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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: Gaster, Barak | Suchsland, Monica Zigman | Fitzpatrick, Annette L. | Liao, Joshua M. | Belza, Basia | Hsu, Amy P. | McKiddy, Sarah | Park, Christina | Olivari, Benjamin S. | Singh, Angad P. | Raetz, Jaqueline
Article Type: Research Article
Abstract: Background: The prevalence of Alzheimer’s disease and related disorders (ADRD) is rising. Primary care providers (PCPs) will increasingly be required to play a role in its detection but lack the training to do so. Objective: To develop a model for cognitive evaluation which is feasible in primary care and evaluate its implementation in a large health system. Methods: The Cognition in Primary Care Program consists of web-based training together with integrated tools built into the electronic record. We implemented the program among PCPs at 14 clinics in a large health system. We (1) surveyed PCPs to …assess the impact of training on their confidence to evaluate cognition, (2) measured the number of cognitive assessments they performed, and (3) tracked the number of patients diagnosed with mild cognitive impairment (MCI). Results: Thirty-nine PCPs completed the training which covered how to evaluate cognition. Survey response rate from those PCPs was 74%. Six months after the end of the training, they reported confidence in assessing cognition (mean 4.6 on 5-point scale). Cognitive assessments documented in the health record increased from 0.8 per month before the training to 2.5 in the six months after the training. Patients who were newly diagnosed with MCI increased from 4.2 per month before the training to 6.0 per month in the six months after the training. Conclusions: This model for cognitive evaluation in a large health system was shown to increase cognitive testing and increase diagnoses of MCI. Such improvements are essential for the timely detection of ADRD. Show more
Keywords: Alzheimer’s disease, cognitive dysfunction, continuing medical education, dementia, early detection of disease, mild cognitive impairment, primary care
DOI: 10.3233/JAD-231200
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2024
Authors: Wu, Bin | Chen, Mulan | Meng, Ling | Tian, Qiuyun | Dong, Zhifang
Article Type: Research Article
Abstract: Background: The amyloid-β (Aβ) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of developing dementia or Alzheimer’s disease (AD). Despite this association, the contribution of bone-resorbing OCs to the progression of AD pathology remains unclear. Objective: Our objective was to investigate the potential impacts of OCs on the development of AD pathology. Methods: We conducted targeted analysis of publicly available whole blood transcriptomes from patients with AD to characterize the blood molecular signatures and pathways associated with hyperactive OCs. In addition, we used APP23 transgenic (APP23 …TG) AD mouse model to assess the effects of OCs pharmacological blockade on AD pathology and behavior. Results: Patients with AD exhibited increased osteoclastogenesis signature in their blood cells, which appears to be positively correlated with dysfunction of peripheral clearance of Aβ mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aβ-degrading enzyme expression, Aβ-deposition, and memory decline. Conclusions: Our findings suggest that OCs have a disease-promoting role in the development and progression of AD, possibly linked to their modulation of peripheral immunity. These findings guide future research to further elucidate the connection between OP and AD pathogenesis, highlighting the potential benefits of preventing OP in alleviating cognitive burden. Show more
Keywords: Alzheimer’s disease, amyloid-β burden, monocyte, osteoclast, osteoporosis
DOI: 10.3233/JAD-240096
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2024
Authors: Asada, Takashi | Tanaka, Mieko | Araki, Wataru | Jon Lebowitz, Adam | Kakuma, Tatsuyuki
Article Type: Research Article
Abstract: Background: Interventions to prevent or attenuate cognitive decline and dementia in older adults are becoming increasingly important. Recently, cognitive training exercise can be via computer or mobile technology for independent or home use. Recent meta-analysis has reported that Computerized Cognitive Training (CCT) is effective at enhancing cognitive function in healthy older and Alzheimer’s disease adults, although little is known about individual characteristics of each computerized program. Objective: We developed a new CCT named Brain Training Based on Everyday Living (BTEL) to enhance cognitive capacity for Instrumental Activities of Daily Living (IADL). We aim to evaluate the efficacy of …the BTEL among cognitively healthy old individuals and to explore its concurrent validity and construct concept. Methods: We conducted a double-blind study where 106 individuals aged 65 years and older (intervened = 53, control = 53) worked on the active and placebo tasks three times a week over three months (clinical trial: UMIN000048730). The main results were examined using ANCOVA and calculating correlation coefficients. Results: We found no effect on total score of the three tests; however, there was significant effect for the BTEL on: recognition in MMSE, and immediate recall in HDSR. The tasks are associated with prefrontal cortex. In addition, correlations indicated that each BTEL domain had some validity as a cognitive assessment tool. Different from previous CCT, we determined the neuropsychological characteristics of specific cognitive tasks of the BTEL to a certain degree. Conclusions: We found modest efficacy of the BTEL in cognitively healthy old individuals and confirmed its concurrent validity and the conceptual construct. Show more
Keywords: Activities of daily living, Alzheimer’s disease, brain training, mild cognitive impairment, neuropsychology
DOI: 10.3233/JAD-231165
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Authors: de Oliveira, Fabricio Ferreira
Article Type: Article Commentary
Abstract: Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer’s disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer’s disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits.
