Journal of Alzheimer's Disease Reports - Volume 7, issue 1

Authors: Ash, Sharon | Nevler, Naomi | Irwin, David J. | Shellikeri, Sanjana | Rascovsky, Katya | Shaw, Leslie | Lee, Edward B. | Trojanowski, John Q. | Grossman, Murray

Article Type: Research Article

Abstract: Background: Apraxia of speech (AOS) is a core feature of nonfluent/agrammatic primary progressive aphasia (naPPA), but its precise characteristics and the prevalence of AOS features in spontaneous speech are debated. Objective: To assess the frequency of features of AOS in the spontaneous, connected speech of individuals with naPPA and to evaluate whether these features are associated with an underlying motor disorder such as corticobasal syndrome or progressive supranuclear palsy. Methods: We examined features of AOS in 30 patients with naPPA using a picture description task. We compared these patients to 22 individuals with behavioral variant frontotemporal …dementia and 30 healthy controls. Each speech sample was evaluated perceptually for lengthened speech segments and quantitatively for speech sound distortions, pauses between and within words, and articulatory groping. We compared subgroups of naPPA with and without at least two features of AOS to assess the possible contribution of a motor impairment to speech production deficits. Results: naPPA patients produced both speech sound distortions and other speech sound errors. Speech segmentation was found in 27/30 (90%) of individuals. Distortions were identified in 8/30 (27%) of individuals, and other speech sound errors occurred in 18/30 (60%) of individuals. Frequent articulatory groping was observed in 6/30 (20%) of individuals. Lengthened segments were observed rarely. There were no differences in the frequencies of AOS features among naPPA subgroups as a function of extrapyramidal disease. Conclusion: Features of AOS occur with varying frequency in the spontaneous speech of individuals with naPPA, independently of an underlying motor disorder. Show more

Keywords: Language, phonetics, primary progressive nonfluent aphasia, speech, verbal apraxia

DOI: 10.3233/ADR-220089

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 589-604, 2023

Authors: Bussè, Cinzia | Zorzi, Giovanni | Pettenuzzo, Ilaria | Mozzetta, Stefano | Cagnin, Annachiara

Article Type: Short Communication

Abstract: Behavioral frontotemporal dementia (bvFTD) may present with episodic memory deficits. In 38 patients with bvFTD and 61 with Alzheimer’s disease (AD) specific measures of verbal memory (learning curves and serial position effects) were studied through the Rey Auditory Verbal Learning test. Forty-two percent of bvFTD showed deficits of delayed recall memory similar to that found in AD including the serial position effects. Amnestic bvFTD had more severe atrophy in the left mesial temporal lobe than non-amnestic bvFTD. AD-like memory deficits are not infrequent in bvFTD and may be in part related to mesial temporal lobe atrophy.

Keywords: Alzheimer’s disease, dementia, frontotemporal dementia, learning, memory

DOI: 10.3233/ADR-230015

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 605-612, 2023

Authors: Ratis, Renan C. | Dacoregio, Maria I. | Simão-Silva, Daiane P. | Mateus, Rogério P. | Machado, Luciana P.B. | Bonini, Juliana S. | Silva, Weber Claudio Francisco Nunes da

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) has several risk factors. APOE4 is the main one, and it has been suggested that there may be a synergy between it and BCHE-K as a risk factor. Objective: To investigate the association between APOE4 and BCHE-K as a risk factor for AD. Methods: We searched PubMed, Web of Science, Embase, and Scopus on August 8, 2021 for studies that analyzed the association of APOE4 and BCHE-K with AD. The random effect model was performed in meta-analysis according to age group. A chi-square was performed with …the meta-analysis data to verify if the effect found is not associated only with the E4 allele. Results: Twenty-one studies with 6,853 subjects (3,528 AD and 3,325 Controls) were included in the meta-analysis. The quality of the evidence is moderate. There is a positive E4-K association for subjects with AD as shown by the odds ratio of 3.43. The chi-square meta test, which measures the probability that the E4-K association is due to chance, has an odds ratio of 6.155, indicating that the E4-K association is not a random event. The odds ratio of an E4-K association in subjects with AD increases to OR 4.46 for the 65- to 75-year-old group and OR 4.15 for subjects older than 75 years. The probability that the E4-K association is due to chance is ruled out by chi-square meta test values of OR 8.638 and OR 9.558. Conclusion: The synergy between APOE4 and BCHE-K is a risk factor for late-onset AD. Show more

Keywords: Alzheimer’s disease, APOE, BaβAC, cholinesterase, dementia, genetics, odds ratio

DOI: 10.3233/ADR-220084

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 613-625, 2023

Authors: Oh, Jean | Crockett, Rachel A. | Hsu, Chun-Liang | Dao, Elizabeth | Tam, Roger | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: As the aging population grows, there is an increasing need to develop accessible interventions against risk factors for cognitive impairment and dementia, such as cerebral small vessel disease (CSVD). The progression of white matter hyperintensities (WMHs), a key hallmark of CSVD, can be slowed by resistance training (RT). We hypothesize RT preserves white matter integrity and that this preservation is associated with improved cognitive and physical function. Objective: To determine if RT preserves regional white matter integrity and if any changes are associated with cognitive and physical outcomes. Methods: Using magnetic resonance imaging data from …a 12-month randomized controlled trial, we compared the effects of a twice-weekly 60-minute RT intervention versus active control on T1-weighted over T2-weighted ratio (T1w/T2w; a non-invasive proxy measure of white matter integrity) in a subset of study participants (N = 21 females, mean age = 69.7 years). We also examined the association between changes in T1w/T2w with two key outcomes of the parent study: (1) selective attention and conflict resolution, and (2) peak muscle power. Results: Compared with an active control group, RT increased T1w/T2w in the external capsule (p  = 0.024) and posterior thalamic radiations (p  = 0.013) to a greater degree. Increased T1w/T2w in the external capsule was associated with an increase in peak muscle power (p  = 0.043) in the RT group. Conclusion: By maintaining white matter integrity, RT may be a promising intervention to counteract the pathological changes that accompany CSVD, while improving functional outcomes such as muscle power. Show more

Keywords: Aged, Alzheimer’s disease, cerebral small vessel diseases, dementia, magnetic resonance imaging, randomized controlled trial, resistance training, white matter

DOI: 10.3233/ADR-220113

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 627-639, 2023

Authors: Cahan, Joshua G. | Vassar, Robert | Bonakdarpour, Borna

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of amyloid-β42 (Aβ42 ) and phosphorylated-tau help clinicians accurately diagnose Alzheimer’s disease (AD). Whether biomarkers help prognosticate behavioral and psychological symptoms of dementia (BPSD) is unclear. Objective: Determine whether CSF biomarker levels aid prognostication of BPSD in AD. Methods: This retrospective cohort study included patients over 65 with a diagnosis of AD based on CSF biomarkers. We measured time from CSF testing to the first antipsychotic use in the following months. We then analyzed time to antipsychotic (AP) use with respect to Aβ42 , total tau, phosphorylated tau, and amyloid-to-tau …index using a survival analysis approach. Results: Of 86 AD patients (average 72±5 years, 46.5% male), 11 patients (12.7%) received APs following CSF testing. Patients with Aβ42 below the median had sooner time-to-AP use. This was significant on a log-rank test (p  = 0.04). There was no difference in time-to-AP use if the group was stratified by levels of total tau, phosphorylated tau, or amyloid-to-tau index. Conclusion: These results suggest a relationship between lower CSF Aβ42 levels and sooner AP use. This supports prior reports suggesting a correlation between BPSD and Aβ deposition on PET. These results highlight the need for further prospective studies on Aβ levels and BPSD. Show more

Keywords: Alzheimer’s disease, antipsychotic agents, behavioral and psychological symptoms of dementia, biomarkers, dementia, neurodegenerative disease

DOI: 10.3233/ADR-220064

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 641-647, 2023

Authors: Saiyed, Nazia | Yilmaz, Ali | Vishweswariah, Sangeetha | Maiti, Amit K. | Ustun, Ilyas | Bartolone, Sarah | Brown-Hughes, Travonia | Thorpe Jr , Roland J. | Osentoski, Tammy | Ruff, Stacey | Pai, Amita | Maddens, Michael | Imam, Khaled | Graham, Stewart F.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia, accounting for 80% of all cases. Mild cognitive impairment (MCI) is a transitional state between normal aging and AD. Early detection is crucial, as irreversible brain damage occurs before symptoms manifest. Objective: This study aimed to identify potential biomarkers for early detection of AD by analyzing urinary cytokine concentrations. We investigated 37 cytokines in AD, MCI, and cognitively normal individuals (NC), assessing their associations with AD development. Methods: Urinary cytokine concentrations were measured in AD (n  = 25), MCI (n  = 25), and NC (n  = 26) patients. …IL6ST and MMP-2 levels were compared between AD and NC, while TNFRSF8, IL6ST, and IL-19 were assessed in AD versus MCI. Diagnostic models distinguished AD from NC, and in-silico analysis explored molecular mechanisms related to AD. Results: Significant perturbations in IL6ST and MMP-2 concentrations were observed in AD urine compared to NC, suggesting their potential as biomarkers. TNFRSF8, IL6ST, and IL-19 differed significantly between AD and MCI, implicating them in disease progression. Diagnostic models exhibited promising performance (AUC: 0.59–0.79, sensitivity: 0.72–0.80, specificity: 0.56–0.78) in distinguishing AD from NC. In-silico analysis revealed molecular insights, including relevant non-coding RNAs, microRNAs, and transcription factors. Conclusion: This study establishes significant associations between urinary cytokine concentrations and AD and MCI. IL6ST, MMP-2, TNFRSF8, IL6ST, and IL-19 emerge as potential biomarkers for early detection of AD. In-silico analysis enhances understanding of molecular mechanisms in AD. Further validation and exploration of these biomarkers in larger cohorts are warranted to assess their clinical utility. Show more

Keywords: Alzheimer’s disease, biomarkers, cytokines, inflammation, mild cognitive impairment, urine

DOI: 10.3233/ADR-220081

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 649-657, 2023

Authors: Roth, Sophie | Burnie, Nerida | Suridjan, Ivonne | Yan, Jessie T. | Carboni, Margherita

Article Type: Research Article

Abstract: Background: Diagnostic pathways for patients presenting with cognitive complaints may vary across geographies. Objective: To describe diagnostic pathways of patients presenting with cognitive complaints across 6 countries. Methods: This real-world, cross-sectional study analyzed chart-extracted data from healthcare providers (HCPs) for 6,744 patients across China, France, Germany, Spain, UK, and the US. Results: Most common symptoms at presentation were cognitive (memory/amnestic; 89.86%), followed by physical/behavioral (87.13%). Clinical/cognitive tests were used in > 95%, with Mini-Mental State Examination being the most common cognitive test (79.0%). Blood tests for APOE ɛ4/other mutations, or to rule out treatable causes, …were used in half of the patients. Clinical and cognitive tests were used at higher frequency at earlier visits, and amyloid PET/CSF biomarker testing at higher frequency at later visits. The latter were ordered at low rates even by specialists (across countries, 5.7% to 28.7% for amyloid PET and 5.0% to 27.3% for CSF testing). Approximately half the patients received a diagnosis (52.1% of which were Alzheimer’s disease [AD]). Factors that influenced risk of not receiving a diagnosis were HCP type (higher for primary care physicians versus specialists) and region (highest in China and Germany). Conclusion: These data highlight variability in AD diagnostic pathways across countries and provider types. About 45% of patients are referred/told to ‘watch and wait’. Improvements can be made in the use of amyloid PET and CSF testing. Efforts should focus on further defining biomarkers for those at risk for AD, and on dismantling barriers such low testing capacity and reimbursement challenges. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, diagnosis, neurology, neuropsychological tests, standard of care, surveys and questionnaires

DOI: 10.3233/ADR230007

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 659-674, 2023

Authors: Fotuhi, Majid | Khorrami, Noah D. | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Non-pharmacologic interventions can potentially improve cognitive function, sleep, and/or mood in patients with attention-deficit/hyperactive disorder (ADHD), post-concussion syndrome (PCS), or memory loss. Objective: We evaluated the benefits of a brain rehabilitation program in an outpatient neurology practice that consists of targeted cognitive training, lifestyle coaching, and electroencephalography (EEG)-based neurofeedback, twice weekly (90 minutes each), for 12 weeks. Methods: 223 child and adult patients were included: 71 patients with ADHD, 88 with PCS, and 64 with memory loss (mild cognitive impairment or subjective cognitive decline). Patients underwent a complete neurocognitive evaluation, including tests for Verbal Memory, …Complex Attention, Processing Speed, Executive Functioning, and Neurocognition Index. They completed questionnaires about sleep, mood, diet, exercise, anxiety levels, and depression—as well as underwent quantitative EEG—at the beginning and the end of the program. Results: Pre-post test score comparison demonstrated that all patient subgroups experienced statistically significant improvements on most measures, especially the PCS subgroup, which experienced significant score improvement on all measures tested (p ≤0.0011; d z ≥0.36). After completing the program, 60% to 90% of patients scored higher on cognitive tests and reported having fewer cognitive and emotional symptoms. The largest effect size for pre-post score change was improved executive functioning in all subgroups (ADHD d z = 0.86; PCS d z = 0.83; memory d z = 1.09). Conclusion: This study demonstrates that a multimodal brain rehabilitation program can have benefits for patients with ADHD, PCS, or memory loss and supports further clinical trials in this field. Show more

