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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Ururahy, Raul dos Reis | do Val, Marina Scott | Ciciliati, Aline Maria Macagnan | Leite, Renata Elaine Paraizo | Paes, Vitor Ribeiro | Rodrigues, Roberta Diehl | Grinberg, Lea Tenenholz | Pasqualucci, Carlos Augusto | Jacob Filho, Wilson | Suemoto, Claudia Kimie
Article Type: Research Article
Abstract: Background: The association of moderate and severe dementia with low body mass index (BMI) is well described, but weight decline seems to also occur in individuals with preclinical neuropathologies. Considering that up to one-fifth of individuals with normal cognition meet the criteria for a dementia-related neuropathological diagnosis, autopsy studies are key to detecting preclinical neurodegenerative and cerebrovascular diseases that could be underlying weight changes. Objective: We investigated the association between dementia-related brain lesions and BMI and evaluated whether the cognitive function was a mediator of this association. Methods: In 1,170 participants, sociodemographic data, clinical history, and …cognitive post-mortem evaluation were assessed with an informant. Neuropathological evaluation was performed in all cases. Linear regression models were used to investigate the association between neuropathological lesions (exposure variable) and BMI (outcome) adjusted for demographic, clinical, and cognitive variables in the whole sample, and in only those with normal cognition. Corrections for multiple comparisons were performed. In addition, a mediation analysis was performed to investigate the direct and indirect effects of cognitive abilities on the association between neuropathology and BMI. Results: Individuals with lower BMI had a higher burden of neuropathological lesions and poorer cognitive abilities. Only neurofibrillary tangles (NFT) and neuropathological comorbidity were associated with low BMI, while other neurodegenerative and cerebrovascular lesions were not. NFT were indirectly associated with BMI through cognitive abilities, and also directly, even in participants with normal cognition. Conclusions: Neurofibrillary tangles were directly associated with low BMI even in individuals with preclinical Alzheimer’s disease. Show more
Keywords: Alzheimer’s disease, autopsy, body mass index, dementia, mediation, neuropathology
DOI: 10.3233/JAD-231366
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Connolly, Evie Margaret | Mc Ardle, Ríona | Bimpong, Kweku Andrew Ampadu | Slight, Sarah
Article Type: Systematic Review
Abstract: Background: Dementia is a major cause of disability and dependency globally. Mild cognitive impairment (MCI) is considered an early indicator of developing dementia. There are growing efforts to detect and diagnose MCI earlier; consequently, we need to understand the perspectives of individuals and carers regarding the implications of an MCI diagnosis. Objective: To systematically review qualitative literature to understand the impact of a MCI diagnosis on both the individual and their carers, focusing on wellbeing, everyday behaviors, and healthcare utilization. Methods: Key search terms were input into five databases. Studies were included if they were peer-reviewed …qualitative research published in English that obtained perspectives of community-dwellers with MCI or carers and focused on either their wellbeing, everyday behaviors and/or healthcare utilization. The protocol was pre-registered on PROSPERO (CRD42021291995). Data was synthesized narratively. Results: Key findings from 15 eligible articles highlighted the negative impact of an MCI diagnosis on the wellbeing of both individuals and carers, due to stigma and limited understanding regarding diagnosis/prognosis. Changes in everyday behavior varied, particularly regarding motivation to engage with physical activity, hobbies and social opportunities. Both individuals and carers were sometimes dissatisfied with healthcare services; ineffective communication during clinical consolations highlighted as a reason for lack of trust in clinicians. Conclusions: Results indicate that an MCI diagnosis impacts both people with MCI and their carers across key facets of life. There is a critical need to effectively communicate the diagnosis and prognosis of MCI to support wellbeing and everyday activities and ensure trust in healthcare services. Show more
Keywords: Alzheimer’s disease, caregivers, cognitive dysfunction, early diagnosis, mild cognitive impairment, quality of life, systematic review
DOI: 10.3233/JAD-231466
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Huynh, Andrew Liem Hieu | Wang, Yihan | Ma, Liwei | Low, Yi Ling Clare | Chen, Weisi | Fowler, Christopher | Tan, Edwin C.K. | Masters, Colin L. | Jin, Liang | Pan, Yijun
Article Type: Research Article
Abstract: Background: Observational Alzheimer’s disease (AD) cohorts including the Australian, Biomarkers, Imaging and Lifestyle (AIBL) Study have enhanced our understanding of AD. The generalizability of findings from AIBL to the general population has yet to be studied. Objective: We aimed to compare characteristics of people with AD dementia in AIBL to 1) the general population of older Australians using pharmacological treatment for AD dementia, and to 2) the general population of older Australians who self-reported a diagnosis of dementia. Methods: Descriptive study comparing people aged 65 years of over (1) in AIBL that had a diagnosis of …AD dementia, (2) dispensed with pharmacological treatment for AD in Australia in 2021 linked to the Australian census in 2021 (refer to as PBS/census), (3) self-reported a diagnosis of dementia in the 2021 Australian census (refer to as dementia/census). Baseline characteristics included age, sex, highest education attainment, primary language, and medical co-morbidities. Results: Participants in AIBL were younger, had more years of education, and had a lower culturally and linguistically diverse (CALD) population compared to the PBS/census cohort and dementia/census cohort (mean age±standard deviation – AIBL 79±7 years, PBS/census 81±7, p < 0.001, dementia/census 83±8, p < 0.001; greater than 12 years of education AIBL 40%, PBS/census 35%, p = 0.020, dementia/census 29%, p < 0.001; CALD – AIBL 3%, PBS/census 20%, p < 0.001, dementia/census 22%, p < 0.001). Conclusions: Our findings suggest that care should be taken regarding the generalizability of AIBL in CALD populations and the interpretation of results on the natural history of AD. Show more
Keywords: Alzheimer’s disease, Australian Biomarkers imaging and lifestyle study, Australian census, culturally and linguistically diverse, dementia, generalizability
DOI: 10.3233/JAD-240241
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Oasa, Sho | Chen, Gefei | Schultzberg, Marianne | Terenius, Lars
Article Type: Research Article
Abstract: Background: Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer’s disease (AD). Aggregates are also recognized by microglia, which in early phases maybe protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aβ oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic. Objective: This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aβ peptide. Methods: The effects of the decoys (NSC 69318, NSC …100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aβ40 and Aβ42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aβ phagocytosis were analyzed. Results: NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aβ40 - and Aβ42 -induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aβ42 , and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aβ42 was not affected by anyone of the decoys. Conclusions: Our findings open the possibility that the molecular decoys of Aβ aggregation may block microglial activation by Aβ40 and Aβ42 in addition to blocking neurotoxicity as shown previously. Show more
Keywords: Alzheimer’s disease, amyloid-β, cytokine, inflammation, interleukin, tumor necrosis factor
DOI: 10.3233/JAD-231399
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Butler, Tracy | Tey, Sin-Ruow | Galvin, James E. | Perry, George | Bowen, Richard L. | Atwood, Craig S.
