function in mild cognitive impairment (MCI) individuals. Objective: This study aimed to evaluate whether this benefit seen in the treatment group would sustain after stopping intervention when patients returned to a real-world. Methods: RCT (ChiCTR-IOR-16008351) was conducted in Tianjin, China. 160 MCI elders aged ≥60 years were randomly divided into four groups: FA + DHA, FA, DHA, and control. 138 MCI elders who completed the 6-month interventional trial underwent another 6-month …follow-up without receiving nutritional therapy. Cognitive performance was measured at 6 and 12 months. Blood amyloid-β peptide (Aβ) and homocysteine (Hcy) related biomarkers were measured at baseline and 6 months. Results: In comparison to the end of nutritional therapy, all intervention groups had considerably lower full-scale IQ, arithmetic, and image completion scores during the follow-up period, while the combined intervention and DHA groups had significantly lower picture arrangement scores. Furthermore, after 6-month treatment with FA and FA + DHA, plasma Aβ40 , Aβ42 , and Hcy levels were significantly decreased. However, these biomarker levels at the start of follow-up were positively correlated with the degree of cognitive function change during follow-up period. Conclusions: FA and DHA supplementation enhance cognitive performance in MCI elderly following a six-month intervention by reducing Hcy or Aβ levels. However, their effects on improving cognitive decline are likely to diminish when the intervention is discontinued. Show more

Keywords: Alzheimer’s disease, amyloid-β-related biomarkers, docosahexaenoic acid, folic acid, mild cognitive impairment, one carbon metabolism, real world study

DOI: 10.3233/ADR-240033

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1285-1295, 2024

Authors: Lesage, Myriam | Cinalioglu, Karin | Chan, Sabrina | Kumar, Sanjeev | Rajji, Tarek | Melichercik, Ashley | Desjardins, Carmen | Friedland, Jess | Burhan, Amer | Colman, Sarah | Chu, Li | Davies, Simon | Derkach, Peter | Elmi, Sarah | Gerretsen, Philip | Graff-Guerrero, Ariel | Hussain, Maria | Ismail, Zahinoor | Kim, Donna | Krisman, Linda | Moghabghab, Rola | Mulsant, Benoit H. | Pollock, Bruce G. | Rostas, Aviva | Van Bussel, Lisa | Rej, Soham

Article Type: Short Communication

Abstract:  Agitation, a common dementia symptom often arising from untreated pain, lacks comprehensive research on its connection with opioids prescribed for long-term pain. This study investigated the relationship between opioid use and agitation in dementia patients. Participants (n  = 188) were categorized into opioid, acetaminophen PRN, or no-pain medication groups. Despite higher reported pain levels in the opioid group, no significant differences in agitation were observed among the groups. In conclusion, opioid use for pain management in older adults with dementia did not significantly impact agitation, emphasizing the ongoing importance of proper pain management in improving dementia care and addressing agitation in …this population. Show more

Keywords: Agitation, Alzheimer’s disease, dementia, opioid, pain management

DOI: 10.3233/ADR-240025

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1297-1300, 2024

Authors: Wang, Xiwu | Ye, Teng | Huang, Ziye | Zhou, Wenjun | Zhang, Jie

Article Type: Research Article

Abstract: Background: Although individualized models using demographic, MRI, and biological markers have recently been applied in mild cognitive impairment (MCI), a similar study is lacking for patients with early Alzheimer’s disease (AD) with biomarker evidence of abnormal amyloid in the brain. Objective: We aimed to develop prognostic models for individualized prediction of cognitive change in early AD. Methods: A total of 421 individuals with early AD (MCI or mild dementia due to AD) having biomarker evidence of abnormal amyloid in the brain were included in the current study. The primary cognitive outcome was the slope of change …in Alzheimer’s Disease Assessment Scale-cognitive subscale-13 (ADAS-Cog-13) over a period of up to 5 years. Results: A model combining demographics, baseline cognition, neurodegenerative markers, and CSF AD biomarkers provided the best predictive performance, achieving an overfitting-corrected R2 of 0.59 (bootstrapping validation). A nomogram was created to enable clinicians or trialists to easily and visually estimate the individualized magnitude of cognitive change in the context of patient characteristics. Simulated clinical trials suggested that the inclusion of our nomogram into the enrichment strategy would lead to a substantial reduction of sample size in a trial of early AD. Conclusions: Our findings may be of great clinical relevance to identify individuals with early AD who are likely to experience fast cognitive deterioration in clinical practice and in clinical trials. Show more

Keywords: Alzheimer’s disease, cognitive decline, individualized prediction, mild cognitive impairment, nomogram

DOI: 10.3233/ADR-240049

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1301-1315, 2024

Authors: Luo, Qian | Crivelli, Simone M. | Zong, Shenghua | Giovagnoni, Caterina | van Kruining, Daan | Mané-Damas, Marina | den Hoedt, Sandra | Berkes, Dusan | De Vries, Helga E. | Mulder, Monique T. | Walter, Jochen | Waelkens, Etienne | Derua, Rita | Swinnen, Johannes V. | Dehairs, Jonas | Losen, Mario | Martinez-Martinez, Pilar