Keywords: Alzheimer’s disease, attention-deficit/hyperactivity disorder, electroencephalography, memory, neurofeedback, post-concussion syndrome, rehabilitation, subjective cognitive decline, subjective cognitive impairment, traumatic brain injury

DOI: 10.3233/ADR-220091

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 675-697, 2023

Authors: Guarnera, Jade | Yuen, Eva | Macpherson, Helen

Article Type: Review Article

Abstract: Social concepts such as loneliness and social isolation are fairly new factors that have been recently gaining attention as to their involvement in changes in cognitive function and association with dementia. The primary aim of this narrative review was to describe the current understanding of how loneliness and social isolation influence cognitive aging and how they are linked to dementia. Studies have shown that there is an association between loneliness, social isolation, and reduced cognitive function, in older adults, across multiple cognitive domains, as well as a heightened risk of dementia. Numerous changes to underlying neural biomechanisms including cortisol secretion …and brain volume alterations (e.g., white/grey matter, hippocampus) may contribute to these relationships. However, due to poor quality research, mixed and inconclusive findings, and issues accurately defining and measuring loneliness and social isolation, more consistent high-quality interventions are needed to determine whether studies addressing loneliness and social isolation can impact longer term risk of dementia. This is especially important given the long-term impact of the COVID-19 pandemic on social isolation in older people is yet to be fully understood. Show more

Keywords: Aging, alzheimer’s disease, cognition, dementia, loneliness, social isolation

DOI: 10.3233/ADR-230011

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 699-714, 2023

Authors: Michaelian, Johannes C. | McCade, Donna | Hoyos, Camilla M. | Brodaty, Henry | Harrison, Fleur | Henry, Julie D. | Guastella, Adam J. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Individuals living with Alzheimer’s disease (AD) demonstrate extensive deficits in social cognition. To date, no studies have investigated the feasibility of an intranasal oxytocin (INOT) treatment to improve social cognition in individuals living with AD. Objective: We conducted a pilot trial to determine recruitment feasibility, enrolment acceptability, and adherence to an INOT treatment to inform on the subsequent design of a future randomized controlled trial (RCT). We also estimated the effect sizes of potential social cognitive function outcome measures related to participants and their caregivers. Methods: Four individuals with AD were enrolled in a single-center, …randomized, double-blind, placebo-controlled crossover trial involving a one-week treatment period with both INOT (72 IU twice daily) and placebo. Results: All participants reported no treatment-causative or serious adverse events following repeated INOT administration. While enrolment acceptability (100%) and INOT adherence (placebo, 95%; INOT, 98%) were excellent, feasibility of recruitment was not acceptable (i.e., n  = 4/58 individuals screened met inclusion criteria). However, positive/large effects were associated with secondary outcomes of self-reported health and wellbeing, caregiver ‘burden’, intimacy and interpersonal-bonding, following repeated INOT administration. No positive effects were associated with participant outcomes of social cognition. Conclusion: This pilot RCT provides first evidence that INOT administration in individuals living with AD is safe and well-tolerated. Despite limitations in sample size, moderate-to-large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and ‘burden’ as reported by a caregiver. This suggests potential broad-ranging beneficial effects of INOT which should be assessed in future RCTs. Show more

Keywords: Alzheimer’s disease, dementia, intranasal oxytocin, oxytocin nasal spray, social cognition

DOI: 10.3233/ADR-230013

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 715-729, 2023

Authors: Takechi, Hajime | Yoshino, Hiroshi

Article Type: Research Article

Abstract: Background: As the number of patients with dementia increases, so do the social costs. In recent years, attempts have been made to reduce risk to be dementia and treat it from the early stages of the disease, making it important to estimate the costs of the early stages. Objective: To estimate the medical and social costs of the early stages of Alzheimer’s disease (AD), which include mild cognitive impairment (MCI) due to AD and mild AD. Methods: Questionnaires were used to obtain basic information (e.g., age, cognitive function) and medical costs, social care costs, family caregiver …medical costs, and family caregiver informal care costs from patients with MCI due to AD or mild AD who were attending a memory clinic. A comparison was then conducted between these two groups. Results: Patients with mild AD had higher total costs, patient medical costs, patient social care costs, and family caregiver informal care costs than did patients with MCI; however, only patient medical costs were significantly different (p  = 0.022). A detailed analysis of patient medical costs revealed that anti-dementia drug treatment costs were significantly higher in patients with mild AD (p  <  0.001). Conclusion: Compared with patients with mild AD, those with MCI may have lower patient and family caregiver costs. As it is important to reduce social costs through risk reduction and therapeutic interventions from the early stages of AD, the present findings could help estimate the social costs and verify the cost-effectiveness of early interventions for AD. Show more

Keywords: Alzheimer’s disease, caregiver, cost, dementia, mild cognitive impairment, resource use

DOI: 10.3233/ADR-230032

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 731-738, 2023

Authors: Keleman, Audrey A. | Nicosia, Jessica | Bollinger, Rebecca M. | Wisch, Julie K. | Hassenstab, Jason | Morris, John C. | Ances, Beau M. | Balota, David A. | Stark, Susan L.

Article Type: Research Article

Abstract: Background: Individuals with Alzheimer’s disease (AD) are more than twice as likely to incur a serious fall as the general population of older adults. Although AD is commonly associated with cognitive changes, impairments in other clinical measures such as strength or functional mobility (i.e., gait and balance) may precede symptomatic cognitive impairment in preclinical AD and lead to increased fall risk. Objective: To examine mechanisms (i.e., functional mobility, cognition, AD biomarkers) associated with increased falls in cognitively normal older adults. Methods: This 1-year study was part of an ongoing longitudinal cohort study. We examined the relationships …among falls, clinical measures of functional mobility and cognition, and neuroimaging AD biomarkers in cognitively normal older adults. We also investigated which domain(s) best predicted fall propensity and severity through multiple regression models. Results: A total of 182 older adults were included (mean age 75 years, 53% female). A total of 227 falls were reported over the year; falls per person ranged from 0–16 with a median of 1. Measures of functional mobility were the best predictors of fall propensity and severity. Cognition and AD biomarkers were associated with each other but not with the fall outcome measures. Conclusion: These results suggest that, although subtle changes in cognition may be more closely associated with AD neuropathology, functional mobility indicators better predict falls in cognitively normal older adults. This study adds to our understanding of the mechanisms underlying falls in older adults and could lead to the development of targeted fall prevention strategies. Show more

Keywords: Alzheimer’s disease, cognition, falls, functional mobility

DOI: 10.3233/ADR-230002

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 739-750, 2023

Authors: de la Monte, Suzanne M. | Goel, Anuva | Tong, Ming | Delikkaya, Busra

Article Type: Research Article

Abstract: Background: Agent Orange, an herbicide used during the Vietnam War, contains 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Agent Orange has teratogenic and carcinogenic effects, and population-based studies suggest Agent Orange exposures lead to higher rates of toxic and degenerative pathologies in the peripheral and central nervous system (CNS). Objective: This study examines the potential contribution of Agent Orange exposures to neurodegeneration. Methods: Human CNS-derived neuroepithelial cells (PNET2) treated with 2,4-D and 2,4,5-T were evaluated for viability, mitochondrial function, and Alzheimer’s disease (AD)-related proteins. Results: Treatment with 250μg/ml 2,4-D or 2,4,5-T significantly impaired mitochondrial …function, caused degenerative morphological changes, and reduced viability in PNET2 cells. Correspondingly, glyceraldehyde-3-phosphate dehydrogenase expression which is insulin-regulated and marks the integrity of carbohydrate metabolism, was significantly inhibited while 4-hydroxy-2-nonenal, a marker of lipid peroxidation, was increased. Tau neuronal cytoskeletal protein was significantly reduced by 2,4,5-T, and relative tau phosphorylation was progressively elevated by 2,4,5-T followed by 2,4-D treatment relative to control. Amyloid-β protein precursor (AβPP) was increased by 2,4,5-T and 2,4-D, and 2,4,5-T caused a statistical trend (0.05 < p<0.10) increase in Aβ. Finally, altered cholinergic function due to 2,4,5-T and 2,4-D exposures was marked by significantly increased choline acetyltransferase and decreased acetylcholinesterase expression, corresponding with responses in early-stage AD. Conclusion: Exposures to Agent Orange herbicidal chemicals rapidly damage CNS neurons, initiating a path toward AD-type neurodegeneration. Additional research is needed to understand the permanency of these neuropathologic processes and the added risks of developing AD in Agent Orange-exposed aging Vietnam Veterans. Show more

Keywords: Agent Orange, Alzheimer’s disease, herbicide, neurodegeneration, neurons, pesticide, Veterans, Vietnam, 2, 4-D, 2, 4, 5-T

DOI: 10.3233/ADR-230046

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 751-766, 2023

Authors: Morrow, Christopher B. | Leoutsakos, Jeannie | Yan, Haijuan | Onyike, Chiadi | Kamath, Vidyulata

Article Type: Short Communication

Abstract: Weight changes, neuropsychiatric symptoms (NPS), and cognitive decline often coincide in Alzheimer’s disease (AD) and frontotemporal dementia (FTD); however, the direction of their relationship remains unclear. This study aims to clarify the connection between weight changes, NPS, and cognition in AD and FTD. We found that cognitive decline was associated with decreased body mass index (BMI) in AD, while BMI gain was associated with increased conversion to FTD. Elevated NPS were associated with decreased BMI in AD and increased BMI in FTD. Identifying early changes in NPS and BMI may facilitate the detection of cognitive decline, providing an opportunity for …early intervention. Show more

Keywords: Alzheimer’s disease, body mass index, cognition, cognitive decline, frontotemporal dementia, neuropsychiatric symptoms, weight changes

DOI: 10.3233/ADR-230034

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 767-774, 2023

Authors: Tran, Todd | Finlayson, Marcia | Nalder, Emily | Trothen, Tracy | Donnelly, Catherine

Article Type: Research Article

Abstract: Background: Community-dwelling older adults with early cognitive deficits experience less efficiency in performing everyday life tasks, resulting in decreased satisfaction and other adverse psychological outcomes. Mindfulness training has been linked to cognitive and psychological improvements and, most recently, has been identified as a potential intervention supporting performance of everyday life activities. Objective: This study aimed to evaluate whether mindfulness practice can improve perceived performance and satisfaction with everyday life activity and secondary psychological outcomes. Methods: This study is a pilot randomized controlled trial (RCT) in an interprofessional primary care team practice in Toronto, Ontario, Canada. The …participants were 27 older adults aged 60 years of age or older living with early cognitive deficits. Participants were randomized into an 8-Week mindfulness training program (n  = 14) group or a Wait-List Control (WLC; n  = 13) group compared at baseline, post-intervention and 4-weeks follow-up. MANOVAs with post-hoc independent t-tests were used to compare between groups at different time points. Results: There was a significant improvement in anxiety for the intervention group compared to the WLC group at post-intervention; Time-2 (mean difference = 3.90; CI  = 0.04-7.75; p  = 0.04) with large effect size (d  = 0.80). Conclusion: Mindfulness training significantly improved anxiety scores for patients with early cognitive deficits post-intervention. Further work is required to test the sustainability of reduced anxiety over time, but this study demonstrated that MBSR is a promising primary care intervention for those living with early cognitive deficits. This study warrants the pursuit of a future study in exploring how long the reduced anxiety effects would be sustained. Show more

Keywords: Activities of daily living, Alzheimer’s disease, anxiety, health promotion, mild cognitive impairment, mindfulness meditation, occupational therapy, older adults, primary care, psychological outcomes, subjective cognitive decline

DOI: 10.3233/ADR-230006

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 775-790, 2023

Authors: Behera, Anindita | Sa, Nishigandha | Pradhan, Sweta Priyadarshini | Swain, Sunsita | Sahu, Pratap Kumar