Article Type: Review Article
Abstract: The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer’s disease (AD), the major form of dementia in our society. In particular, the …elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD. Show more
Keywords: Alzheimer’s disease, amyloid-β , andropause, cell cycle, cognition, endocrine dyscrasia, 17β-estradiol, GnRH analogues, gonadotropins, hypothalamic-pituitary-gonadal axis, menopause, neurodegeneration, neuropathology, progesterone, tau
DOI: 10.3233/JAD-240334
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Zhu, Yongbin | Wu, Yueping | Shi, Liping | Yang, Yue | Wang, Yanrong | Pan, Degong | He, Shulan | Wang, Liqun | Li, Jiangping
Article Type: Research Article
Abstract: Background: The widespread exposure to plastic products and the increasing number of individuals with cognitive impairments have imposed a heavy burden on society. Objective: This study aims to investigate the relationship between plastic product exposure in daily life and cognitive function in older Chinese individuals. Methods: Data were obtained from the 2023 Ningxia Older Psychological Health Cohort, comprising 4045 participants aged 60 and above. Cognitive function was assessed using the Mini-Mental State Examination scale. A population-based plastic exposure questionnaire was used to calculate plastic exposure scores (PES). Binary logistic regression was employed to analyze the relationship …between PES and cognitive function, while restricted cubic splines were used to examine the dose-response relationship between PES and cognitive function. Latent profile analysis (LPA) was employed to explore the potential patterns of plastic exposure, and logistic regression was used to investigate the relationship between different exposure patterns and cognitive function. A linear regression model was utilized to investigate the relationship between PES and different dimensions of cognitive function. Results: Among the 4045 participants, 1915 individuals were assessed with mild cognitive impairment (MCI). After adjusting for all covariates, PES (OR = 1.04, 95% CI 1.02–1.06) was significantly associated with the risk of MCI and exhibited a dose-response relationship. LPA identified two potential categories of plastic exposure, with a higher risk of MCI observed in the group using plastic utensils. Conclusions: This study indicates a positive correlation between plastic exposure levels and MCI risk, particularly among individuals who frequently use plastic tableware. Show more
Keywords: Alzheimer’s disease, cognitive function, latent profile analysis, older adults, plastic exposure
DOI: 10.3233/JAD-240746
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Cardoso, Remy | Teunissen, Charlotte E. | Oliveira, Catarina Resende
Article Type: Article Commentary
Abstract: Biomarkers that accurately identify mild cognitive impairment (MCI) are of greater importance for Alzheimer’s disease (AD) management and treatment. On the other hand, blood-based biomarkers are not only more practical but also less invasive than the common cerebrospinal fluid biomarkers. In their report in the Journal of Alzheimer ’s Disease , Wang and collaborators identified 67 upregulated and 220 downregulated long noncoding RNAs (lncRNAs). They further demonstrated that 4 of these lncRNAs could discriminate MCI from cognitively healthy individuals. Apart from their significance as potential biomarkers for MCI diagnosis, these lncRNAs can offer additional information on the cellular mechanisms of …AD pathology. Show more
Keywords: Alzheimer’s disease, biomarkers, lncRNA, mild cognitive impairment, plasma
DOI: 10.3233/JAD-240724
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Guo, Hongxiu | Sun, Shangqi | Yang, Yang | Ma, Rong | Wang, Cailin | Zheng, Siyi | Wang, Xiufeng | Li, Gang
Article Type: Research Article
Abstract: Background: Identifying high-risk individuals with mild cognitive impairment (MCI) who are likely to progress to Alzheimer’s disease (AD) is crucial for early intervention. Objective: This study aimed to develop and validate a novel clinical score for personalized estimation of MCI-to-AD conversion. Methods: The data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study were analyzed. Two-thirds of the MCI patients were randomly assigned to a training cohort (n = 478), and the remaining one-third formed the validation cohort (n = 239). Multivariable logistic regression was performed to identify factors associated with MCI-to-AD progression within 4 years. A prediction score …was developed based on the regression coefficients derived from the logistic model and tested in the validation cohort. Results: A lipidomics-signature was obtained that showed a significant association with disease progression. The MCI conversion scoring system (ranged from 0 to 14 points), consisting of the lipidomics-signature and five other significant variables (Apolipoprotein ɛ 4, Rey Auditory Verbal Learning Test immediate and delayed recall, Alzheimer’s Disease Assessment Scale delayed recall test, Functional Activities Questionnaire, and cortical thickness of the AD signature), was constructed. Higher conversion scores were associated with a higher proportion of patients converting to AD. The scoring system demonstrated good discrimination and calibration in both the training cohort (AUC = 0.879, p of Hosmer-Lemeshow test = 0.597) and the validation cohort (AUC = 0.915, p of Hosmer-Lemeshow test = 0.991). The risk classification achieved excellent sensitivity (0.84) and specificity (0.75). Conclusions: The MCI-to-AD conversion score is a reliable tool for predicting the risk of disease progression in individuals with MCI. Show more
Keywords: Alzheimer’s disease, conversion score, individual prediction, lipid metabolism, noninvasive biomarkers, progression
DOI: 10.3233/JAD-240532
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Kostenko, Anna | Prezzavento, Orazio | de Leo, Gioacchino | D’Arco, David | Gulino, Rosario | Caccamo, Antonella | Leanza, Giampiero
Article Type: Research Article
Abstract: Background: Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1 R,2 S/1 S,2 R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(±)-PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction. Objective: In this study, we sought to assess the role of (±)-PPCC on working memory deficits caused by noradrenergic depletion. Methods: Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist …just prior to the beginning of each behavioral testing session. Results: While (±)-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation. Conclusions: Future studies are thus necessary to address the effects of long-lasting (±)-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer’s disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases. Show more
Keywords: Alzheimer’s disease, neurotransmitters, noradrenaline, sigma-1 agonist
DOI: 10.3233/JAD-240618
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: van de Schraaf, Sara A.J. | Rhodius-Meester, Hanneke F.M. | Rijnsent, Lindsey M. | Natawidjaja, Meyrina D. | van den Berg, Esther | Wolters, Frank J. | Visser-Meily, J.M. Anne | Biessels, Geert Jan | de Vugt, Marjolein | Muller, Majon | Hertogh, Cees M.P.M. | Sizoo, Eefje M.
Article Type: Research Article
Abstract: Background: Post-diagnostic care for people with vascular cognitive impairment (VCI) typically involves multiple professions and disjointed care pathways not specifically designed to aid VCI needs. Objective: Exploring perspectives of healthcare professionals on post-diagnostic care for people with VCI. Methods: We conducted a qualitative focus group study. We used purposive sampling to include healthcare professionals in different compositions of primary and secondary care professionals per focus group. Thematic saturation was reached after seven focus groups. Transcripts were iteratively coded and analyzed using inductive thematic analysis. Results: Forty participants were included in seven focus groups (4–8 …participants). Results showed knowledge and awareness of VCI as prerequisites for adequate post-diagnostic care, and for pre-diagnostic detection of people with VCI (theme 1). In light of perceived lack of differentiation between cognitive disorders, participants shared specific advice regarding post-diagnostic care for people with VCI and informal caregivers (theme 2). Participants thought current care for VCI was fragmented and recommended further integration of care and collaboration across settings (theme 3). Conclusions: People with VCI and their caregivers risk getting stuck in a “no man’s land” between post-diagnostic care pathways; challenges lie in acknowledgement of VCI and associated symptoms, and alignment between healthcare professionals. Education about the symptoms and consequences of VCI, to healthcare professionals, people with VCI and caregivers, may increase awareness of VCI and thereby better target care. Specific attention for symptoms common in VCI could further tailor care and reduce caregiver burden. Integration could be enhanced by combining expertise of dementia and stroke/rehabilitation pathways. Show more
Keywords: Aftercare, Alzheimer’s disease, cerebrovascular diseases, patient care management, post-stroke cognitive impairment, rehabilitation, vascular cognitive impairment, vascular dementia
DOI: 10.3233/JAD-240526
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Walsh, Michael | Uretsky, Madeline | Tripodis, Yorghos | Nowinski, Christopher J. | Rasch, Abigail | Bruce, Hannah | Ryder, Megan | Martin, Brett M. | Palmisano, Joseph N. | Katz, Douglas I. | Dwyer, Brigid | Daneshvar, Daniel H. | Walley, Alexander Y. | Kim, Theresa W. | Goldstein, Lee E. | Stern, Robert A. | Alvarez, Victor E. | Huber, Bertrand Russell | McKee, Ann C. | Stein, Thor D. | Mez, Jesse | Alosco, Michael L.
Article Type: Research Article
Abstract: Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy more frequently found in deceased former football players. CTE has heterogeneous clinical presentations with multifactorial causes. Previous literature has shown substance use (alcohol/drug) can contribute to Alzheimer’s disease and related tauopathies pathologically and clinically. Objective: To examine the association between substance use and clinical and neuropathological endpoints of CTE. Methods: Our sample included 429 deceased male football players. CTE was neuropathologically diagnosed. Informant interviews assessed features of substance use and history of treatment for substance use to define indicators: history of substance use treatment (yes vs no, …primary variable), alcohol severity, and drug severity. Outcomes included scales that were completed by informants to assess cognition (Cognitive Difficulties Scale, BRIEF-A Metacognition Index), mood (Geriatric Depression Scale-15), behavioral regulation (BRIEF-A Behavioral Regulation Index, Barratt Impulsiveness Scale-11), functional ability (Functional Activities Questionnaire), as well as CTE status and cumulative p-tau burden. Regression models tested associations between substance use indicators and outcomes. Results: Of the 429 football players (mean age = 62.07), 313 (73%) had autopsy confirmed CTE and 100 (23%) had substance use treatment history. Substance use treatment and alcohol/drug severity were associated with measures of behavioral regulation (FDR-p -values<0.05, Δ R2 = 0.04–0.18) and depression (FDR-p -values<0.05, Δ R2 = 0.02–0.05). Substance use indicators had minimal associations with cognitive scales, whereas p-tau burden was associated with all cognitive scales (p -values <0.05). Substance use treatment had no associations with neuropathological endpoints (FDR-p -values>0.05). Conclusions: Among deceased football players, substance use was common and associated with clinical symptoms. Show more
Keywords: Alcohol use, Alzheimer’s disease, chronic traumatic encephalopathy, dementia, repetitive head impacts, substance use, traumatic brain injury
DOI: 10.3233/JAD-240300
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2024
Authors: Bolshakov, Alexey P. | Gerasimov, Konstantin | Dobryakova, Yulia V.
