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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: 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
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