Article Type: Review Article

Abstract: Nanotechnology has emerged in different fields of biomedical application, including lifestyle diseases like diabetes, hypertension, and chronic kidney disease, neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease, and different types of cancers. Metal nanoparticles are one of the most used drug delivery systems due to the benefits of their enhanced physicochemical properties as compared to bulk metals. Neurodegenerative diseases are the second most cause affecting mortality worldwide after cancer. Hence, they require the most specific and targeted drug delivery systems for maximum therapeutic benefits. Metal nanoparticles are the preferred drug delivery system, possessing greater blood-brain barrier permeability, biocompatibility, and enhanced …bioavailability. But some metal nanoparticles exhibit neurotoxic activity owing to their shape, size, surface charge, or surface modification. This review article has discussed the pathophysiology of AD. The neuroprotective mechanism of gold, silver, selenium, ruthenium, cerium oxide, zinc oxide, and iron oxide nanoparticles are discussed. Again, the neurotoxic mechanisms of gold, iron oxide, titanium dioxide, and cobalt oxide are also included. The neuroprotective and neurotoxic effects of nanoparticles targeted for treating AD are discussed elaborately. The review also focusses on the biocompatibility of metal nanoparticles for targeting the brain in treating AD. The clinical trials and the requirement to develop new drug delivery systems are critically analyzed. This review can show a path for the researchers involved in the brain-targeted drug delivery for AD. Show more

Keywords: Alzheimer’s disease, biocompatibility, clinical trials, metal nanoparticles, neuroprotective, neurotoxicity

DOI: 10.3233/ADR-220112

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 791-810, 2023

Authors: Wei, Tao | Shi, Xiaolei | Sun, Wei | Song, Weiyi | Zhou, Shaojiong | Zhao, Yiwei | Wang, Zhibin | Tang, Yi

Article Type: Research Article

Abstract: Background: Neurological disorders, such as Alzheimer’s disease (AD), comprise a major cause of health-related disabilities in human. However, biomarkers towards pathogenesis or novel targets are still limited. Objective: To identify the causality between plasma proteins and the risk of AD and other eight common neurological diseases using a Mendelian randomization (MR) study. Methods: Exposure data were obtained from a genome-wide association study (GWAS) of 2,994 plasma proteins in 3,301 healthy adults, and outcome datasets included GWAS summary statistics of nine neurological disorders. Inverse variance-weighted MR method as the primary analysis was used to estimate causal effects. …Results: Higher genetically proxied plasma myeloid cell surface antigen CD33 level was found to be associated with increased risk of AD (odds ratio [OR] 1.079, 95% confidence interval [CI] 1.047–1.112, p  = 8.39×10-7 ). We also discovered the causality between genetically proxied elevated prolactin and higher risk of epilepsy (OR = 1.068, 95% CI = 1.034–1.102; p  = 5.46×10-5 ). Negative associations were identified between cyclin-dependent kinase 8 and ischemic stroke (OR = 0.927, 95% CI = 0.896–0.959, p  = 9.32×10-6 ), between neuralized E3 ubiquitin-protein ligase 1 and migraine (OR = 0.914, 95% CI = 0.878–0.952, p  = 1.48×10-5 ), and between Fc receptor-like protein 4 and multiple sclerosis (MS) (OR = 0.929, 95% CI = 0.897–0.963, p  = 4.27×10-5 ). Conclusion: The findings identified MR-level protein-disease associations for AD, epilepsy, ischemic stroke, migraine, and MS. Show more

Keywords: Alzheimer’s disease, causality, Mendelian randomization, neurological disorders, plasma proteins

DOI: 10.3233/ADR-230058

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 811-822, 2023

Authors: Mehramiz, Mehrane | Porter, Tenielle | O’Brien, Eleanor K. | Rainey-Smith, Stephanie R. | Laws, Simon M.

Article Type: Review Article

Abstract: Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer’s disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing …the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-β and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia. Show more

Keywords: Alzheimer’s disease, dementia, lifestyle, SIRT1, sirtuin-1

DOI: 10.3233/ADR-220088

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 823-843, 2023

Authors: Fernandes, Mariana | Chiaravalloti, Agostino | Nuccetelli, Marzia | Placidi, Fabio | Izzi, Francesca | Camedda, Riccardo | Bernardini, Sergio | Sancesario, Giuseppe | Schillaci, Orazio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Research Article

Abstract: Background: Sleep impairment has been commonly reported in Alzheimer’s disease (AD) patients. The association between sleep dysregulation and AD biomarkers has been separately explored in mild cognitive impairment (MCI) and AD patients. Objective: The present study investigated cerebrospinal-fluid (CSF) and 18 F-fluoro-deoxy-glucose positron emission tomography (18 F-FDG-PET) biomarkers in MCI and AD patients in order to explore their association with sleep parameters measured with polysomnography (PSG). Methods: MCI and AD patients underwent PSG, 18 F-FDG-PET, and CSF analysis for detecting and correlating these biomarkers with sleep architecture. Results: Thirty-five patients were included in the …study (9 MCI and 26 AD patients). 18 F-FDG uptake in left Brodmann area 31 (owing to the posterior cingulate cortex) correlated negatively with REM sleep latency (p  = 0.013) and positively with REM sleep (p  = 0.033). 18 F-FDG uptake in the hippocampus was negatively associated with sleep onset latency (p  = 0.041). Higher CSF orexin levels were associated with higher sleep onset latency (p  = 0.042), Non-REM stage 1 of sleep (p  = 0.031), wake after sleep onset (p  = 0.028), and lower sleep efficiency (p  = 0.045). CSF levels of Aβ42 correlated negatively with the wake bouts index (p  = 0.002). CSF total-tau and phosphorylated tau levels correlated positively with total sleep time (p  = 0.045) and time in bed (p  = 0.031), respectively. Conclusion: Sleep impairment, namely sleep fragmentation, REM sleep dysregulation, and difficulty in initiating sleep correlates with AD biomarkers, suggesting an effect of sleep on the pathological processes in different AD stages. Targeting sleep for counteracting the AD pathological processes represents a timely need for clinicians and researchers. Show more

Keywords: Alzheimer’s disease, biomarkers, brain, cerebrospinal fluid, dementia, orexin, positron emission tomography, sleep

DOI: 10.3233/ADR-220111

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 845-854, 2023

Authors: Yu, Zhentao | Shi, Zhuoyu | Dan, Tingting | Dere, Mustafa | Kim, Minjeong | Li, Quefeng | Wu, Guorong

Article Type: Research Article

Abstract: Background: The AT[N] research framework focuses on three major biomarkers in Alzheimer’s disease (AD): amyloid-β deposition (A), pathologic tau (T), and neurodegeneration [N]. Objective: We hypothesize that the diverse mechanisms such as A⟶T and A⟶[N] pathways from one brain region to others, may underlie the wide variation in clinical symptoms. We aim to uncover the causal-like effect of regional AT[N] biomarkers on cognitive decline as well as the interaction with non-modifiable risk factors such as age and APOE4 . Methods: We apply multi-variate statistical inference to uncover all possible mechanistic spreading pathways through which the aggregation …of an upstream biomarker (e.g., increased amyloid level) in a particular brain region indirectly impacts cognitive decline, via the cascade build-up of a downstream biomarker (e.g., reduced metabolism level) in another brain region. Furthermore, we investigate the survival time for each identified region-to-region pathological pathway toward the AD onset. Results: We have identified a collection of critical brain regions on which the amyloid burdens exert an indirect effect on the decline in memory and executive function (EF) domain, being mediated by the reduction of metabolism level at other brain regions. APOE4 status has been found not only involved in many A⟶N mechanistic pathways but also significantly contributes to the risk of developing AD. Conclusion: Our major findings include 1) the region-to-region A⟶N⟶MEM and A⟶N⟶MEM pathways exhibit distinct spatial patterns; 2) APOE4 is significantly associated with both direct and indirect effects on the cognitive decline while sex difference has not been identified in the mediation analysis. Show more

Keywords: Alzheimer’s disease, biomarkers, mediation analysis, multi-variate variable selection, pathogenesis mechanism

DOI: 10.3233/ADR-230081

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 855-872, 2023

Authors: Loeffler, David A.

Article Type: Review Article

Abstract: Immunotherapeutic efforts to slow the clinical progression of Alzheimer’s disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither Aβ vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable Aβ; phase III results released at that …time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab’s phase III trial revealed that primary and secondary end points had been met. Antibody binding to Aβ facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar Aβ, and binding of antibody-Aβ complexes to blood-brain barrier receptors. Antibody binding to Aβ in peripheral blood may also promote cerebral efflux of Aβ by a peripheral sink mechanism. According to the amyloid hypothesis, for Aβ targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of Aβ clearance, findings in AD trials involving Aβ vaccination, IVIG, and anti-Aβ monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the Aβ-clearing ability of monoclonal antibodies. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid hypothesis, antibodies, clearance, clinical trials, downstream effects, intravenous immunoglobulin

DOI: 10.3233/ADR-230025

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 873-899, 2023

Authors: Wang, Mengxue | Wang, Yanjuan | Wang, Zan | Ren, Qingguo

Article Type: Systematic Review

Abstract: Background: Cognitive impairment (CI) is an important extrapulmonary complication in patients with chronic obstructive pulmonary disease (COPD). Multimodal Neuroimaging Examination can display changes in brain structure and functions in patients with COPD. Objective: The purpose of this systematic review is to provide an overview of the variations in brain imaging in patients with COPD and their potential relationship with CI. Furthermore, we aim to provide new ideas and directions for future research. Methods: Literature searches were performed using the electronic databases PubMed, Scopus, and ScienceDirect. All articles published between January 2000 and November 2021 that met …the eligibility criteria were included. Results: Twenty of the 23 studies focused on changes in brain structure and function. Alterations in the brain’s macrostructure are manifested in the bilateral frontal lobe, hippocampus, right temporal lobe, motor cortex, and supplementary motor area. The white matter microstructural changes initially appear in the bilateral frontal subcortical region. Regarding brain function, patients with COPD exhibited reduced frontal cerebral perfusion and abnormal alterations in intrinsic brain activity in the bilateral posterior cingulate cortex, precuneus, right lingual gyrus, and left anterior central gyrus. Currently, there is limited research related to brain networks. Conclusion: CI in patients with COPD may present as a type of dementia different from Alzheimer’s disease, which tends to manifest as frontal cognitive decline early in the disease. Further studies are required to clarify the neurobiological pathways of CI in patients with COPD from the perspective of brain connectomics based on the whole-brain system in the future. Show more

Keywords: Alzheimer’s disease, brain imaging, chronic obstructive pulmonary disease, cognitive impairment, mechanism

DOI: 10.3233/ADR-220083

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 901-919, 2023

Authors: Volloch, Vladimir | Rits-Volloch, Sophia

Article Type: Other

Abstract: With the Amyloid Cascade Hypothesis (ACH) largely discredited, the ACH2.0 theory of Alzheimer’s disease (AD) has been recently introduced. Within the framework of the ACH2.0, AD is triggered by amyloid-β protein precursor (AβPP)-derived intraneuronal Aβ (i Aβ) and is driven by i Aβ produced in the AβPP-independent pathway and retained intraneuronally. In this paradigm, the depletion of extracellular Aβ or suppression of Aβ production by AβPP proteolysis, the two sources of AβPP-derived i Aβ, would be futile in symptomatic AD, due to its reliance on i Aβ generated independently of AβPP, but effective in preventing AD and treating Aging-Associated …Cognitive Decline (AACD) driven, in the ACH2.0 framework, by AβPP-derived i Aβ. The observed effect of lecanemab and donanemab, interpreted in the ACH2.0 perspective, supports this notion and mandates AD-preventive clinical trials. Such trials are currently in progress. They are likely, however, to fail or to yield deceptive results if conducted conventionally. The present study considers concepts of design of clinical trials of lecanemab, donanemab, or any other drug, targeting the influx of AβPP-derived i Aβ, in prevention of AD and treatment of AACD. It analyzes possible outcomes and explains why selection of high-risk asymptomatic participants seems reasonable but is not. It argues that outcomes of such AD preventive trials could be grossly misleading, discusses inevitable potential problems, and proposes feasible solutions. It advocates the initial evaluation of this type of drugs in clinical trials for treatment of AACD. Whereas AD protective trials of these drugs are potentially of an impractical length, AACD clinical trials are expected to yield unequivocal results within a relatively short duration. Moreover, success of the latter, in addition to its intrinsic value, would constitute a proof of concept for the former. Furthermore, this study introduces concepts of the active versus passive i Aβ depletion, contends that targeted degradation of i Aβ is the best therapeutic strategy for both prevention and treatment of AD and AACD, proposes potential i Aβ-degrading drugs, and describes their feasible and unambiguous evaluation in clinical trials. Show more