Article Type: Review Article
Abstract: This review is an attempt to compile existing hypotheses on the mechanisms underlying the initiation and progression of Alzheimer’s disease (AD), starting from sensory impairments observed in AD and concluding with molecular events that are typically associated with the disease. These events include spreading of amyloid plaques and tangles of hyperphosphorylated tau and formation of Hirano and Biondi bodies as well as the development of oxidative stress. We have detailed the degenerative changes that occur in several neuronal populations, including the cholinergic neurons in the nucleus basalis of Meynert, the histaminergic neurons in the tuberomammillary nucleus, the serotonergic neurons in …the raphe nuclei, and the noradrenergic neurons in the locus coeruleus. Furthermore, we discuss the potential role of iron accumulation in the brains of subjects with AD in the disease progression which served as a basis for the idea that iron chelation in the brain may mitigate oxidative stress and decelerate disease development. We also draw attention to possible role of sympathetic system and, more specifically, noradrenergic neurons of the superior cervical ganglion in triggering of the disease. We also explore the alternative possibility of compensatory protective changes that may occur in these neurons to support cholinergic function in the forebrain of subjects with AD. Show more
Keywords: Alzheimer’s disease, amyloid, astrocytes, cholinergic neurons, noradrenergic neurons, neurodegeneration, oxidative stress, sympathetic system, tauopathy
DOI: 10.3233/JAD-240620
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2024
Authors: Zhao, Huimin | Yang, Changlin | Xing, Fangkai
Article Type: Research Article
Abstract: Background: The relationship between serum fatty acids and cognitive function has been the subject of extensive study. Objective: To analyze the relationship between serum fatty acids composition and cognitive function by NHANES database and multivariate Mendelian randomization (MR) analysis. Methods: A sub-cohort of 1,339 individuals with serum fatty acids and Digit Symbol Substitution Test (DSST) examinations from the 2011–2014 wave of the NHANES were analyzed using fully adjusted multiple linear regression models for associations between serum hydrolyzed fatty acid levels and cognitive function. Univariable and multivariable MR was used to analyze the correlation between 98 exposures …related to serum fatty acids and cognitive function. Results from different database sources were combined using meta-analysis. Results: The fully adjusted regression analysis showed that linoleic acid (LA), Omega 6, fatty acids (FAs), and LA/FAs were positively correlated with DSST. 27 exposures were included for univariate MR analysis. Ultimately, only 2 traits had IVW test p -values ranging between 0.0019 and 0.05, both of which were LA/FAs. The meta-analysis of univariate MR revealed that LA/FAs was positively associated with cognitive function (β: 0.040, 95% CI = 0.013–0.067, p = 0.0041). In multivariate MR analysis, after adjusting for education, ischemic stroke, and age, LA/FAs was positively independently associated with cognitive function (IVW β: 0.049, 95% CI = 0.021–0.077, p = 0.0006). The results of MVMR are well in line with the univariate results. Conclusions: Both the Cross-sectional observational analyses and MR-based studies supported a suggestive causal relationship between the serum ratio of Linoleic acid in fatty acids and cognitive function. Show more
Keywords: Alzheimer’s disease, cognitive function, fatty acids, linoleic acid, Mendelian randomization, NHANES
DOI: 10.3233/JAD-240715
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Liu, Shu | Maruff, Paul | Fedyashov, Victor | Masters, Colin L. | Goudey, Benjamin
Article Type: Research Article
Abstract: Background: Integrating scores from multiple cognitive tests into a single cognitive composite has been shown to improve sensitivity to detect AD-related cognitive impairment. However, existing composites have little sensitivity to amyloid-β status (Aβ +/–) in preclinical AD. Objective: Evaluate whether a data-driven approach for deriving cognitive composites can improve the sensitivity to detect Aβ status among cognitively unimpaired (CU) individuals compared to existing cognitive composites. Methods: Based on the data from the Anti-Amyloid Treatment in the Asymptomatic Alzheimer’s Disease (A4) study, a novel composite, the Data-driven Preclinical Alzheimer’s Cognitive Composite (D-PACC), was developed based on test …scores and response durations selected using a machine learning algorithm from the Cogstate Brief Battery (CBB). The D-PACC was then compared with conventional composites in the follow-up A4 visits and in individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Result: The D-PACC showed a comparable or significantly higher ability to discriminate Aβ status [median Cohen’s d = 0.172] than existing composites at the A4 baseline visit, with similar results at the second visit. The D-PACC demonstrated the most consistent sensitivity to Aβ status in both A4 and ADNI datasets. Conclusions: The D-PACC showed similar or improved sensitivity when screening for Aβ+ in CU populations compared to existing composites but with higher consistency across studies. Show more
Keywords: Alzheimer’s disease, amyloid-β peptides, machine learning, neuropsychological tests
DOI: 10.3233/JAD-231319
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Sato, Kenichiro | Niimi, Yoshiki | Ihara, Ryoko | Iwata, Atsushi | Iwatsubo, Takeshi
Article Type: Short Communication
Abstract: Anti-amyloid drugs for early Alzheimer’s disease, including lecanemab, are associated with adverse events (AEs), such as amyloid-related imaging abnormalities (ARIA)-edema/effusion (E), ARIA-hemorrhage, and infusion-related reactions, which can indicate allocated arms in clinical trials. Herein, we evaluated the predictive value of AEs using a meta-analysis to estimate their incidence and simulated positive predictive value (PPV). The PPV for ARIA-E was high (0.915), but that for ARIA hemorrhage was low (0.630). Infusion-related reactions had a high PPV of 0.910, but with a wide confidence interval. Our results suggest the need to ameliorate the unblinding effects of AEs, particularly ARIA-E in trials.