Article Type: Research Article

Abstract: Background: During Alzheimer’s disease (AD) progression, there is a decline in the bioactive sphingolipid sphingosine-1-phosphate (S1P). Previous research showed that FTY720, an S1P mimetic, prevented cognitive decline and reduced ceramide levels in transgenic mice with familial AD carrying the human APOE4 gene (E4FAD) at 6–7 months of age. Objective: The objective of this study is to explore the protective effects of FTY720 at late-stage AD. Methods: Male mice aged 9.5 to 10.5 months were orally administered FTY720 (0.1 mg/kg) via oral gavage for 6 weeks. A pre-test of water maze was used for evaluating the pathological status. …After 4 weeks of administration, memory, locomotion, and anxiety were assessed. Cortex samples were analyzed for amyloid-β (Aβ) and sphingolipid levels. Results: Compared with APOE3 mice, APOE4, E3FAD and E4FAD mice exhibited significant memory deficits. After 6 weeks administration, FTY720 did not alleviate memory deficits in EFAD mice. Lipid analysis revealed that S1P was significantly reduced in EFAD mice (E3FAD or E4FAD) compared to controls (APOE3 and APOE4). Ceramide level alterations were predominantly dependent on APOE isoforms rather than AD transgenes. Interestingly, Cer (d18 : 1/22 : 1) was elevated in APOE4 mice compared to APOE3, and FTY720 reduced it. Conclusions: E4FAD and APOE4 mice exhibited significant spatial memory deficits and higher ceramide concentrations compared to APOE3 mice. FTY720 did not reverse memory deficits in E4FAD and APOE4 mice but reduced specific ceramide species. This study provides insights into the association between sphingolipids and APOE4 in advanced AD stages, exploring potential therapeutic targeting of sphingolipid metabolism. Show more

Keywords: Alzheimer’s disease, APOE4, ceramide, FTY720, sphingolipid

DOI: 10.3233/ADR-230053

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1317-1327, 2024

Authors: Dong, Qiwei | Li, Yuanjing | Song, Yiming | Zhang, Yu | Han, Xiaodong | Ren, Yifei | Wang, Jiafeng | Han, Xiaojuan | Du, Yifeng

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) may be beneficial to the physical function of the elderly. Objective: We aimed to examine the association of CR proxies and composite CR capacity with physical function in older adults while considering age and sex. Methods: This population-based cross-sectional study included 4,714 participants living in rural China (age≥60 years) who were dementia-free. Structural equation modeling was used to generate a composite CR score by integrating early-life education, midlife occupational complexity, and late-life mental activity and social support. The Short Physical Performance Battery (SPPB) measured physical function. Data were analyzed using linear regression …models. Results: Greater educational attainment and mental activity were associated with higher composite SPPB scores and those of its three subtests (p  < 0.05). Skilled occupations were associated with higher SPPB, chair stand, and walking speed scores, while greater social support was associated with higher scores for SPPB and chair stand (p  < 0.05). Each 1-point increase in composite CR score (range: –0.77 to 1.03) was linearly associated with a multivariable-adjusted β-coefficient of 0.74 (95% confidence interval (CI): 0.58–0.89) for total SPPB score, 0.16 (0.10–0.22) for balance test, 0.40 (0.32–0.48) for chair stand, and 0.17 (0.12–0.23) for walking speed. The association between higher composite CR and total SPPB scores was more prominent in those≥75 years than those aged 60–74 years (p  < 0.01). There was no statistical interaction of composite CR score and sex in physical function. Conclusions: High CR is associated with better physical function, especially among older adults (≥75 years). Show more

Keywords: Alzheimer’s disease, cognitive reserve, physical fitness, population-based study

DOI: 10.3233/ADR-240064

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1329-1338, 2024

Authors: Malaty, Giovanni R. | Decourt, Boris | Shill, Holly A. | Sabbagh, Marwan N.

Article Type: Research Article

Abstract: Background: Plasma biomarker assays provide an opportunity to reassess whether Alzheimer’s disease, Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB) plasma biomarkers are diagnostically useful. Objective: We hypothesized that immunomagnetic reduction (IMR) of plasma biomarkers could differentiate between patients with PDD and DLB and healthy patients when combined with established clinical testing measures. Methods: Plasma samples from 61 participants (12 PDD, 12 DLB, 37 controls) were analyzed using IMR to quantify amyloid-β 42 (Aβ42 ), total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and α-synuclein (α-syn). Receiver operating characteristic curve (ROC) analysis was …used to obtain sensitivity, specificity, and area under the ROC curve. Biomarker results were combined with clinical measures from the Unified Parkinson’s Disease Rating Scale (UPDRS), Montreal Cognitive Assessment, and Hoehn-Yahr stage to optimize diagnostic test performance. Results: Participants with PDD had higher α-syn than those with DLB and healthy participants and were distinguishable by their biomarker products Aβ42 ×p-tau181 and Aβ42 ×α-syn. Patients with DLB had higher p-tau181 than those with PDD and healthy participants and were distinguishable by their concentrations of α-syn×p-tau181. Plasma α-syn plus UPDRS versus either test alone increased sensitivity, specificity, and AUC when healthy patients were compared with those with PDD and DLB. Combined clinical examination scores and plasma biomarker products demonstrated utility in differentiating PDD from DLB when p-tau181 was combined with UPDRS, α-syn was combined with UPDRS, and α-syn×p-tau181 was combined with UPDRS. Conclusions: In this pilot study, IMR plasma p-tau181 and α-syn may discriminate between PDD and DLB when used in conjunction with clinical testing. Show more

Keywords: Alzheimer’s disease, α-synuclein, dementia with Lewy bodies, immunomagnetic reduction assay, Parkinson’s disease dementia, p-tau181, Unified Parkinson’s Disease Rating Scale

DOI: 10.3233/ADR-240110

Citation: Journal of Alzheimer's Disease Reports, vol. 8, no. 1, pp. 1361-1371, 2024