Keywords: Aging-associated cognitive decline, Alzheimer’s disease, Amyloid Cascade Hypothesis 2.0 (ACH2.0), BACE1 and BACE2 activators, clinical trial design, donanemab, intraneuronal Aβ , lecanemab, verubecestat

DOI: 10.3233/ADR-230037

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 921-955, 2023

Authors: Patel, Ashay O. | Caldwell, Andrew B. | Ramachandran, Srinivasan | Subramaniam, Shankar

Article Type: Research Article

Abstract: Background: While Alzheimer’s disease (AD) pathology is associated with altered brain structure, it is not clear whether gene expression changes mirror the onset and evolution of pathology in distinct brain regions. Deciphering the mechanisms which cause the differential manifestation of the disease across different regions has the potential to help early diagnosis. Objective: We aimed to identify common and unique endotypes and their regulation in tangle-free neurons in sporadic AD (SAD) across six brain regions: entorhinal cortex (EC), hippocampus (HC), medial temporal gyrus (MTG), posterior cingulate (PC), superior frontal gyrus (SFG), and visual cortex (VCX). Methods: …To decipher the states of tangle-free neurons across different brain regions in human subjects afflicted with AD, we performed analysis of the neural transcriptome. We explored changes in differential gene expression, functional and transcription factor target enrichment, and co-expression gene module detection analysis to discern disease-state transcriptomic variances and characterize endotypes. Additionally, we compared our results to tangled AD neuron microarray-based study and the Allen Brain Atlas. Results: We identified impaired neuron function in EC, MTG, PC, and VCX resulting from REST activation and reversal of mature neurons to a precursor-like state in EC, MTG, and SFG linked to SOX2 activation. Additionally, decreased neuron function and increased dedifferentiation were linked to the activation of SUZ12. Energetic deficit connected to NRF1 inactivation was found in HC, PC, and VCX. Conclusions: Our findings suggest that SAD manifestation varies in scale and severity in different brain regions. We identify endotypes, such as energetic shortfalls, impaired neuronal function, and dedifferentiation. Show more

Keywords: Alzheimer’s disease, dedifferentiation, endotype, energetics, NRF1, REST, SOX2, sporadic Alzheimer’s disease, SUZ12, transcriptome

DOI: 10.3233/ADR-220098

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 957-972, 2023

Authors: Yu, Ruan-Ching | Lai, Jen-Chieh | Hui, Esther K. | Mukadam, Naaheed | Kapur, Narinder | Stott, Joshua | Livingston, Gill

Article Type: Systematic Review

Abstract: Background: Chinese is the most commonly spoken world language; however, most cognitive tests were developed and validated in the West. It is essential to find out which tests are valid and practical in Chinese speaking people with suspected dementia. Objective: We therefore conducted a systematic review and meta-analysis of brief cognitive tests adapted for Chinese-speaking populations in people presenting for assessment of suspected dementia. Methods: We searched electronic databases for studies reporting brief (≤20 minutes) cognitive test’s sensitivity and specificity as part of dementia diagnosis for Chinese-speaking populations in clinical settings. We assessed …quality using Centre for Evidence Based Medicine (CEBM) criteria and translation and cultural adaptation using the Manchester Translation Reporting Questionnaire (MTRQ), and Manchester Cultural Adaptation Reporting Questionnaire (MCAR). We assessed heterogeneity and combined sensitivity in meta-analyses. Results: 38 studies met inclusion criteria and 22 were included in meta-analyses. None met the highest CEBM criteria. Five studies met the highest criteria of MTRQ and MCAR. In meta-analyses of studies with acceptable heterogeneity (I2  <  75%), Addenbrooke’s Cognitive Examination Revised &III (ACE-R & ACE-III) had the best sensitivity and specificity; specifically, for dementia (93.5% & 85.6%) and mild cognitive impairment (81.4% & 76.7%). Conclusions: Current evidence is that the ACE-R and ACE-III are the best brief cognitive assessments for dementia and mild cognitive impairment in Chinese-speaking populations. They may improve time taken to diagnosis, allowing people to access interventions and future planning. Show more

Keywords: Alzheimer’s disease, cognitive assessment, dementia, diagnosis, mild cognitive impairment

DOI: 10.3233/ADR-230024

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 973-987, 2023

Authors: Aborode, Abdullahi Tunde | Idowu, Nike Jesutofunmi | Tundealao, Samuel | Jaiyeola, Joseph | Ogunware, Adedayo Emmanuel

Article Type: Article Commentary

Abstract: This paper explores the emerging field of neuroscience in Africa, considering the unique genetic diversity, socio-cultural determinants, and health inequalities in the continent. It presents numerous brain research initiatives, such as ABDRN, AMARI, APCDR, and H3Africa, aimed at understanding genetic and environmental factors influencing brain disorders in Africa. Despite numerous challenges like the brain drain phenomenon, inadequate infrastructure, and scarce research expertise, significant progress has been achieved. The paper proposes solutions, including international collaboration, capacity-building efforts, and policies to promote neuroscience research, to enhance the understanding of brain function and address brain-related health issues within the African context.

Keywords: Africa, Alzheimer’s disease, brain drain, brain research, collaboration, global partnerships, health inequities, infrastructure, neuroscience, research capacity

DOI: 10.3233/ADR-230062

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 989-992, 2023

Authors: Kropf, Mario

Article Type: Research Article

Abstract: Dementia currently affects more than 55 million people worldwide, and scientists predict that this number will continue to rise. The most common form is Alzheimer’s disease (AD), which is triggered, among other things, by dysfunctional cells in the human brain. Stem cell research attempts to counteract neurodegenerative processes, for example by replacing or treating diseased cells. In addition to human embryonic stem cells, since the successes of Takahashi and Yamanaka in 2006, there has been an increased focus on human induced pluripotent stem cells (hiPS cells). These cells avoid ethically challenging questions about the moral status of human embryos, but …there are numerous problems, such as high production costs, side effects from the reprogramming process, or a potentially new moral status. These ethical issues will be examined primarily in relation to AD. The first part will be a discussion of hiPS cells and their importance for stem cell research, after which the focus turns to AD. Based on scientific studies, the relationship between hiPS cells and AD will be outlined as well as ethical implications presented. While potential limitations of hiPS cells have been discussed by numerous authors, an ethical perspective on the link between hiPS cells and AD seems to be neglected in the scientific community. The following risk analysis aims to identify a possible research agenda. In conclusion, the focus on individuals with AD may help to adopt an ethical stance that recognizes existing limitations and constructively engages with the possibilities of research. Show more

Keywords: Alzheimer’s disease, ethics, human induced pluripotent stem cells, moral issues, stem cells

DOI: 10.3233/ADR-230018

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 993-1006, 2023

Authors: Alves-Borba, Laryssa | Espinosa-Fernández, Verónica | Canseco-Rodríguez, Ania | Sánchez-Pérez, Ana María

Article Type: Short Communication

Abstract: Insulin resistance underlies Alzheimer’s disease (AD) by affecting neuroinflammation and brain-derived neurotrophic factor (BDNF) expression. Here, we evaluated the effect of early and late-start abscisic acid (ABA) intervention on hippocampal BDNF, tumor necrosis factor α (TNFα), and insulin receptors substrates (IRS) 1/2 mRNA levels in a triple-transgenic mice model of AD. Transgenic mice displayed lower BDNF and IRS2, equal IRS1, and higher TNFα expression compared to wild-type mice. Late ABA treatment could rescue TNFα and increased IRS1/2 expression. However, early ABA administration was required to increase BDNF expression. Our data suggests that early intervention with ABA can prevent AD, via …rescuing IRS1/2 and BDNF expression. Show more

Keywords: Alzheimer’s disease, hippocampus, insulin signal, neuroinflammation, neuroprotector, neurotrophic factor, phytohormones

DOI: 10.3233/ADR-230056

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1007-1013, 2023

Authors: Willis, Brian A. | Lo, Albert C. | Dage, Jeffrey L. | Shcherbinin, Sergey | Chinchen, Louise | Andersen, Scott W. | LaBell, Elizabeth S. | Perahia, David G.S. | Hauck, Paula M. | Lowe, Stephen L.

Article Type: Research Article

Abstract: Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer’s disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. …Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed. Clinicaltrials.gov: NCT03019536 Show more

Keywords: Aggregated tau, Alzheimer’s disease, antibody, safety pharmacokinetics, zagotenemab

DOI: 10.3233/ADR-230012

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1015-1024, 2023

Authors: Franks, Katherine H. | Cribb, Lachlan | Bransby, Lisa | Buckley, Rachel | Yassi, Nawaf | Chong, Trevor T.-J. | Lim, Yen Ying | Pase, Matthew P.

Article Type: Short Communication

Abstract: Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-β42 , phosphorylated tau-181, total tau, or neurofilament light chain. Cohen’s f2 effect sizes were small in magnitude (f2 ≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels …of stress. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, psychological stress

DOI: 10.3233/ADR-230052

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1025-1031, 2023

Authors: Zhou, Aoshuang | Britt, Carlene | Woods, Robyn L. | Orchard, Suzanne G. | Murray, Anne M. | Shah, Raj C. | Rajan, Ramesh | McNeil, John J. | Chong, Trevor T.-J. | Storey, Elsdon | Ryan, Joanne

Article Type: Research Article

Abstract: Background: The Controlled Oral Word Association Test (COWAT) is a commonly used measure of verbal fluency. While a normal decline in verbal fluency occurs in late adulthood, significant impairments may indicate brain injury or diseases such as Alzheimer’s disease. Normative data is essential to identify when test performance falls below expected levels based on age, gender, and education level. Objective: This study aimed to establish normative performance data on single-letter COWAT for older community-dwelling adults. Methods: Over 19,000 healthy men and women, without a diagnosis of dementia or a Modified Mini-Mental State Examination score below 77/100, …were recruited for the ASPREE trial. Neuropsychological assessments, including the COWAT with letter F, were administered at study entry. Results: Median participant age was 75 years (range 65–98), with 56.5% being women. The majority of participants had 9–11 years of education in Australia and over 12 years in the U.S. The COWAT performance varied across ethno-racial groups and normative data were thus presented separately for 16,335 white Australians, 1,084 white Americans, 896 African-Americans, and 316 Hispanic/Latinos. Women generally outperformed men in the COWAT, except for Hispanic/Latinos. Higher education levels consistently correlated with better COWAT performance across all groups, while the negative association with age was weaker. Conclusions: This study provides comprehensive normative data for the COWAT stratified by ethno-racial groups in Australia and the U.S., considering age, gender, and education level. These norms can serve as reference standards for screening cognitive impairments in older adults in both clinical and research settings. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, normative data, phonemic fluency

DOI: 10.3233/ADR-230089

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1033-1043, 2023

Authors: Xiao, Qing | Li, Yonggang | Li, Benchao | Li, Tingting | Li, Fengping | Li, Yuanyuan | Chen, Liangkai | Zhao, Zhuangju | Wang, Qing | Rong, Shuang

Article Type: Research Article

Abstract: Background: The evidence concerning dietary diversity and cognitive function remains insufficient. Objective: To investigate the association of dietary diversity score (DDS) with mild cognitive impairment (MCI) and cognitive performance in different domains. Methods: Data from The Lifestyle and Healthy Aging of Chinese Square Dancer Study was used in this study. DDS was constructed based on the intake frequencies of 9 food groups assessed by a validated food frequency questionnaire. MCI was diagnosed by Petersen’s criteria. A neuropsychological test battery was used to assess the performance on cognitive domains, and test scores were standardized to Z scores. …Multiple linear regression models and logistic regression models were used to estimate the β and odds ratios and their 95% CIs, respectively. Results: Among 1,982 participants, the mean (SD) age was 63.37 (5.00) years, 1,778 (89.71%) were women, and 279 (14.08%) had MCI. Compared to the DDS quartile (0, 6], the multivariable-adjusted odds ratios (95% CI) were 0.74 (0.48, 1.15) for DDS quartile (6, 7], 0.65 (0.43, 0.97) for DDS quartile (7, 8], and 0.55 (0.37, 0.84) for DDS quartile (8, 9]. Furthermore, higher DDS was positively associated with better performance of cognitive domains, including global cognitive function (β= 0.20, 95% CI: 0.12, 0.30), episodic memory (β= 0.21, 95% CI: 0.07, 0.35), attention (β= 0.15, 95% CI: 0.03, 0.26), language fluency (β= 0.24, 95% CI: 0.10, 0.38), and executive function (β= – 0.24, 95% CI: – 0.38, – 0.10). Conclusions: This study indicated that higher DDS was associated with better cognitive function among middle-aged and older Chinese people. Show more