Keywords: Adverse event, Alzheimer’s disease, anti-amyloid drug, clinical trial, unblinding
DOI: 10.3233/JAD-240623
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2024
Authors: Schicktanz, Silke | Alpinar-Segawa, Zümrüt | Ulitsa, Natalie | Perry, Julia | Werner, Perla
Article Type: Review Article
Abstract: Biomarkers for predicting Alzheimer’s disease (AD) are advancing and their implementation in various healthcare systems is imminent. There is a need for ethical standards addressing information needs, socio-ethical concerns, and expectations of healthy and at-risk persons. We present an ethical approach that integrates different existing ethical frameworks and discussion of our empirical, cross-cultural findings in a multi-layered perspective by addressing three levels. The micro-level focuses on the communication between counseling professionals, persons at risk or in an early stage of dementia, and family members. The meso-level addresses interprofessional cooperation and exchange as a key element for best person-centered care. The …macro-level considers public health promotion, the media, and public-funded research. This approach allows to address key ethical concepts including beneficence, non-maleficence, autonomy, informational self-determination, empowerment, and justice. Our contribution specifically examines the ethical challenges associated with AD prediction by means of biomarkers, based on insights from a German-Israeli comparison, and promotes a transdisciplinary discussion across different healthcare contexts. We propose a reflection on three levels to go beyond the clinical counseling context and to consider the rapidly evolving field of biomarkers in the coming years. Our ethical-practical recommendations should not be considered final, but rather procedural and will require continuous adaptation regarding culturally varying practices, new algorithms, meta-analyses, and re-evaluation of established recommendations. Show more
Keywords: Alzheimer’s disease, communication, counseling, cross-cultural comparison, dementia, ethical recommendations, literacy, prediction
DOI: 10.3233/JAD-231137
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2024
Authors: Spencer, Felicity S.E. | Elsworthy, Richard J. | Breen, Leigh | Bishop, Jonathan | Morrissey, Sol | Aldred, Sarah
Article Type: Review Article
Abstract: Background: Modifiable (physical activity) and non-modifiable (sex and genotype) risk factors interact to affect Alzheimer’s disease (AD) risk. Further investigation is necessary to understand if these factors influence brain volume and cognition. Objective: The study aimed to assess the effect of physical activity, APOE genotype, and sex on AD risk, brain volume, and cognition. Methods: UK Biobank data from 2006 to 2023 was accessed. Physical activity was measured by accelerometers, and International Physical Activity Questionnaire. Outcomes were AD incidence; brain volume (ventricular cerebrospinal fluid and total brain); and cognition (executive function, memory, visuospatial ability, processing …speed, and reaction time). Logistic and linear regression models were conducted. Results: 69,060 participants met inclusion criteria (mean age: 62.28 years, SD: 7.84; 54.64% female). Higher self-reported (OR = 0.63, 95% CI [0.40, 1.00], p = 0.047) and accelerometer-assessed (OR = 0.96 [0.93, 0.98], p = 0.002) physical activity was associated with lower disease incidence. Smaller ventricular cerebrospinal fluid volume (β = – 65.43 [– 109.68, – 17.40], p = 0.007), and larger total brain volume (β = 4398.46 [165.11, 8631.82], p < 0.001) was associated with increased accelerometer-assessed and self-reported physical activity respectively. Both brain volume analyses were moderated by sex. Increased accelerometer-assessed physical activity levels were associated with faster reaction time (β = – 0.43 [– 0.68, – 0.18], p = 0.001); though poorer visuospatial ability (β = – 0.06 [– 0.09, – 0.03], p < 0.001), and executive function (β = 0.49 [0.31, 0.66], p < 0.001; β = 0.27 [0.10, 0.45], p = 0.002) was related to self-reported physical activity levels. Conclusions: Higher levels of physical activity reduce AD risk independently of non-modifiable risk factors. Moderation of sex on brain volume highlighted the importance of incorporating non-modifiable risk factors in analysis. Show more
Keywords: Alzheimer’s disease, apolipoprotein E4, brain, cognition, exercise, sex, UK Biobank
DOI: 10.3233/JAD-240269
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Hamedani, Mehrnaz | Caneva, Stefano | Mancardi, Gian Luigi | Alì, Paolo Alessandro | Fiaschi, Pietro | Massa, Federico | Schenone, Angelo | Pardini, Matteo
Article Type: Systematic Review
Abstract: Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder which primarily involves memory and cognitive functions. It is increasingly recognized that motor involvement is also a common and significant aspect of AD, contributing to functional decline and profoundly impacting quality of life. Motor impairment, either at early or later stages of cognitive disorders, can be considered as a proxy measure of cognitive impairment, and technological devices can provide objective measures for both diagnosis and prognosis purposes. However, compared to other neurodegenerative disorders, the use of technological tools in neurocognitive disorders, including AD, is still in its infancy. …Objective: This report aims to evaluate the role of technological devices in assessing motor involvement across the AD spectrum and in other dementing conditions, providing an overview of the existing devices that show promise in this area and exploring their clinical applications. Methods: The evaluation involves a review of the existing literature in the PubMed, Web of Science, Scopus, and Cochrane databases on the effectiveness of these technologies. 21 studies were identified and categorized as: wearable inertial sensors/IMU, console/kinect, gait analysis, tapping device, tablet/mobile, and computer. Results: We found several parameters, such as speed and stride length, that appear promising for detecting abnormal motor function in MCI or dementia. In addition, some studies have found correlations between these motor aspects and cognitive state. Conclusions: Clinical application of technological tools to assess motor function in people with cognitive impairments of a neurodegenerative nature, such as AD, may improve early detection and stratification of patients. Show more
Keywords: Alzheimer’s disease, cognitive impairment, dementia, mild cognitive impairment, motor function, sensors, technology assessment
DOI: 10.3233/JAD-240559
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2024
Authors: Sang, Xian-Zheng | Chen, Wen | Hou, Xiao-Xiang | Wang, Chun-Hui | Zhang, Dan-Feng | Hou, Li-Jun
Article Type: Review Article
Abstract: Background: Emerging evidence suggests the potential of hydroxymethylglutaryl-coenzyme A (HMG-CoA, statins) as a therapeutic option for dementia. Objective: The primary objective of this study is to assess the current state of research on statins use in dementia, with a focus on identifying pivotal questions within the field. Methods: A systemic search for publications on statin use in dementia between 2007 and 2023 was conducted, utilizing the Web of Science Core Collection. The scientific output was analyzed from various perspectives through VOSviewer, CiteSpace, and the bibliometrics website (https://bibliometric.com/ ). Results: 560 articles authored by 2,977 …individuals and 999 institutions across 58 countries were included, which were published in 295 periodicals and cited 21,176 references from 16,424 authors. The annual publication output remained steady, while the number of citations increased consistently. The U.S. and Mayo Clinic emerged as the most significant country and institution, respectively. B. McGuinness and D.L. Sparks were the most eminent authors. Journal of Alzheimer ’s Disease was the most influential journal. Three sets of keywords and the top 10 references were identified, suggesting pivotal questions within the field. Conclusions: While statins show promising potential as a treatment option for dementia, their use remains uncertain due to the reported short-term cognitive impairment events and questionable long-term protective effects against dementia. The pivotal question is to ascertain the association between statins and cognition. The mechanisms underlying the effects of statins on cognition are multifaceted. This study provides insights into the current status within the field of statin use in dementia. Show more
Keywords: Alzheimer’s disease, association, bibliometrics, dementia, hydroxymethylglutaryl-CoA reductase inhibitors, mechanism, statins, vascular dementia
DOI: 10.3233/JAD-240270
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-30, 2024
Authors: Vyhnalek, Martin | Laczó, Martina | Laczó, Jan
Article Type: Article Commentary
Abstract: Hippocampal dysfunction is associated with early clinical signs of Alzheimer’s disease (AD). Due to the limited availability or invasiveness of current biomarkers, the AD diagnosis is usually based on cognitive assessment and structural brain imaging. The recent study by Lalive and colleagues examined the specificity of brain morphometry for the AD diagnosis in a memory clinic cohort with hippocampal-type amnestic syndrome. The results indicate that memory deficits and hippocampal atrophy are similar in AD and non-AD patients, highlighting their low diagnostic specificity. These findings challenge the traditional AD diagnosis and underscore the need for biomarkers to differentiate specific neuropathological entities.
Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, cerebrospinal fluid, Lewy body dementia, limbic-predominant age-related TDP-43 encephalopathy, mild cognitive impairment, positron emission tomography, primary age-related tauopathy, subjective cognitive decline, suspected non-Alzheimer’s disease pathophysiology
DOI: 10.3233/JAD-240660
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Seligmann, Bruce | Camiolo, Salvatore | Hernandez, Monica | Yeakley, Joanne M. | Sahagian, Gregory | McComb, Joel
Article Type: Research Article
Abstract: Background: There is no molecular test for Alzheimer’s disease (AD) using self-collected samples, nor is there a definitive molecular test for AD. We demonstrate an accurate and potentially definitive TempO-Seq® gene expression test for AD using fingerstick blood spotted and dried on filter paper, a sample that can be collected in any doctor’s office or can be self-collected. Objective: Demonstrate the feasibility of developing an accurate test for the classification of persons with AD from a minimally invasive sample of fingerstick blood spotted on filter paper which can be obtained in any doctor’s office or self-collected to …address health disparities. Methods: Fingerstick blood samples from patients clinically diagnosed with AD, Parkinson’s disease (PD), or asymptomatic controls were spotted onto filter paper in the doctor’s office, dried, and shipped to BioSpyder for testing. Three independent patient cohorts were used for training/retraining and testing/retesting AD and PD classification algorithms. Results: After initially identifying a 770 gene classification signature, a minimum set of 68 genes was identified providing classification test areas under the ROC curve of 0.9 for classifying patients as having AD, and 0.94 for classifying patients as having PD. Conclusions: These data demonstrate the potential to develop a screening and/or definitive, minimally invasive, molecular diagnostic test for AD and PD using dried fingerstick blood spot samples that are collected in a doctor’s office or clinic, or self-collected, and thus, can address health disparities. Whether the test can classify patients with AD earlier then possible with cognitive testing remains to be determined. Show more
Keywords: Alzheimer’s disease, dementia, diagnostic classifier, fingerstick blood, gene expression signature, health disparity, Parkinson’s disease, self-test, TempO-seq, whole blood
DOI: 10.3233/JAD-240174
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Wang, Tao | Yan, Shaozhen | Shan, Yi | Xing, Yi | Bi, Sheng | Chen, Zhigeng | Xi, Hanyu | Xue, Hanxiao | Qi, Zhigang | Tang, Yi | Lu, Jie
Article Type: Research Article
Abstract: Background: Transcranial alternating current stimulation (tACS) could improve cognition in patients with Alzheimer’s disease (AD). However, the effects of tACS on brain activity remain unclear. Objective: The purpose is to investigate the change in regional neuronal activity after tACS in AD patients employing resting-state functional magnetic resonance imaging (rs-fMRI). Methods: A total of 46 patients with mild AD were enrolled. Each patient received 30 one-hour sessions of real or sham tACS for three weeks (clinical trial: NCT03920826). The fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) measured by rs-fMRI were calculated to evaluate …the regional brain activity. Results: Compared to baseline, AD patients in the real group exhibited increased fALFF in the left middle frontal gyrus-orbital part and right inferior frontal gyrus-orbital part, as well as increased ReHo in the left precentral gyrus and right middle frontal gyrus at the end of intervention. At the 3-month follow-up, fALFF increased in the left superior parietal lobule and right inferior temporal gyrus, as well as ReHo, in the left middle frontal gyrus and right superior medial frontal gyrus. A higher fALFF in the right lingual gyrus and ReHo in the right parahippocampal gyrus were observed in the response group than in the nonresponse group. Conclusions: The findings demonstrated the beneficial effects of tACS on the neuronal activity of the prefrontal cortex and even more extensive regions and provided a neuroimaging biomarker of treatment response in AD patients. Show more
Keywords: Alzheimer’s disease, functional magnetic resonance imaging, transcranial alternating current stimulation
DOI: 10.3233/JAD-240400
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Wang, Qiuchen | Fu, Mengjie | Gao, Lihui | Yuan, Xin | Wang, Ju
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that is the most common form of dementia in the elderly. The drugs currently used to treat AD only have limited effects and are not able to cure the disease. Drug repositioning has increasingly become a promising approach to find potential drugs for diseases like AD. Objective: To screen potential drug candidates for AD based on the relationship between risk genes of AD and drugs. Methods: We collected the risk genes of AD and retrieved the information of known drugs from DrugBank. Then, the AD-related genes and the …targets of each drug were mapped to the human protein-protein interaction network (PPIN) to represent AD and the drugs on the network. The network distances between each drug and AD were calculated to screen the drugs proximal to AD-related genes on PPIN, and the screened drug candidates were further analyzed by molecular docking and molecular dynamics simulations. Results: We compiled a list of 714 genes associated with AD. From 5,833 drugs used for human diseases, we identified 1,044 drugs that could be potentially used to treat AD. Then, amyloid-β (Aβ) protein, the key molecule involved in the pathogenesis of AD was selected as the target to further screen drugs that may inhibit Aβ aggregation by molecular docking. We found that ergotamine and RAF-265 could bind stably with Aβ. In further analysis by molecular dynamics simulations, both drugs exhibited reasonable stability. Conclusions: Our work indicated that ergotamine and RAF-265 may be potential candidates for treating AD. Show more
Keywords: Alzheimer’s disease, drug repositioning, ergotamine, molecular docking, risk genes
DOI: 10.3233/JAD-240235
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Kitagawa, Kazuo | Toi, Sono | Hosoya, Megumi | Seki, Misa | Yamagishi, Sae | Hoshino, Takao | Yoshizawa, Hiroshi
Article Type: Research Article
Abstract: Background: Total small vessel disease (SVD) score is used to measure the burden of SVD. Objective: This study aimed to clarify the predictive value of total SVD score for incident dementia and functional outcomes in independent outpatients with vascular risk factors. Methods: We derived data from a Japanese cohort in which patients underwent magnetic resonance imaging and cognitive examinations. They were followed up until March 2023. The primary outcomes was dementia. Secondary outcome was functional outcomes. We measured a modified Rankin scale (mRS) score at the last visit and defined poor functional outcomes as mRS score …≥3. Results: After excluding those with a mRS score ≥2, Mini-Mental State Examination score in Japanese version < 24, and missing T2* images, 692 patients were included. During a median follow-up period of 4.6 years, dementia occurred in 31 patients. In multivariate analysis, the score 4 group showed a significantly higher risk of incident dementia than the score 0–3 groups (adjusted hazard ratio, 6.25; 95% CI, 1.83–21.40, p = 0.003). The total SVD score was also independently related to poor functional outcome. Conclusions: The total SVD score of 4, and ≥1 could predict dementia and poor functional outcomes, respectively. Our results suggest intensive management of patients with SVD to prevent dementia and to maintain independent activities of daily living. Show more
Keywords: Alzheimer’s disease, dementia, functional outcome, small vessel disease score
DOI: 10.3233/JAD-240166
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Verdelho, Ana | Correia, Manuel | Gonçalves-Pereira, Manuel | Madureira, Sofia | Vilela, Pedro | Santos, Ana Catarina | Rodrigues, Mário | Borges, Mariana | Ferro, José M. | Santa-Clara, Helena
Article Type: Research Article
Abstract: Background: Vascular cognitive impairment is frequent, in mild (mVCI) or severe forms (vascular dementia). Objective: To do a randomized controlled-trial to evaluate the impact of physical activity on cognition (primary outcome), neurocognitive measures, quality of life, functional status, and physical function (secondary outcomes), in patients with mVCI. Methods: A hundred and four patients with mVCI (mean age 71.2 years; 53 women) were randomized for a six-month intervention of moderate physical activity (60-minute sessions, 3 times/week) (n = 53) or best-practice “usual care” (n = 51). Comprehensive evaluations of primary and secondary outcomes included an objective measure of physical …activity through accelerometry at baseline and after intervention. Results: Mean session attendance was 58%. Adverse events were negligible. After 6 months, no significant primary outcome change was observed, either in the intervention or ‘usual care’ group. The intervention group improved significantly in some secondary outcomes in physical function - aerobic capacity (U = 403; p = 0.000) and agility (U = 453; p = 0.005) after 6 months. Regardless of randomization arm, a post-hoc analysis based on fulfilling at least 21.5 minutes/day of moderate or 10.7 minutes/day of vigorous physical activity (World Health Organization-WHO standards) revealed improvements. These were not only in motor capacity but also on the global measure of cognition, executive functions and memory. Conclusions: Physical activity was safe and beneficial regarding domains of physical function. No significant cognitive decline was registered over 6-months, regardless of intervention allocation. Larger samples, longer follow-ups and focus on intervention adherence are needed to fully analyze the impact of WHO recommendations for physical activity in mVCI populations. Show more
Keywords: Alzheimer’s disease, intervention, non-Alzheimer’s disease neurocognitive disorder, physical activity, prevention, vascular cognitive impairment
DOI: 10.3233/JAD-240246
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Babulal, Ganesh M. | Zha, Wenqing | Trani, Jean-Francois | Guerra, Jorge Llibre | Tee, Boon Lead | Zhu, Yiqi | Chen, Yaohua | Chen, Ling | Bubu, Michael | Josephy-Hernandez, Sylvia | Wandera, Stephen | Karanja, Wambūi | Ellajosyula, Ratnavalli | Caramelli, Paulo
Article Type: Research Article