Keywords: Alzheimer’s disease, cognitive domains, cross-sectional study, dietary diversity, mild cognitive impairment

DOI: 10.3233/ADR-230060

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1045-1053, 2023

Authors: Teipel, Stefan J | Dyrba, Martin | Levin, Fedor | Altenstein, Slawek | Berger, Moritz | Beyle, Aline | Brosseron, Frederic | Buerger, Katharina | Burow, Lena | Dobisch, Laura | Ewers, Michael | Fliessbach, Klaus | Frommann, Ingo | Glanz, Wenzel | Goerss, Doreen | Gref, Daria | Hansen, Niels | Heneka, Michael T. | Incesoy, Enise I. | Janowitz, Daniel | Keles, Deniz | Kilimann, Ingo | Laske, Christoph | Lohse, Andrea | Munk, Matthias H. | Perneczky, Robert | Peters, Oliver | Preis, Lukas | Priller, Josef | Rostamzadeh, Ayda | Roy, Nina | Schmid, Matthias | Schneider, Anja | Spottke, Annika | Spruth, Eike Jakob | Wiltfang, Jens | Düzel, Emrah | Jessen, Frank | Kleineidam, Luca | Wagner, Michael

Article Type: Research Article

Abstract: Background: Cognitive decline is a key outcome of clinical studies in Alzheimer’s disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial …models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid. Show more

Keywords: Alzheimer’s disease, executive function, longitudinal, memory, mild cognitive impairment, non-linear, practice effects, subjective cognitive decline

DOI: 10.3233/ADR-230027

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1055-1076, 2023

Authors: Funayama, Michitaka | Kuramochi, Shin | Kudo, Shun

Article Type: Short Communication

Abstract: Diagnosing neurosyphilis can be challenging and it may be misdiagnosed as behavior variant frontotemporal dementia, given its affinity for the frontal and temporal lobes. Here we present a model case, who, in his 40 s, was initially misdiagnosed with behavioral variant frontotemporal dementia based on extreme self-neglect and disinhibition over six months and frontal lobe atrophy. He was later diagnosed as neurosyphilis with positive syphilis tests in his cerebrospinal fluid. He underwent penicillin treatment and fully recovered. Relatively rapid cognitive decline, particularly if young, should prompt physicians to consider neurosyphilis as a treatable dementia, which could completely change a patient’s life.

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, differential diagnosis, dysexecutive function, frontal lobe, neurosyphilis, treatable dementia

DOI: 10.3233/ADR-230107

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1077-1083, 2023

Authors: Sagalajev, Boriss | Lennartz, Lina | Vieth, Lukas | Gunawan, Cecilia Tasya | Neumaier, Bernd | Drzezga, Alexander | Visser-Vandewalle, Veerle | Endepols, Heike | Sesia, Thibaut

Article Type: Research Article

Abstract: Background: The TgF344-AD ratline represents a transgenic animal model of Alzheimer’s disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance. Methods: TgF344-AD rats were divided into two groups balanced by sex and genotype. The first …group underwent the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14–16 months old during DMS testing and PET. Results: In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats. Conclusions: TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with past clinical research. In rats with preserved spatial orientation, working memory remains intact. Show more

Keywords: Alzheimer’s disease, brain imaging, glucose, microglia, PET, rat model, spatial orientation, working memory

DOI: 10.3233/ADR-230038

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1085-1094, 2023

Authors: Roe, Catherine M. | Bayat, Sayeh | Babulal, Ganesh M.

Article Type: Research Article

Abstract: Background: Declines in instrumental activities of daily living like driving are hallmarks sequelae of Alzheimer’s disease (AD). Although driving has been shown to be associated with traditional imaging and cerebrospinal fluid (CSF) biomarkers, it is possible that some biomarkers have stronger associations with specific aspects of driving behavior. Furthermore, associations between newer plasma biomarkers and driving behaviors are unknown. Objective: This study assessed the extent to which individual plasma, imaging, and CSF biomarkers are related to specific driving behaviors and cognitive functions among cognitively normal older adults. Methods: We analyzed naturalistic driving behavior from cognitively healthy …older drivers (N = 167, 47% female, mean age = 73.3 years). All participants had driving, clinical, and demographic data and completed biomarker testing, including imaging, CSF, and/or plasma, within two years of study commencement. Results: AD biomarkers were associated with different characteristics of driving and cognitive functioning within the same individuals. Elevated levels of plasma Aβ40 were associated with more speeding incidents, higher levels of CSF tau were related to shorter duration of trips, and higher CSF neurofilament light chain values were associated with traveling shorter distances, smaller radius of gyration, and fewer trips at night. We demonstrated that plasma, like CSF and imaging biomarkers, were helpful in predicting everyday driving behaviors. Conclusions: These findings suggest that different biomarkers offer complementary information with respect to driving behaviors. These distinct relationships may help in understanding how different biological changes that occur during the preclinical stage of AD can impact various sensorimotor and cognitive processes. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, imaging, naturalistic driving

DOI: 10.3233/ADR-230088

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1095-1102, 2023

Authors: Siriwardhana, Chathura | Carrazana, Enrique | Liow, Kore | Chen, John J.

Article Type: Research Article

Abstract: Background: There is an expanding body of literature implicating heart disease and stroke as risk factors for Alzheimer’s disease (AD). Hawaii is one of the six majority-minority states in the United States and has significant racial health disparities. The Native-Hawaiians/Pacific-Islander (NHPI) population is well-known as a high-risk group for a variety of disease conditions. Objective: We explored the association of cardiovascular disease with AD development based on the Hawaii Medicare data, focusing on racial disparities. Methods: We utilized nine years of Hawaii Medicare data to identify subjects who developed heart failure (HF), ischemic heart disease (IHD), …atrial fibrillation (AF), acute myocardial infarction (AMI), stroke, and progressed to AD, using multistate models. Propensity score-matched controls without cardiovascular disease were identified to compare the risk of AD after heart disease and stroke. Racial/Ethnic differences in progression to AD were evaluated, accounting for other risk factors. Results: We found increased risks of AD for AF, HF, IHD, and stroke. Socioeconomic (SE) status was found to be critical to AD risk. Among the low SE group, increased AD risks were found in NHPIs compared to Asians for all conditions selected and compared to whites for HF, IHD, and stroke. Interestingly, these observations were found reversed in the higher SE group, showing reduced AD risks for NHPIs compared to whites for AF, HF, and IHD, and to Asians for HF and IHD. Conclusions: NHPIs with poor SE status seems to be mostly disadvantaged by the heart/stroke and AD association compared to corresponding whites and Asians. Show more

Keywords: Alzheimer’s disease, heart disease, racial groups, stroke

DOI: 10.3233/ADR-230003

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1103-1120, 2023

Authors: Swerdlow, Russell H. | Jawdat, Omar | Swint-Kruse, Liskin | Townley, Ryan

Article Type: Case Report

Abstract: Fused in sarcoma (FUS) mutations cause frontotemporal dementia (FTD) and motor neuron disease (MND). Here, we describe a 43-year-old man with progressive behavioral and cognitive change, myelopathy, clinical and electrophysiologic evidence of MND, and a FUS variant of unknown significance (VUS). This VUS, a heterozygous G559A transition (Gly187Ser), was previously reported in a patient with sporadic MND and affects important FUS biophysical properties. While this rare variant’s presence in a second patient with a related neurodegenerative syndrome does not establish pathogenicity, it raises the question of whether its association with our patient is coincidental and increases the possibility that FUS …G559A is pathogenic. Show more

Keywords: Case report, frontotemporal dementia, FUS, motor neuron disease

DOI: 10.3233/ADR-230103

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1121-1126, 2023

Authors: Wang, Jing-Juan | Zhang, Qiao-Feng | Liu, Di | Du, Qing | Xu, Cheng | Wu, Quan-Xin | Tang, Yi | Jin, Wang-Sheng

Article Type: Research Article

Abstract: Background: The acute stage of COVID-19 often presents with neurological manifestations. Objective: This study aims to investigate the long-term neurological effects on survivors. Methods: This study recruited 1,546 COVID-19 survivors from Wuhan, including 1,119 nonsevere cases and 427 severe survivors. Participants were interviewed two years after discharge to report their neurological symptoms. The neurological symptoms of COVID-19 were compared between survivors of severe and nonsevere COVID-19. Results: Among the 1,546 COVID-19 survivors, 44.24% discovered at least one neurological symptom. The most prevalent self-reported symptom was fatigue (28.33%), memory deficit (13.26%), attention deficit (9.96%), myalgia …(8.34%), dizziness (3.82%), and headache (2.52%). Severe cases had higher incidences of fatigue, myalgia, memory deficit, attention deficit than nonsevere cases. Older age, severe COVID-19, and comorbidity burden were associated with long-term neurological symptoms. Conclusion: Neurological symptoms are common among COVID-19 survivors, especially in severe cases. Show more

Keywords: COVID-19, long-COVID, neurological symptoms, sequelae

DOI: 10.3233/ADR-230078

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1127-1132, 2023

Authors: Marefat, Haniyeh | Vahabi, Zahra | Afzalian, Neda | Khanbagi, Mahdiyeh | Karimi, Hamed | Ebrahiminia, Fatemeh | Kalafatis, Chris | Modarres, Mohammad Hadi | Khaligh-Razavi, Seyed-Mahdi

Article Type: Research Article

Abstract: Background: In early Alzheimer’s disease (AD), high-level visual functions and processing speed are impacted. Few functional magnetic resonance imaging (fMRI) studies have investigated high-level visual deficits in AD, yet none have explored brain activity patterns during rapid animal/non-animal categorization tasks. Objective: To address this, we utilized the previously known Integrated Cognitive Assessment (ICA) to collect fMRI data and compare healthy controls (HC) to individuals with mild cognitive impairment (MCI) and mild AD. Methods: The ICA encompasses a rapid visual categorization task that involves distinguishing between animals and non-animals within natural scenes. To comprehensively explore variations in …brain activity levels and patterns, we conducted both univariate and multivariate analyses of fMRI data. Results: The ICA task elicited activation across a range of brain regions, encompassing the temporal, parietal, occipital, and frontal lobes. Univariate analysis, which compared responses to animal versus non-animal stimuli, showed no significant differences in the regions of interest (ROIs) across all groups, with the exception of the left anterior supramarginal gyrus in the HC group. In contrast, multivariate analysis revealed that in both HC and MCI groups, several regions could differentiate between animals and non-animals based on distinct patterns of activity. Notably, such differentiation was absent within the mild AD group. Conclusions: Our study highlights the ICA task’s potential as a valuable cognitive assessment tool designed for MCI and AD. Additionally, our use of fMRI pattern analysis provides valuable insights into the complex changes in brain function associated with AD. This approach holds promise for enhancing our understanding of the disease’s progression. Show more

Keywords: Alzheimer’s disease, high-level visual categorization, functional MRI, mild cognitive impairment, multivariate pattern analysis

DOI: 10.3233/ADR-230132

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1133-1152, 2023

Authors: Ma, Yuanyuan | Gong, Juan | Zeng, Lingli | Wang, Qinghua | Yao, Xiuqing | Li, Huiming | Chen, Yaozhi | Liu, Feng | Zhang, Mengyuan | Ren, Hui | Xiao, Lily Dongxia | Lian, Yan

Article Type: Research Article

Abstract: Background: As the primary caregivers for people with dementia in China, family caregivers face a significant care burden that can negatively impact their mental and physical health. It is vital to investigate ways to support these caregivers. Objective: To assess the effectiveness of a program led by community nurses to support caregivers of individuals with dementia. Methods: A total of 30 caregivers received nurse-led support in addition to usual care, while 28 caregivers received only usual care. The primary outcome was caregivers’ sense of competency in providing dementia care, which was measured using the Short Sense …of Competence Questionnaire (SSCQ). Secondary outcomes included caregivers’ ability to perform daily activities, behavioral and psychological symptoms of dementia (BPSD) using a neuropsychiatric inventory questionnaire, and quality of life using the short form health survey (SF-36). The trial was registered at the Chinese Clinical Trial Registry (ChiCTR 2300071484). Results: Compared to the control group, the intervention group had significantly higher SSCQ scores and a lower caregiver distress index over time. Physical and mental health-related quality of life also improved significantly among caregivers in the intervention group. However, there was no significant difference between the two groups in terms of activities of daily living and BPSD. Conclusions: The community nurse-led support program significantly improved caregivers’ competency in providing dementia care and quality of life and reduced distress. These findings have important implications for dementia care policies, resources, and workforce development in China, including strengthening community dementia care services through collaboration with specialists in hospitals. Show more