Abstract: Background: The significant increase in Alzheimer’s disease and related dementia prevalence is a global health crisis, acutely impacting low- and lower-middle and upper-middle-income countries (LLMICs/UMICs). Objective: The objective of this study is to identify key barriers and gaps in dementia care and research in LLMICs and UMICs. Methods: We conducted an international, cross-sectional survey among clinicians and healthcare professionals (n = 249 in 34 countries) across LLMICs and UMICs, exploring patient demographics, use of clinical diagnosis, dementia evaluation, screening/evaluation tools, and care and treatment. Results: Significant disparities were found in diagnostic practices, access to assessments, …and access to care. On average, clinicians in LLMICs saw more patients, had less time for evaluations, lower use of formal screening and tools, and less access to biomarkers. They were also under-resourced compared to UMICs. Conclusions: The findings provide insights for policymakers, healthcare organizations, and researchers to address the complex challenges associated with dementia care in diverse settings. Addressing these challenges requires a multipronged approach involving local, national, and international stakeholders. Show more
Keywords: Alzheimer’s disease, dementia, disparity, low and middle-income countries, resources, underserved
DOI: 10.3233/JAD-240650
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Park, Jiae | Oh, Jung-Pyo | Ku, Kyojin | Jin, Yeonsun | Kim, Eun Jung | Lee, Ji-Hyun
Article Type: Research Article
Abstract: Background: Drug-induced adverse symptoms affect patients’ quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer’s disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL. Objective: Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and …investigate the underlying mechanisms. Methods: Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes. Results: High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2 + ]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2 + ]i levels in muscle cells. Conclusions: Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2 + ]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients. Show more
Keywords: Acetylcysteine, adverse effects, Alzheimer’s disease, donepezil
DOI: 10.3233/JAD-240709
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Wang, Jiayu | Xu, Lisi | Chen, Xuemei | Wu, Jiajing | Chen, Yu | Feng, Ziqian | Dong, Li | Yao, Dezhong | Cai, Qingyan | Jian, Wei | Li, Hongyi | Duan, MingJun | Wang, Ziqi
Article Type: Research Article
Abstract: Background: Apolipoproteins and cortical morphology are closely associated with memory complaints, and both may contribute to the development of Alzheimer’s disease. Objective: To examine whether apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA1), and their ratio (ApoB/ApoA1) are associated with cortical morphology in patients with memory complaints. Methods: Ninety-seven patients underwent neuropsychological testing, measurements of ApoB, ApoA1, ApoB/ApoA1, plasma Alzheimer’s biomarker, apolipoprotein E (ApoE) genotyping, and 3T structural magnetic resonance imaging (sMRI) scans. Based on sMRI scanning locations, patients were categorized into the University of Electronic Science and Technology (UESTC) and the Fourth People’s Hospital of Chengdu (FPHC). …The Computational Anatomy Toolbox within Statistical Parametric Mapping was used to calculate each patient’s cortical morphology index based on sMRI data. The cortical morphology index and apolipoproteins were also analyzed. Results: Significant positive correlations were found between ApoB and sulcal depth in the lateral occipital cortex among the UESTC, the FPHC, and the total sample groups, and negative correlations were observed between sulcal depth in the lateral occipital cortex and the scores of the Shape Trails Test Part A and B. In the FPHC group, the scores of the Montreal Cognitive Assessment Basic, delayed recall of the Auditory Verbal Learning Test, Animal Fluency Test and Boston Naming Test were positively correlated with the sulcal depth. Conclusions: ApoB is associated with the sulcal depth in the lateral occipital cortex, potentially relating to speed/executive function in individuals with memory complaints. Show more
Keywords: Alzheimer’s disease, ApoB, lateral occipital cortex, memory complaints, sulcal depth
DOI: 10.3233/JAD-230863
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Allé, Mélissa C. | Joseph, Christelle | Antoine, Pascal
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is characterized by severe memory alterations, affecting especially memories of personal past events. Until now, autobiographical memory impairments have been characterized using formal memory assessments, requiring patients to strategically and deliberately recall past events. However, contrary to this highly cognitively demanding mode of memory recall, autobiographical memories frequently come to mind unexpectedly based on automatic associative processes. The involuntary recall of personal memories is effortless and possibly represents a preserved way for AD patients to remember past events. Objective: This study aimed to investigate involuntary autobiographical memory in AD patients and compare the characteristics …of these memories with those of healthy controls. Methods: Involuntary autobiographical memory was measured in 24 AD patients and 24 matched control participants using self-report measures. Participants were asked to report the frequency with which involuntary autobiographical memories were experienced in their daily life and to describe and self-assess one example of an involuntary memory. Results: We showed that AD patients and control participants did not differ in terms of the frequency or subjective characteristics of their involuntary autobiographical memories in daily life, except for feelings of intrusiveness. Compared to control participants, AD patients reported their involuntary autobiographical memories as being more intrusive. In addition, more negative and vague involuntary autobiographical memories were associated with greater depressive symptoms. Conclusions: These findings open up a new avenue for research to better understand the extent to which involuntary autobiographical memory might be preserved in AD patients and why these memories may in turn become intrusive to patients. Show more
Keywords: Alzheimer’s disease, autobiographical memory, intrusiveness, involuntary retrieval
DOI: 10.3233/JAD-240180
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Beckmann, Matthew N.
Article Type: Research Article
Abstract: Background: When Ronald Reagan revealed his Alzheimer’s diagnosis in 1994, it rekindled a lingering question: did dementia affect Reagan during his eight years as president? Amid countless countervailing anecdotes, Berisha et al. (2015) stepped in with an inventive systematic test. Scouring Ronald Reagan’s 46 formal press conferences for specific linguistic markers, the study discovered “significant differences in variables known to be associated with the onset of dementia” (962). Objective: Here I test whether Reagan’s unique word usage rate decline is spurious, a function of reporters’ increasing penchant for asking “follow-up” questions. Methods: Focusing on the …President’s specific responses to distinct questions, I reanalyze Reagan’s unique word usage rate while holding constant the number and type of reporter questions. Results: I find Reagan’s unique word usage rate held form throughout his eight years in the White House. Conclusions: I conclude by considering the implications for Reagan’s legacy and Alzheimer’s research. Show more
Keywords: Alzheimer’s disease, early diagnosis, natural language processing, research methodology
DOI: 10.3233/JAD-240294
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2024
Authors: Abi-Ghanem, Charly | Salinero, Abigail E. | Smith, Rachel M. | Kelly, Richard D. | Belanger, Kasey M. | Richard, Riane N. | Paul, Aaron S. | Herzog, Ava A. | Thrasher, Christina A. | Rybka, Krystyna A. | Riccio, David | Gannon, Olivia J. | Kordit, David | Kyaw, Nyi-Rein | Mansour, Febronia M. | Groom, Emily | Brooks, Heddwen L. | Robison, Lisa S. | Pumiglia, Kevin | Zuloaga, Damian G. | Zuloaga, Kristen L.
Article Type: Research Article
Abstract: Background: About two-thirds of those with Alzheimer’s disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. Objective: Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause. Methods: First, 3-month-old AppNL-F and WT female …mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure. Results: Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance. Conclusions: This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD. Show more
Keywords: Alzheimer’s disease, glucose metabolism, hypothalamus, menopause, metabolic disease, obesity
DOI: 10.3233/JAD-231332
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Mattke, Soeren | Tang, Yu | Hanson, Mark | von Arnim, Christine A.F. | Frölich, Lutz | Grimmer, Timo | Onur, Oezguer A. | Perneczky, Robert | Teipel, Stefan | Thyrian, Jochen René
Article Type: Research Article
Abstract: Background: Amyloid-targeting therapies for Alzheimer’s disease (AD) might become available in Germany soon. The combination of a large pool of prevalent cases and a complex diagnostic process to determine eligibility for these treatments is likely to challenge health systems’ capacity. Objective: To analyze Germany’s healthcare system capacity to identify treatment-eligible patients in a timely and equitable manner. Methods: We modeled patients’ diagnostic journey and projects wait times due to capacity constraints for AD specialist visits and PET scans from 2024 to 2043. Model parameters were derived from published data and expert input. Results: Wait …times would be ∼50 months over the model horizon, if patients were referred to specialists based on a brief cognitive assessment in primary care. Wait times for patients with social health insurance are projected to be 1.9 times those of patients with private insurance, with peak wait times of around 76 and 40 months, respectively. Adding a blood test for the AD pathology as additional triage step would reduce wait times to below 24 months. Conclusions: In spite of having a well-resourced health system, Germany is projected to be unable to cope with the demand for biomarker-based AD diagnosis, if a disease-modifying AD treatment were introduced. As these treatments might become available by the end of 2024, decisive action, in particular dissemination of high-performing AD blood tests for triage in primary care, will be needed to prevent delays in access and potentially avoidable and inequitable disease progression. Show more
Keywords: Alzheimer’s disease, biomarker, disease-modifying treatment, health system preparedness, specialty care, diagnosis, wait times
DOI: 10.3233/JAD-240728
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Utyro, Olga | Włoczkowska-Łapińska, Olga | Jakubowski, Hieronim
Article Type: Research Article
Abstract: Background: Glyoxalase domain containing protein 4 (GLOD4), a protein of an unknown function, is associated with Alzheimer’s disease (AD). Three GLOD4 isoforms are known. The mechanism underlying GLOD4’s association with AD was unknown. Objective: To assess GLOD4’s role in the central nervous system by studying GLOD4 isoforms expression in human frontal cerebral cortical tissues from AD patients and in brains of Blmh –/– 5xFAD mouse AD model of AD. Methods: GLOD4 protein and mRNA were quantified in human and mouse brains by western blotting and RT-qPCR, respectively. Mouse brain amyloid-β (Aβ) was quantified by western blotting. …Behavioral assessments of mice were performed by cognitive/neuromotor testing. Glod4 gene in mouse neuroblastoma N2a-APPswe cells was silenced by RNA interference and Glod4 protein/mRNA, Aβ precursor protein (Aβpp)/mRNA, Atg5 , p62 , and Lc3 mRNAs were quantified. Results: GLOD4 mRNA and protein isoforms were downregulated in cortical tissues from AD patients compared to non-AD controls. Glod4 mRNA was downregulated in brains of Blmh –/– 5xFAD mice compared to Blmh +/+ 5xFAD sibling controls, but not in Blmh –/– mice without the 5xFAD transgene compared to Blmh +/+ sibling controls. The 5xFAD transgene downregulated Glod4 mRNA in Blmh –/– mice of both sexes and in Blmh +/+ males but not females. Attenuated Glod4 was associated with elevated Aβ and worsened memory/sensorimotor performance in Blmh –/– 5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated AβPP, and downregulated autophagy-related Atg5 , p62 , and Lc3 genes. Conclusions: These findings suggest that GLOD4 interacts with AβPP and the autophagy pathway, and that disruption of these interactions leads to Aβ accumulation and cognitive/neurosensory deficits. Show more
Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, autophagy, bleomycin hydrolase, Blmh–/–5xFAD mouse, GLOD4, N2a-APPswe mouse neuroblastoma cells
DOI: 10.3233/JAD-240512
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Rajamaki, Blair | Braithwaite, Billy | Hartikainen, Sirpa | Tolppanen, Anna-Maija
Article Type: Research Article
Abstract: Background: Multimorbidity is common in older adults and complicates diagnosing and care for this population. Objective: We investigated co-occurrence patterns (clustering) of medical conditions in persons with Alzheimer’s disease (AD) and their matched controls. Methods: The register-based Medication use and Alzheimer’s disease study (MEDALZ) includes 70,718 community-dwelling persons with incident AD diagnosed during 2005-2011 in Finland and a matched comparison cohort. Latent Dirichlet Allocation was used to cluster the comorbidities (ICD-10 diagnosis codes). Modeling was performed separately for AD and control cohorts. We experimented with different numbers of clusters (also known as topics in the field …of Natural Language Processing) ranging from five to 20. Results: In both cohorts, 17 of the 20 most frequent diagnoses were the same. Based on a qualitative assessment by medical experts, the cluster patterns were not affected by the number of clusters, but the best interpretability was observed in the 10-cluster model. Quantitative assessment of the optimal number of clusters by log-likelihood estimate did not imply a specific optimal number of clusters. Multidimensional scaling visualized the variability in cluster size and (dis)similarity between the clusters with more overlapping of clusters and variation in group size seen in the AD cohort. Conclusions: Early signs and symptoms of AD were more commonly clustered together in the AD cohort than in the comparison cohort. This study experimented with using natural language processing techniques for clustering patterns from an epidemiological study. From the computed clusters, it was possible to qualitatively identify multimorbidity that differentiates AD cases and controls. Show more
Keywords: Alzheimer’s disease, ICD-10 codes, latent Dirichlet allocation, natural language processing, register-based studies, topic modeling
DOI: 10.3233/JAD-240490
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Veronelli, Laura | Daini, Roberta | Mannino, Alice | Rossetti, Alessia | Gilardone, Giulia | Corbo, Massimo | Primativo, Silvia
Article Type: Research Article
Abstract: Background: Visuo-perceptual and visuo-attentional disorders, such as global processing deficit and simultanagnosia, are not routinely investigated in prodromal forms of typical Alzheimer’s disease, as amnestic mild cognitive impairment (MCI). Objective: This study evaluated global processing abilities through Navon’s classical paradigm in individuals with amnestic MCI and investigated the related visuo-perceptual and attentional components involved in simultanagnosia. Methods: Sixteen consecutive patients with amnestic MCI (6 single-domain, 10 multiple-domain) and 16 matched controls were requested to identify global and local elements of hierarchical Navon letters, and to name large and small solid letters. Results: While correctly …identifying solid letters, patients with multiple-domain amnestic MCI were less accurate in processing the global level of hierarchical stimuli compared to controls. Single-case analyses suggested that global processing may also be impaired in single-domain amnestic MCI. In addition, patients with pathological performance in the Navon task showed perceptual and/or visual focal attention deficits. Conclusions: Early dysfunction of holistic processing can be detected in amnestic MCI. Visuo-perceptual and/or visual focal attention mechanisms, which have been shown to be damaged in Posterior Cortical Atrophy patients with simultanagnosia, may be impaired in individuals with amnestic MCI. Investigation and identification of global processing deficits in MCI could contribute to early diagnosis and longitudinal monitoring of the disease. Show more
Keywords: Alzheimer’s disease, focal attention, global processing deficits, mild cognitive impairment, Navon, simultanagnosia, visuo-perceptual processing
DOI: 10.3233/JAD-240375
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Méndez-Barrio, Carlota | Medina-Rodríguez, Manuel | Mendoza-Vázquez, Gonzalo | García-Roldán, Ernesto | Rodrigo-Herrero, Silvia | Luque-Tirado, Andrea | Almodóvar-Sierra, Ángela | Franco-Macías, Emilio
Article Type: Research Article
Abstract: Background: Predicting which patients with prodromal AD (pAD) will imminently convert to dementia may be paramount in a memory clinical setting, especially with potential disease-modifying therapies on the horizon. Objective: To explore a practical tool for this prediction, combining cognitive tests and cerebrospinal fluid (CSF) biomarkers. Methods: We designed a longitudinal prospective, observational, and multicenter study, enrolling patients with pAD. Inclusion criteria comprised memory complaints, Mini-Mental State Examination (MMSE) score of≥22, memory impairment as indicated by the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) and/or TMA-93, Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, …and positive CSF Aβ 42 /Aβ 40 ratio (<0.095, Euroimmun). The primary outcome was the conversion to dementia (CDR-GS≥1) within the first year of follow-up, referred to as “short-term conversion”. A multiple regression logistic model was adopted to design the “Predict Short-Term Conversion” (PSTC) score. Results: Between 2020 and 2022, 83 patients were recruited. The median age was 74, with 49.4% being women. Twenty-five (30.1%) patients were classified as short-term converters. The PSTC score incorporated baseline scores on MMSE (≤24 = 3, >24 = 0) and FCSRT + IR Total Recall (≤14 = 4, >14 = 0), and CSF neurofilament light chains (NfLs) concentrations (β =0.001299). The PSTC score demonstrated an area under the curve of 0.79 (95% CI: 0.71–0.91, p < 0.0001), with a cutoff value of 5.14 presenting 76% sensitivity and 80% specificity. Conclusions: The PSTC score, comprising two relatively brief cognitive test scores and NfLs CSF concentrations, could be useful for predicting short-term converters among patients diagnosed with pAD. Show more
Keywords: Alzheimer’s disease, conversion to dementia, Free and Cued Selective Reminding Test, global cognition, Mini-Mental State Examination, neurofilament light chains
DOI: 10.3233/JAD-240689
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Zhang, Xiaohong | Wang, Mingzhen | Chen, Kaiyue | Shi, Na | Cui, Xia | Yang, Zhicheng | Chen, Feifei | Lin, Xingfeng
Article Type: Research Article
Abstract: Background: Alzheimer’s disease and related dementias (ADRD) are progressive conditions. Family caregivers of patients, especially those caring for patients with ADRD exhibiting behavioral and psychological symptoms of dementia (BPSD), undergo significant physical and mental changes during long-term care. While most researchers have focused on the specific needs of family caregivers, the comprehensive understanding of these needs is limited. In this study, Alderfer’s existence, relatedness, and growth theory was used to develop an interview framework to systematically and comprehensively understand the needs of family caregivers of individuals with ADRD. Objective: The objective of this study was to understand family …caregivers’ needs in coping with BPSD in individuals with ADRD, aiming to alleviate caregivers’ stress and promote their overall well-being. Methods: This study used a hermeneutic–phenomenological interview research design. Data were collected via remote conferences involving interviews with 17 participants selected via maximum variation sampling. The Colaizzi seven-step method was utilized, and the interview contents were analyzed using NVivo 12.0 software. Results: The needs of family caregivers in coping with the BPSD of individuals with ADRD could be summarized into three themes, namely existence needs, relatedness needs, and growth needs, and 10 sub-themes. Conclusions: The study findings provide new insights into the needs of family caregivers in coping with patients exhibiting BPSD. Family caregivers experience significant negative emotions, poor caregiving experiences, heavy caregiving burdens, and a desire for professional assistance and policy support. Show more