Keywords: Alzheimer’s disease, caregivers, community health nursing, community support, dementia

DOI: 10.3233/ADR-230067

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1153-1164, 2023

Authors: Tian, Jing | Du, Eric | Guo, Lan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a lethal neurodegenerative disorder characterized by severe brain pathologies and progressive cognitive decline. While the exact cause of this disease remains unknown, emerging evidence suggests that dysregulation of neurotransmitters contributes to the development of AD pathology and symptoms. Serotonin, a critical neurotransmitter in the brain, plays a pivotal role in regulating various brain processes and is implicated in neurological and psychiatric disorders, including AD. Recent studies have shed light on the interplay between mitochondrial function and serotonin regulation in brain physiology. In AD, there is a deficiency of serotonin, along with impairments in mitochondrial function, particularly …in serotoninergic neurons. Additionally, altered activity of mitochondrial enzymes, such as monoamine oxidase, may contribute to serotonin dysregulation in AD. Understanding the intricate relationship between mitochondria and serotonin provides valuable insights into the underlying mechanisms of AD and identifies potential therapeutic targets to restore serotonin homeostasis and alleviate AD symptoms. This review summarizes the recent advancements in unraveling the connection between brain mitochondria and serotonin, emphasizing their significance in AD pathogenesis and underscoring the importance of further research in this area. Elucidating the role of mitochondria in serotonin dysfunction will promote the development of therapeutic strategies for the treatment and prevention of this neurodegenerative disorder. Show more

Keywords: Alzheimer’s disease, mitochondria, neurobiology, pathogenesis, serotonin

DOI: 10.3233/ADR-230070

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1165-1177, 2023

Authors: Luque-Tirado, Andrea | Montiel-Herrera, Fátima | Maestre-Bravo, Rebeca | Barril-Aller, Claudia | García-Roldán, Ernesto | Arriola-Infante, José Enrique | Sánchez-Arjona, María Bernal | Rodrigo-Herrero, Silvia | Vargas-Romero, Juan Pedro | Franco-Macías, Emilio

Article Type: Research Article

Abstract: Background: The “Triana Test” is a novel story recall test based on emotional material with demonstrated accuracy in diagnosing mild cognitive impairment patients. Objective: This study aims to obtain normative data for the “Triana Test”. Methods: A normative study was conducted at a university hospital in Spain. Partners of patients were systematically recruited if eligible (age ≥50, no memory complaints, and a total TMA-93 score at or above the 10th percentile). The “Triana Test” was administered and scored. For developing the normative data, a regression-based method was followed. Results: The final sample included 362 …participants (median age = 66, range = 50–88; 64.9% females). A model including age and educational level better predicted the total scores. Combinations of these variables resulted in different 10th percentile scores. Conclusions: Norms for using the “Triana Test” are now available. The provided cutoffs for the 10th percentile will aid in the diagnosis of prodromal Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive assessment, emotional memory, neuropsychology, normative data

DOI: 10.3233/ADR-230096

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1179-1186, 2023

Authors: Gaber, Heba Ahmed | Aly, Eman Mohamed | Mohamed, Eman Saad | Elfoly, Marwa | Rabie, Mostafa Adel | Talaat, Mona Salah | El-Sayed, El-Sayed Mahmoud

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that progresses over time. Fourier Transform Infrared Spectroscopy (FTIR) analysis gives identification of the main metabolic changes that happen during neurodegeneration, by monitoring biochemical and molecular structure alterations that can help in AD diagnosis or treatment approach. Objective: The aim of the present work is to assess AD hallmarks in molecular structure of retina and monitor accumulation of amyloid beta42 (Aβ42 ) in brain and retina during disease progression. Methods: AD induced in rats by Aluminum Chloride (AlCl3 ). Retinal molecular structure during disease progression for 2,4,6 and …8 weeks was assessed by Fourier-transform infrared spectroscopy (FTIR) and the incidence of the disease was confirmed by a behavioural assessment; the Morris Water Maze test. Aβ42 levels in the brain and retina were also measured. Results: The results indicated that cognitive impairment starting from 6 weeks of AlCl3 administration. Retinal concentration of Aβ42 was significant increase (p  < 0.05) from 2 weeks that precedes the observed increase of Aβ42 in the brain which appeared after 4 weeks of AlCl3 administration. Multivariate principal component analysis discovers that the variance noticed in the infrared spectra due to AD condition and it is time dependent for progression of the disease. Conclusions: The accumulation of Aβ42 is a sensitive early biomarker in retina for AD. FTIR analysis of the retina revealed changes in hydrogen bond formation or destruction, alterations in lipid chain length and branching accompanied by depleted lipid content and carbonization, as well as degeneration of the retinal tissue due to AD. Show more

Keywords: Aluminum, Alzheimer’s disease, amyloid-β , behavior test, chloride, retina

DOI: 10.3233/ADR-230051

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1187-1200, 2023

Authors: Ibrahim, Yehia | Xie, Jianyang | Macerollo, Antonella | Sardone, Rodolfo | Shen, Yaochun | Romano, Vito | Zheng, Yalin

Article Type: Systematic Review

Abstract: Background: Traditional methods for diagnosing dementia are costly, time-consuming, and somewhat invasive. Since the retina shares significant anatomical similarities with the brain, retinal abnormalities detected via optical coherence tomography (OCT) and OCT angiography (OCTA) have been studied as a potential non-invasive diagnostic tool for neurodegenerative disorders; however, the most effective retinal changes remain a mystery to be unraveled in this review. Objective: This study aims to explore the relationship between retinal abnormalities in OCT/OCTA images and cognitive decline as well as evaluating biomarkers’ effectiveness in detecting neurodegenerative diseases. Methods: A systematic search was conducted on PubMed, …Web of Science, and Scopus until December 2022, resulted in 64 papers using agreed search keywords, and inclusion/exclusion criteria. Results: The superior peripapillary retinal nerve fiber layer (pRNFL) is a trustworthy biomarker to identify most Alzheimer’s disease (AD) cases; however, it is inefficient when dealing with mild AD and mild cognitive impairment (MCI). The global pRNFL (pRNFL-G) is another reliable biomarker to discriminate frontotemporal dementia from mild AD and healthy controls (HCs), moderate AD and MCI from HCs, as well as identifing pathological Aβ42 /tau in cognitively healthy individuals. Conversely, pRNFL-G fails to realize mild AD and the progression of AD. The average pRNFL thickness variation is considered a viable biomarker to monitor the progression of AD. Finally, the superior and average pRNFL thicknesses are considered consistent for advanced AD but not for early/mild AD. Conclusions: Retinal changes may indicate dementia, but further research is needed to confirm the most effective biomarkers for early and mild AD. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, neurodegenerative disorders, optical coherence tomography, optical coherence tomography angiography, retinal biomarkers

DOI: 10.3233/ADR-230042

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1201-1235, 2023

Authors: Vassilaki, Maria | Syrjanen, Jeremy A. | Krell-Roesch, Janina | Graff-Radford, Jonathan | Vemuri, Prashanthi | Scharf, Eugene L. | Machulda, Mary M. | Fields, Julie A. | Kremers, Walter K. | Lowe, Val J. | Jack Jr., Clifford R. | Knopman, David S. | Petersen, Ronald C. | Geda, Yonas E.

Article Type: Short Communication

Abstract: The study included 1,738 Mayo Clinic Study of Aging participants (≥50 years old; 1,460 cognitively unimpaired and 278 with mild cognitive impairment (MCI)) and examined the cross-sectional association between cerebrovascular (CVD) imaging biomarkers (e.g., white matter hyperintensities (WMH), infarctions) and Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) scores, as well as their association with MCI. High (abnormal) WMH burden was significantly associated with having BDI-II>13 and BAI > 7 scores, and both (CVD imaging biomarkers and depression/anxiety) were significantly associated with MCI when included simultaneously in the model, suggesting that both were independently associated with the odds of MCI.

Keywords: Alzheimer’s disease, anxiety, cerebrovascular, depression, mild cognitive impairment, neuroimaging

DOI: 10.3233/ADR-230073

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1237-1246, 2023

Authors: Ding, Yanfei | Chen, Haijuan | Yan, Yi | Qiu, Yinghui | Zhao, Aonan | Li, Binyin | Xu, Wei | Deng, Yulei

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multi-gene inherited disease, and apolipoprotein E (APOE ) ɛ4 is a strong risk factor. Other genetic factors are important but limited. Objective: This study aimed to investigate the relationship between 17 single-nucleotide polymorphisms (SNPs) and AD in the Southern Chinese populations. Methods: We recruited 242 AD patients and 208 controls. The SNaPshot technique was used to detect the SNPs. Results: Adjusted for sex and age, we found rs6572869 (FERMT2 ), rs11604680 (CELF1 ), and rs1317149 (CELF1 ) were associated with AD risk in the dominant (rs6572869: p  = 0.022, …OR = 1.55; rs11604680: p  = 0.007, OR = 1.68; rs1317149: p  = 0.033, OR = 1.50) and overdominant models (rs6572869: p  = 0.001, OR = 1.96; rs11604680: p  = 0.002, OR = 1.82; rs1317149: p  = 0.003, OR = 1.80). rs9898218 (COPI ) was associated with AD risk in the overdominant model (p  = 0.004, OR = 1.81). Further, rs2741342 (CHRNA2 ) was associated with AD protection in the dominant (p  = 0.002, OR = 0.5) and additive models (p  = 0.002, OR = 0.64). Mutations in rs10742814 (CELF1 ), rs11039280 (CELF1 ), and rs3752242 (ABCA7 ) contributed to AD protection. Among them, rs10742814 (CELF1 ), rs3752242 (ABCA7 ), and rs11039280 (CELF1 ) were more significantly associated with AD carrying APOE ɛ4, whereas rs1317149 (CELF1 ) showed an opposite trend. Interestingly, rs4147912 (ABCA7 ) and rs2516049 (HLA-DRB1 ) were identified to be relevant with AD carrying APOE ɛ4. Using expression quantitative trait locus analysis, we found polymorphisms in CELF1 (rs10742814 and rs11039280), ABCA7 (rs4147912), HLA-DRB1 (rs2516049), and ADGRF4 (rs1109581) correlated with their corresponding gene expression in the brain. Conclusions: We identified four risk and four protective SNPs associated with AD in the Southern Chinese population, with different correlations between APOE ɛ4 carriers and non-carriers. rs4147912 (ABCA7 ) and rs2516049 (HLA-DRB1 ) were associated with AD carrying APOE ɛ4. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, neurodegenerative disease, single nucleotide polymorphisms

DOI: 10.3233/ADR-230072

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1247-1257, 2023

Authors: Domene-Serrano, Indalo | Cuadros, Raquel | Hernandez, Felix | Avila, Jesus | Santa-Maria, Ismael

Article Type: Research Article

Abstract: Background: Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Recently, we have discovered a new, human specific, tau isoform termed W-tau that originates by intron 12 retention. Our preliminary data suggests this newly discovered W-tau isoform might prevent aberrant aggregation of other tau isoforms but is significantly downregulated in tauopathies such as Alzheimer's disease. Objective: To accurately predict, examine, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Methods: A tridimensional deep learning-based approach and in vitro polymerization assay was included to accurately predict, analyze, …and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Results: Our findings demonstrate: a) the predicted protein tridimensionality structure of the tau isoforms raised by intron retention and their comparison with the other tau isoforms; b) the interaction of W-tau peptide (from W-tau isoform) with other tau isoforms; c) the effect of W-tau peptide in the polymerization of those tau isoforms. Conclusions: This study supports the importance of the structure-function relationship on the neuroprotective behavior of W-tau inhibiting tau fibrillization in vitro . Show more

Keywords: Alzheimer’s disease, deep learning, intron retention, isoform, polymerization, splicing, tau protein, tridimensional structure

DOI: 10.3233/ADR-230074

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1259-1265, 2023

Authors: Chen, Yuanyuan | Lan, Meijuan

Article Type: Other

Abstract: Background: One of the most popular ways to address cognitive decline is cognitive training. The fact that cognitive deterioration is permanent is one of the main issues. This issue might be resolved by preventive cognitive training when it is acute. As a result, this study aims to design and assess how well stroke patients respond to hierarchical, multi-dimensional preventative cognitive training. Objective: To describe the study design of this center implementation trial. Methods: Participants in the study will be recruited from a hospital in China and randomly assigned to the intervention group or the usual care …group. Interventions will include four-week hierarchical multi-dimensional preventive cognitive training through a WeChat program. for Primary outcome measures will be the Montreal Cognitive Assessment, Mini-Mental State Examination, and Post-Stroke Cognitive Impairment (PSCI) Incidence. The secondary outcome measure will include the Hamilton Depression Scale, Hamilton Anxiety Scale, Modified Barthel Index, and National Institutes of Health Neurological Deficit Score. Outcomes will be measured at baseline, 12 weeks, and 24 weeks from the baseline. Results: We expect that the hierarchical multi-dimensional preventive cognitive training program will be easy to implement, and the cognitive function, cognitive psychology, ability of daily living will vary in each setting. Conclusions: The results will provide evidence highlighting differences in a new strategy of cognitive training through the WeChat program, which allows the home-based practice, puts forward an advanced idea of preventive cognitive training in the acute stage, and has the highest effectiveness of reducing cognitive impairment, and Alzheimer’s disease. Show more