Keywords: Alzheimer’s disease, family caregivers, hermeneutic phenomenology, needs assessment, nonprofessional home care
DOI: 10.3233/JAD-240629
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
Authors: Wu, Yanjuan | Liu, Yixuan | Liu, Yuyang | Chen, Yuntao | Lobanov-Rostovsky, Sophia | Zhang, Yuting | Liu, Yuanli | Brunner, Eric J. | French, Eric | Liao, Jing
Article Type: Research Article
Abstract: Background: Previous estimates on future socioeconomic costs of dementia in China are inconsistent, and the main drivers of these costs are unclear. Objective: This study projected future socioeconomic costs (healthcare, formal social care, and informal care costs) and value of quality adjusted life years (QALYs) lost to dementia in China and assessed drivers of socioeconomic costs. Methods: Based on our prior projection on dementia cases to 2050 by a Markov model, we forecasted future socioeconomic costs and the value of QALYs from a societal perspective, utilizing the China Health and Retirement Longitudinal Study and the Chinese …Longitudinal Healthy Longevity Survey. In our main analysis, dementia incidence increased by 2.9% annually, while sensitivity analyses considered a flat or 1.0% annual decrease in the temporal trend of dementia incidence. Furthermore, we decomposed socioeconomic costs changes (2018 US$) into population growth, population aging, dementia prevalence and average socioeconomic costs per case. Results: The annual socioeconomic costs and value of QALYs lost to dementia will reach $1,233 billion and $702 billion by 2050. If dementia incidence stays constant or decreases by 1.0% annually, the costs and QALYs would respectively decrease by 34% or 43% in 2050. Informal care is currently, and projected to remain, the largest share of socioeconomic costs. Population aging and rising dementia prevalence will mainly drive the growth in socioeconomic costs through 2050. Conclusions: Dementia casts an increasingly large economic burden on Chinese society, mainly driven by fast aging population and growing dementia prevalence. Show more
Keywords: Alzheimer’s disease, China, costs of quality of life lost, dementia, modeling studies, socioeconomic costs
DOI: 10.3233/JAD-240583
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2024
Authors: Zhang, Tan | Wang, Xin | Jester, Hannah M. | Zhou, Xueyan | Ma, Tao
Article Type: Research Article
Abstract: Background: Apathy is a state of decreased interest, lack of initiative, reduced goal-directed activity and blunted emotional responses. Apathy is one of the most common neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) and is also relatively omnipresent in individuals with Down syndrome (DS). Little is known about the apathy-like behaviors in rodent models of AD and DS. Objective: This study aimed to characterize apathy-like behaviors with aging in two established DS mouse models: Ts65Dn and Dp16. Methods: A battery of behavioral tests including nestlet shredding, marble burying, nest building, and burrowing were performed to …examine apathy-like behaviors. Individual z-scores for each mouse for each test, and a composite z-score of apathy-like behavior were analyzed for all mice from these behavioral tests. Results: Analysis of individual test results and composite z-score revealed significant apathy-like behaviors in Ts65Dn mice compared to WT controls. In contrast, Dp16 mice did not exhibit significant apathy-like behaviors. Conclusions: Our study is the first to characterize apathy-like behaviors in mouse models of DS with aging and highlights the difference between Ts65Dn and Dp16 DS model mice regarding apathy-like manifestations with aging. Show more
Keywords: Alzheimer’s disease, apathy-like behavior, Down syndrome, Dp16, mouse model, Ts65Dn
DOI: 10.3233/JAD-240675
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: Manakkadan, Anoop | Krishnan, Dolly | Rui Xia Ang, Sheila | Sajikumar, Sreedharan
Article Type: Research Article
Abstract: Background: Impairment of synaptic plasticity along with the formation of amyloid-β (Aβ) plaques and tau-protein neurofibrillary tangles have been associated with Alzheimer’s disease (AD). Earlier studies with rat and mouse hippocampal slices have revealed the association of AD with the absence of synthesis of memory related proteins leading to impairment in cognitive functions. The role of hydrogen sulfide (H2 S), a gaseous neurotransmitter, has been gaining attention as a neuroprotective agent. However, its role in AD-like conditions has not been studied so far. Objective: To study the neuroprotective role of H2 S in AD conditions using rat hippocampal …slices and the organic molecule GYY4137, a slow releasing H2 S donor. Methods: Electrophysiological recordings were carried out in rat hippocampal slices to look into the impairment of LTP, a cellular correlate of memory. The Aβ 42 peptide was bath-applied to mimic AD-like conditions and checked for both late-LTP and synaptic tagging and capture (STC) mechanisms of the synapses. GYY4137 was applied to look into its neuroprotective role at different stages during the recording of fEPSP. Results: There has been a steady decline in the plasticity properties of the synapses, in the form of late-LTP and STC, after the application of Aβ 42 peptide in the hippocampal slices. However, application of GYY4137 rescued these conditions in vitro . Conclusions: GYY4137, with its slow release of H2 S, could possibly act as a therapeutic agent in cognitive dysfunctions of the brain, mainly AD. Show more
Keywords: Alzheimer’s disease, gaseous neurotransmitter, hippocampus, H2S, long term potentiation, synaptic plasticity, synaptic tagging and capture
DOI: 10.3233/JAD-240456
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Nowell, Joseph | Raza, Sanara | Livingston, Nicholas R. | Sivanathan, Shayndhan | Gentleman, Steve | Edison, Paul
Article Type: Research Article
Abstract: Background: Tau aggregation demonstrates close associations with hypometabolism in Alzheimer’s disease (AD), although differing pathophysiological processes may underlie their development. Objective: To establish whether tau deposition and glucose metabolism have different trajectories in AD progression and evaluate the utility of global measures of these pathological hallmarks in predicting cognitive deficits. Methods: 279 participants with amyloid-β (Aβ ) status, and T1-weighted MRI scans, were selected from the Alzheimer’s Disease Neuroimaging Initiative (http://adni.loni.usc.edu ). We created the standard uptake value ratio images using Statistical Parametric Mapping 12 for [18 F]AV1451-PET (tau) and [18 F]FDG-PET (glucose metabolism) scans. …Voxel-wise group and single-subject level SPM analysis evaluated the relationship between global [18 F]FDG-PET and [18 F]AV1451-PET depending on the Aβ status. Linear models assessed whether tau deposition or glucose metabolism better predicted clinical progression. Results: There was a dissociation between global cerebral glucose hypometabolism and global tau load in amyloid-positive AD and amyloid-negative mild cognitive impairment (MCI) (p > 0.05). Global hypometabolism was only associated with global cortical tau in amyloid-positive MCI. Voxel-level single subject tau load better predicted neuropsychological performance, Alzheimer’s disease assessment scale-cognitive (ADAS-Cog) 13 score, and one-year change compared with regional and global hypometabolism. Conclusions: A dissociation between tau pathology and glucose metabolism at a global level in AD could imply that other pathological processes influence glucose metabolism. Furthermore, as tau is a better predictor of clinical progression, these processes may have independent trajectories and require independent consideration in the context of therapeutic interventions. Show more
Keywords: Alzheimer’s disease, fluorodeoxyglucose F18, positron-emission tomography, tau proteins
DOI: 10.3233/JAD-240434
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Liu, Xin Lian | Yeerlan, Jianishaya | Liu, Zhirong | Bai, Yang | Wang, Qin | Yan, YiRui | Xu, LuKe | Jia, Cui | Zhang, LuShun
Article Type: Research Article
Abstract: Background: No effective drugs currently exist to cure Alzheimer’s disease (AD) due to its complexity and the lack of understanding of the involved molecular signaling and pathways. The relationship between liver health and AD is now widely recognized. Still, molecular links and shared pathways between the liver and brain remain unclear, making the liver-brain axis in AD therapies a new area for exploration. However, bibliometric studies on this topic are lacking. Objective: This study aims to review the liver-brain axis in AD and identify future research hotspots and trends through bibliometric analysis. Methods: Articles and reviews …related to AD and liver and its related diseases were searched in the Web of Science Core Collection (WoSCC) database up to 2024. Data were processed and visually analyzed using VOSviewer, CiteSpace, and Pajek. Results: We collected 1,777 articles on AD and liver and its related diseases from 2,517 institutions across 80 countries. Keyword cluster analysis identified 11 clusters, with ‘insulin resistance,’ ‘amyloid-beta,’ ‘apolipoprotein-E,’ ‘oxidative stress,’ and ‘inflammation’ appearing most frequently, and exhibiting strong total link strength. These results indicate that these topics have been the primary focus of research on the liver-brain axis in AD. Conclusions: This study is the first to comprehensively analyze the liver-brain axis in AD using bibliometric methods. The research results identify recent research frontiers and hotspots, aiding scholars in gaining a deeper understanding of the correlation between AD and the liver. Show more
Keywords: Alzheimer’s disease, bibliometric analysis, liver, liver-brain axis, review
DOI: 10.3233/JAD-240688
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
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