Keywords: Acute stage, Alzheimer’s disease, cognitive training, post-stroke cognitive impairment, preventive

DOI: 10.3233/ADR-230097

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1267-1275, 2023

Authors: Gharbi, Alya | Nasri, Amina | Sghaier, Ikram | Kacem, Imen | Mrabet, Saloua | Souissi, Amira | Ben Djebara, Mouna | Gargouri, Amina | Gouider, Riadh

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disease with various clinical symptoms. Limited data have described the clinical subtypes of DLB. Objective: We aimed to compare clinical subtypes of DLB according to initial symptoms and to study the effect of Apolipoprotein E (APOE ) gene in DLB. Methods: We included DLB patients classified into three groups based on initial symptoms: non-motor onset (cognitive and/or psychiatric) (NMO-DLB), motor onset (parkinsonism and/or gait disorders) (MO-DLB), and mixed onset (non-motor and motor symptoms) (MXO-DLB). Clinical and APOE genotype associations and survival were analyzed. …Results: A total of 268 patients were included (NMO-DLB = 75%, MXO-DLB = 15.3%, MO-DLB = 9.7%). Visual hallucinations were more frequent (p = 0.025), and attention was less commonly impaired in MXO-DLB (p = 0.047). When adjusting with APOE ɛ 4 status (APOE genotype performed in 155 patients), earlier falls and frontal lobe syndrome were more common in MXO-DLB (p = 0.044 and p = 0.023, respectively). The median MMSE decline was 2.1 points/year and the median FAB decline was 1.9 points/year, with no effect of clinical subtypes. Median survival was 6 years. It was similar in DLB subtypes (p = 0.62), but shorter for patients with memory symptoms at onset (p = 0.04) and for males (p = 0.0058). Conclusions: Our study revealed a few differences between DLB clinical subtypes. APOE ɛ 4 appears to be associated with earlier falls and a higher prevalence of frontal syndrome in MXO-DLB. However, DLB clinical subtypes did not impact on survival. Nevertheless, survival analysis identified other poor prognosis factors, notably inaugural memory impairment and male gender. Show more

Keywords: Alzheimer’s disease, dementia, genetic, Lewy bodies, survival

DOI: 10.3233/ADR-230064

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1277-1288, 2023

Authors: Zhu, Haohao | Lu, Rongrong | Zhou, Qin | Du, Zhiqiang | Jiang, Ying

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder whose etiology involves multiple genetic and environmental factors. Sphingomyelin (SM) is a type of sphingolipid found in cell membranes, and recent evidence suggests a potential link between SM and AD. However, the nature of this relationship remains unclear. Objective: To elucidate the potential causal relationship between SM levels and the risk of developing AD using a two-sample Mendelian randomization approach. Methods: The study utilized data extracted from the genome wide association study database. The primary analysis method was the inverse variance weighted (IVW) method, which was supplemented …by weighted median, weighted mode, and MR Egger methods. The study specifically investigated the bidirectional causal relationship between SM and AD, evaluating odds ratios (OR) with a 95% confidence interval (95% CI). Results: Elevated levels of SM were found to be a risk factor for AD, as shown by IVW(MRE) [OR: 1.001, 95% CI: 1.000 to 1.002; p  = 0.020 < 0.05], IVW(FE) [OR: 1.001, 95% CI: 1.001 to 1.002; p  = 3.36e-07 < 0.05], and MR Egger. Conversely, AD was demonstrated to lead to an increase in SM levels [IVW(MRE): OR: 5.64e+08, 95% CI: 1.69e+05 to 1.89e+12; p  = 1.14e-06 < 0.05], with consistent findings across the IVW(FE), MR Egger, weighted median, and weighted mode methods. Conclusions: The study establishes a bidirectional positive correlation between SM and AD. Increased SM levels are associated with a higher risk of developing AD, and the presence of AD can further elevate SM levels, potentially exacerbating the disease’s progression. Show more

Keywords: Alzheimer’s disease, bidirectional Mendelian randomization, genome-wide association study, relationship, sphingomyelin

DOI: 10.3233/ADR-230126

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1289-1297, 2023

Authors: van Gils, Veerle | Ramakers, Inez | Jansen, Willemijn J. | Banning, Leonie | Kučikienė, Domantė | Costa, Ana Sofia | Schulz, Jörg B. | Visser, Pieter Jelle | Verhey, Frans | Reetz, Kathrin | Vos, Stephanie J.B.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline. Objective: To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population. Methods: We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aβ42 using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive …functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions. Results: At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ – 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions. Conclusions: Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cardiovascular risk, cognitive decline, magnetic resonance imaging, vascular diseases

DOI: 10.3233/ADR-230040

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1299-1311, 2023

Authors: Feldner, Alyssa C. | Turner, Andrew K. | Simpson, James F. | Estus, Steven

Article Type: Research Article

Abstract: Background: Understanding the mechanisms whereby genetic variants influence the risk of Alzheimer’s disease (AD) may provide insights into treatments that could reduce AD risk. Objective: Here, we sought to test the hypothesis that a single nucleotide polymorphism (SNP) associated with AD risk, rs2070902, influences splicing of FCER1G exon 2. Methods: AD and non-AD brain samples were analyzed for FCER1G expression by genotyping, immunohistochemistry, immunofluorescence, and qPCR. Results: The protein encoded by FCER1G, FcRγ , is robustly expressed in microglia in both AD and non-AD brain. The FCER1G isoform lacking exon …2 (D2-FCER1G ) was readily detectable. Moreover, the proportion of FCER1G expressed as this isoform was increased in brains with high AD neuropathology. However, the proportion of FCER1G expressed as the D2-FCER1G isoform was not associated with rs2070902 genotype. Conclusions: In summary, the proportion of FCER1G expressed as the D2-FCER1G isoform is increased with AD neuropathology but is not associated with rs2070902. Show more

Keywords: Alzheimer’s disease, genetics, microglia, polymorphism, RNA splicing

DOI: 10.3233/ADR-230076

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1313-1322, 2023

Authors: Mudalige, Dinithi | Guan, Dylan X. | Ghahremani, Maryam | Ismail, Zahinoor

Article Type: Research Article

Abstract: Background: Clinical guidelines recommend incorporating non-cognitive markers like mild behavioral impairment (MBI) and sleep disturbance (SD) into dementia screening to improve detection. Objective: We investigated the longitudinal associations between MBI, SD, and incident dementia. Methods: Participant data were from the National Alzheimer’s Coordinating Center in the United States. MBI was derived from the Neuropsychiatric Inventory Questionnaire (NPI-Q) using a published algorithm. SD was determined using the NPI-Q nighttime behaviors item. Cox proportional hazard regressions with time-dependant variables for MBI, SD, and cognitive diagnosis were used to model associations between baseline 1) MBI and incident SD (n … = 11,277); 2) SD and incident MBI (n  = 10,535); 3) MBI with concurrent SD and incident dementia (n  = 13,544); and 4) MBI without concurrent SD and incident dementia (n  = 11,921). Models were adjusted for first-visit age, sex, education, cognitive diagnosis, race, and for multiple comparisons using the Benjamini-Hochberg method. Results: The rate of developing SD was 3.1-fold higher in older adults with MBI at baseline compared to those without MBI (95% CI: 2.8–3.3). The rate of developing MBI was 1.5-fold higher in older adults with baseline SD than those without SD (95% CI: 1.3–1.8). The rate of developing dementia was 2.2-fold greater in older adults with both MBI and SD, as opposed to SD alone (95% CI:1.9–2.6). Conclusions: There is a bidirectional relationship between MBI and SD. Older adults with SD develop dementia at higher rates when co-occurring with MBI. Future studies should explore the mechanisms underlying these relationships, and dementia screening may be improved by assessing for both MBI and SD. Show more

Keywords: Alzheimer’s disease, dementia, longitudinal studies, neurobehavioral manifestations, sleep disorders

DOI: 10.3233/ADR-230086

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1323-1334, 2023

Authors: Zainuddin, Muhammad-Safuan | Bhuvanendran, Saatheeyavaane | Radhakrishnan, Ammu K. | Azman, Adzzie-Shazleen

Article Type: Review Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized as rapid and progressive cognitive decline affecting 26 million people worldwide. Although immunotherapies are ideal, its clinical safety and effectiveness are controversial, hence, treatments are still reliant on symptomatic medications. Concurrently, the Streptomyces genus has attracted attention given its pharmaceutically beneficial secondary metabolites to treat neurodegenerative diseases. Objective: To present secondary metabolites from Streptomyces sp. with regulatory effects on proteins and identified prospective target proteins for AD treatment. Methods: Research articles published between 2010 and 2021 were collected from five databases and 83 …relevant research articles were identified. Post-screening, only 12 research articles on AD-related proteins were selected for further review. Bioinformatics analyses were performed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network, PANTHER Go-Slim classification system (PANTHER17.0), and Kyoto Encyclopedia of Genes and Genomes (KEGG) Mapper. Results: A total of 20 target proteins were identified from the 12 shortlisted articles. Amyloid-β, BACE1, Nrf-2, Beclin-1, and ATG5 were identified as the potential target proteins, given their role in initiating AD, mitigating neuroinflammation, and autophagy. Besides, 10 compounds from Streptomyces sp., including rapamycin, alborixin, enterocin, bonnevillamides D and E, caniferolide A, anhydroexfoliamycin, rhizolutin, streptocyclinone A and B, were identified to exhibit considerable regulatory effects on these target proteins. Conclusions: The review highlights several prospective target proteins that can be regulated through treatments with Streptomyces sp. compounds to prevent AD’s early stages and progression. Further identification of Streptomyces sp. compounds with potential anti-AD properties is recommended. Show more

Keywords: Alzheimer’s disease, amyloid-β , secondary metabolites, Streptomyces sp

DOI: 10.3233/ADR-230065

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1335-1350, 2023

Authors: Zhang, Hongwei | Liu, Da | Duan, Yuanyuan | Liu, Yan | Liu, Jianyu | Bai, Na | Zhou, Qiang | Xu, Zhiyao | Li, Linyan | Liu, Hua

Article Type: Systematic Review

Abstract: Background: The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer’s disease (AD) has been widely studied across populations; however, the results are inconsistent. Objective: This study aimed to evaluate the association of A2M gene with AD by the application of meta-analysis. Methods: Relevant studies were identified by comprehensive searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratio (OR) with corresponding 95% confidence intervals (CI) was calculated using a random-effects or fixed-effects model. The Cochran Q statistic and I2 …metric was used to evaluate heterogeneity, and Egger’s test and Funnel plot were used to assess publication bias. Results: A total of 62 studies were identified and included in the current meta-analysis. The G allele of rs226380 reduced AD risk (OR: 0.64, 95% CI: 0.47–0.87, pFDR = 0.012), but carrier with the TT genotype was more likely to develop AD in Asian populations (OR: 1.56, 95% CI: 1.12–2.19, pFDR = 0.0135). The V allele of the A2M-I/V (rs669) increased susceptibility to AD in female population (OR, 95% CI: 2.15, 1.38–3.35, pFDR = 0.0024); however, the II genotype could be a protective factor in these populations (OR, 95% CI: 0.43, 0.26–0.73, pFDR = 0.003). Sensitivity analyses confirmed the reliability of the original results. Conclusions: Existing evidence indicate that A2M single nucleotide polymorphisms (SNPs) may be associated with AD risk in sub-populations. Future studies with larger sample sizes will be necessary to confirm the results. Show more

Keywords: Alpha 2-macroglobulin, Alzheimer’s disease, A2M, meta-analysis, SNPs, systematic review

DOI: 10.3233/ADR-230131

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1351-1370, 2023

Authors: Tsapanou, Angeliki | Zoi, Panagiota | Kalligerou, Faidra | Blekou, Patra | Sakka, Paraskevi

Article Type: Short Communication

Abstract: What is the impact of long COVID-19 on people with mild cognitive impairment (MCI) or dementia? Self-reported questionnaire was used for the report of long COVID-19 symptoms. People with MCI or dementia or their caregivers regarding patients’ health were recruited COVID-19 throughout from the Athens Alzheimer’s Association. We included 72 participants. Thirty had the diagnosis of MCI and 39 had dementia. Most symptoms lasted for 3-4 weeks. The majority of patients reported having all the symptoms, with fatigue being the major disturbance. The diagnosis and the management of long COVID-19 symptoms requires a more holistic and comprehensive approach.

Keywords: Alzheimer’s disease, COVID-19, dementia, long COVID, mild cognitive impairment

DOI: 10.3233/ADR-230119

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1371-1375, 2023

Authors: Tsatali, Marianna | Angelidou, Ioanna Antigoni | Tsolaki, Magda | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: Measuring dementia knowledge can be a valuable tool for assessing the effectiveness of dementia awareness activities, identifying the potential benefits of dementia training programs, and breaking down common myths and stereotypes about dementia. Objective: To compare the psychometric properties of three widely used dementia knowledge tools, the Dementia Knowledge Assessment Tool 2 (DKAT2-G), the Dementia Knowledge Assessment Scale (DKAS-G), and the Knowledge in Dementia Scale (KIDE-G) in the Greek adult population. Methods: A convenience sample of 252 participants from the general population completed the survey online. Statistical analyses included Cronbach’s internal reliability, retest reliability, factor …analysis, concurrent and construct validity, and floor and ceiling effects. Results: The DKAS-G had the most appropriate reliability levels (Cronbach’s alpha  =  0.845; retest reliability  =  0.921), whereas the DKAT2-G had satisfactory indexes (Cronbach’s α = 0.760; retest reliability  =  0.630). The KIDE-G showed unsatisfactory reliability (Cronbach’s α = 0.419; retest reliability  =  0.619). Construct validity was confirmed for all questionnaires, showing that all of them detected participants with pre-existing knowledge of dementia. Confirmatory factor analysis revealed a four-factor model for the DKAS-G and proposed the removal of 5 items. Floor and ceiling effects were found for the DKAT2-G and the KIDE-G, mainly among those who had previously participated in dementia training. Conclusions: The DKAS-G was found to have the highest levels of reliability and validity. The results prove that the DKAS-G meets the requirements for measuring dementia knowledge and evaluating dementia training programs in health professionals, caregivers, and the general population. Show more

Keywords: Alzheimer’s disease, knowledge, reliability and validity, test-retest reliability, validation study

DOI: 10.3233/ADR-230161

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1377-1393, 2023

Authors: André, Séverine | Verteneuil, Sébastien | Ris, Laurence | Kahvecioglu, Zehra-Cagla | Nonclercq, Denis | De Winter, Julien | Vander Elst, Luce | Laurent, Sophie | Muller, Robert N. | Burtea, Carmen

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA2 -IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach. Objective: A cPLA2 -IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy. Methods: We targeted the cPLA2 -IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic …acid dosage [AA], cPLA2 -IVA cellular translocation) before being tested in vivo . We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA2 -IVA itself, the NMDA receptor, AβPP and tau by IHC after i.v. injection in APP/PS1 mice. Results: Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA2 -IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA2 -IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation. Conclusions: cPLA2 -IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, amyloid plaques, cytosolic phospholipase A2, peptides, phage display, tau protein

DOI: 10.3233/ADR-230075

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1395-1426, 2023

Authors: Goodman, Max J. | Li, Xin Ran | Livschitz, Jennifer | Huang, Chiang-Ching | Bendlin, Barbara B. | Granadillo, Elias D.

Article Type: Research Article

Abstract: Background: Physicians may soon be able to diagnose Alzheimer’s disease (AD) in its early stages using fluid biomarkers like amyloid. However, it is acknowledged that additional biomarkers need to be characterized which would facilitate earlier monitoring of AD pathogenesis. Objective: To determine if a potential novel inflammation biomarker for AD, symmetric dimethylarginine, has utility as a baseline serum biomarker for discriminating prodromal AD from cognitively unimpaired controls in comparison to cerebrospinal fluid amyloid-β42 (Aβ42 ). Methods: Data including demographics, magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography scans, Mini-Mental State Examination and Functional Activities Questionnaire scores, and …biomarker concentrations were obtained from the Alzheimer’s Disease Neuroimaging Initiative for a total of 146 prodromal AD participants and 108 cognitively unimpaired controls. Results: Aβ42 (p  = 0.65) and symmetric dimethylarginine (p  = 0.45) were unable to predict age-matched cognitively unimpaired controls and prodromal AD participants. Aβ42 was negatively associated with regional brain atrophy and hypometabolism as well as cognitive and functional decline in cognitively unimpaired control participants (p  < 0.05) that generally decreased in time. There were no significant associations between Aβ42 and symmetric dimethylarginine with imaging or neurocognitive biomarkers in prodromal AD patients. Conclusions: Correlations were smaller between Aβ42 and neuropathological biomarkers over time and were absent in prodromal AD participants, suggesting a plateau effect dependent on age and disease stage. Evidence supporting symmetric dimethylarginine as a novel biomarker for AD as a single measurement was not found. Show more

Keywords: Alzheimer’s disease, amyloid, biomarker, methylarginines, SDMA, serum markers

DOI: 10.3233/ADR-230054

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1427-1444, 2023

Authors: Balietti, Marta | Galeazzi, Roberta | Giacconi, Robertina | Santillo, Elpidio | Giuli, Cinzia

Article Type: Research Article

Abstract: Background: Elevated cortisol levels represent a risk factor for Alzheimer’s disease (AD), prompting treatments to lower hormone concentrations for preventive or therapeutic purposes. Objective: To assess the efficacy of a comprehensive intervention (CI) in modulating serum cortisol levels in patients with AD. Methods: CI consisted in a 2-month protocol involving cognitive stimulation, psychological support, lifestyle guidance, leisure activities, and socialization. AD subjects were randomly assigned to experimental (EG, n  = 45) and control (CG, n  = 45) groups. A wide range of sociodemographic, cognitive, psychosocial, and functional conditions were evaluated before, at the conclusion, and 24 months after …CI. Data about lifestyle and drug prescription were also recorded. Results: Baseline evaluations revealed that higher cortisol levels correlated with worse cognitive status (higher CDR and ADAS-Cog values and lower MMSE scores), increased depressive symptoms, and reduced physical and social engagement. Following CI, EG exhibited reduced cortisol levels, improved overall cognitive status, and enhanced verbal working memory and executive functions compared to CG. However, at the 24-month follow-up, EG displayed a rebound effect, characterized by elevated cortisol levels and cognitive decline compared to CG. Conclusions: These findings strengthen the adverse relationship between excessive cortisol and deficits in cognition/behavior in AD, demonstrate the short-term benefits of CI, and emphasize the potential long-term risks, which may be attributed to the fragile nature of the AD brain. Comprehensive interventions can yield positive results, but careful calibration of type and duration is necessary, considering disease progression and the potential need for re-administration. Show more

Keywords: Alzheimer’s disease, cognitive performance, comprehensive intervention, cortisol

DOI: 10.3233/ADR-230125

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1445-1453, 2023

Authors: Bonilla-Santos, Jasmin | González-Hernández, Alfredis | Cala-Martínez, Dorian Yisela | Gómez-Morales, Duván Fernando | Calceto-Garavito, Laura Natalia | Forero-Aldana, Arnulfo Eduardo | González-Montealegre, Rodrigo Alberto | Cardona Cumaco, Yeing Alexandra | Rojas-Bernal, Luz Angela | Zabaleta-Orozco, Mario Alberto | Parra, Mario Alfredo

Article Type: Research Article

Abstract: Background: Recent reports suggest that by 2050 there will be an increase of around 310% of cases affected by dementia in Latin American countries. A previous study in a Southern region reported one of the highest prevalences of dementia in Latin America. Objective: To investigate the prevalence of mild cognitive impairment associated with low education, rurality, and demographic characteristics. Methods: A cross-sectional study recruited a community-dwelling sample of 823 adults from rural and urban areas of two Southern provinces of Colombia from 2020–2022. Participants were assessed with a neuropsychological protocol validated in Colombia. To obtain general …and region-specific prevalence rates, age, sex, schooling, and socioeconomic level were considered and controlled for. Results: Most of the participants reported low education and socioeconomic level, the participation of women was higher. It was determined that the prevalence of mild cognitive impairment (MCI) was 53.6%, with 56.6% in the province of Caquetá followed by 51.9% in the province of Huila. The amnestic MCI represented 42.6%, the amnestic multi-domain was 39%, the non-amnestic 16.55%, and the non-amnestic multi-domain 1.81%. Our participants reported comorbidities such as diabetes and hypertension. We also observed a relationship between exposure to pesticides and MCI. Conclusions: We observed one of the highest prevalences of MCI in Latin America reported to date. Variables such as age, gender, and education proved risk factors for MCI in the explored regions. Our findings are very much in line with recent studies that highlight the influence of non-canonical risk factors of dementia in underrepresented countries from Latin America. Show more

Keywords: Alzheimer’s disease, epidemiology, mild cognitive impairment, pesticides, prevalence

DOI: 10.3233/ADR-230041

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1455-1464, 2023

Authors: Han, Sang-Won | Lee, Sang-Hwa | Kim, Jong Ho | Lee, Jae-Jun | Park, Young Ho | Kim, SangYun | Nho, Kwangsik | Sohn, Jong-Hee

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles in the brain. Emerging evidence has suggested potential interactions between the brain and periphery, particularly the liver, in regulating Aβ homeostasis. Objective: This study aimed to investigate the association of serum liver enzymes with brain amyloidopathy and cognitive performance in patients with complaints of cognitive decline. Methods: A total of 1,036 patients (mean age 74 years, 66.2% female) with subjective cognitive decline, mild cognitive impairment, AD dementia, and other neurodegenerative diseases were included using the Smart Clinical Data Warehouse. Amyloid positron emission …tomography (PET) imaging, comprehensive neuropsychological evaluations, and measurements of liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, and albumin, were assessed. After propensity score matching, logistic and linear regression analyses were used to investigate the associations between liver enzymes, amyloid status, and cognitive performance. Additionally, a machine learning approach was used to assess the classification performance of liver enzymes in predicting amyloid PET positivity. Results: Lower ALT levels and higher AST-to-ALT ratios were significantly associated with amyloid PET positivity and AD diagnosis. The AST-to-ALT ratio was also significantly associated with poor memory function. Machine learning analysis revealed that the classification performance of amyloid status (AUC = 0.642) for age, sex, and apolipoprotein E ɛ 4 carrier status significantly improved by 6.2% by integrating the AST-to-ALT ratio. Conclusions: These findings highlight the potential association of liver function on AD and its potential as a diagnostic and therapeutic implications. Show more

Keywords: Alzheimer’s disease, amyloid PET, cognition, liver enzymes, machine learning

DOI: 10.3233/ADR-230148

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1465-1474, 2023

Authors: Baldimtsi, Eleni | Mouzakidis, Christos | Karathanasi, Eleni Maria | Verykouki, Eleni | Hassandra, Mary | Galanis, Evangelos | Hatzigeorgiadis, Antonis | Goudas, Marios | Zikas, Paul | Evangelou, Giannis | Papagiannakis, George | Bellis, George | Kokkotis, Christos | Tsatalas, Themistoklis | Giakas, Giannis | Theodorakis, Yannis | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Virtual reality (VR) technology has become increasingly used for assessment and intervention in the neuroscience field. Objective: We aimed to investigate the effects of a VR Training System, named VRADA (VR Exercise App for Dementia and Alzheimer’s Patients), on the cognitive functioning of older people with mild cognitive impairment (MCI). Methods: In this intervention study, 122 older adults with MCI were randomly assigned to five groups (the VRADA group (n  = 28), a bike group (n  = 11), a physical exercise group (n  = 24), a mixed group (physical and cognitive exercise) (n  = 31), and a non-contact control …group (n  = 28). The VRADA group underwent 32 physical and cognitive training sessions, performed 2 or 3 times weekly for 12 weeks in the VR environment. All participants had detailed neuropsychological assessments before and after intervention. Results: A series of linear regression models revealed that the VRADA group showed improvement or no deterioration in cognitive decline in global cognitive function (MMSE), verbal memory (Rey Auditory Verbal Learning Test and WAIS forward test), and executive functions, mental flexibility (Trail Making Test B). Conclusions: This interventionstudy indicates that the VRADA system improves the cognitive function of elders with MCI. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, multi-component intervention, physical-cognitive training, virtual reality

DOI: 10.3233/ADR-230099

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1475-1490, 2023