Keywords: Alzheimer’s disease, amyloidosis, APOE , biomarkers, dementia, hypertension, renin-angiotensin system, tau proteins
DOI: 10.3233/JAD-240032
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Ohno, Masuo
Article Type: Review Article
Abstract: Given continued failure of BACE1 inhibitor programs at symptomatic and prodromal stages of Alzheimer’s disease (AD), clinical trials need to target the earlier preclinical stage. However, trial design is complex in this population with negative diagnosis of classical hippocampal amnesia on standard memory tests. Besides recent advances in brain imaging, electroencephalogram, and fluid-based biomarkers, new cognitive markers should be established for earlier diagnosis that can optimize recruitment to BACE1 inhibitor trials in presymptomatic AD. Notably, accelerated long-term forgetting (ALF) is emerging as a sensitive cognitive measure that can discriminate between asymptomatic individuals with high risks for developing AD and healthy …controls. ALF is a form of declarative memory impairment characterized by increased forgetting rates over longer delays (days to months) despite normal storage within the standard delays of testing (20–60 min). Therefore, ALF may represent a harbinger of preclinical dementia and the impairment of systems memory consolidation, during which memory traces temporarily stored in the hippocampus become gradually integrated into cortical networks. This review provides an overview of the utility of ALF in a rational design of next-generation BACE1 inhibitor trials in preclinical AD. I explore potential mechanisms underlying ALF and relevant early-stage biomarkers useful for BACE1 inhibitor evaluation, including synaptic protein alterations, astrocytic dysregulation and neuron hyperactivity in the hippocampal-cortical network. Furthermore, given the physiological role of the isoform BACE2 as an AD-suppressor gene, I also discuss the possible association between the poor selectivity of BACE1 inhibitors and their side effects (e.g., cognitive worsening) in prior clinical trials. Show more
Keywords: Accelerated long-term forgetting, Alzheimer’s disease, amyloid-β , BACE1 inhibitors, BACE2, biomarkers, clinical trials, mouse models, preclinical stage, side effects
DOI: 10.3233/JAD-231451
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024
Authors: Georgescu, Michael F. | Beydoun, May A. | Ashe, Jason | Maino Vieytes, Christian A. | Beydoun, Hind A. | Evans, Michele K. | Zonderman, Alan B.
Article Type: Research Article
Abstract: Background: Loneliness, dementia, and mortality are interconnected. Objective: We aimed at understanding mediating pathways and interactions between loneliness and dementia in relation to mortality risk. Methods: The study tested bi-directional relationships between dementia, loneliness, and mortality, by examining both interactions and mediating effects in a large sample of older US adults participating in the nationally representative Health and Retirement Study. Out of≤6,468 older participants selected in 2010, with mean baseline age of 78.3 years and a follow-up time up to the end of 2020, 3,298 died at a rate of 64 per 1,000 person-years (P-Y). Cox …proportional hazards and four-way decomposition models were used. Results: Algorithmically defined dementia status (yes versus no) was consistently linked with a more than two-fold increase in mortality risk. Dementia status and Ln(odds of dementia) were strongly related with mortality risk across tertiles of loneliness score. Loneliness z-score was also linked to an elevated risk of all-cause mortality regardless of age, sex, or race or ethnicity, and its total effect (TE) on mortality was partially mediated by Ln(odds of dementia), z-scored, (≤40% of the TE was a pure indirect effect). Conversely, a small proportion (<5% ) of the TE of Ln (odds of dementia), z-scored, on mortality risk was explained by the loneliness z-score. Conclusions: In sum, dementia was positively associated with all-cause mortality risk, in similar fashion across loneliness score tertiles, while loneliness was associated with mortality risk. TE of loneliness on mortality risk was partially mediated by dementia odds in reduced models. Show more
Keywords: Aging, Alzheimer’s disease, cohort studies, dementia, loneliness, mortality
DOI: 10.3233/JAD-231359
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2024
Authors: Li, Yaoru | Yang, Ziying | Zhang, Yanxin | Liu, Fang | Xu, Jing | Meng, Yaping | Xing, Gebeili | Ruan, Xuqin | Sun, Jun | Zhang, Nan
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or …likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO , and DCTN1 , were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases. Show more
Keywords: Alzheimer’s disease, frontotemporal lobar degeneration, variant, whole-exome sequencing
DOI: 10.3233/JAD-231361
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2024
Authors: Chu, Yili | Xie, Qihui | Meng, Rongrong | Leng, Bing | Cao, Zhenxiang
Article Type: Research Article
Abstract: Background: With the increasing popularity of the internet, a growing number of patients and their companions are actively seeking health-related information online. Objective: The aim of this study was to assess the quality and readability of online information about Alzheimer’s disease (AD) in China. Methods: A total of 263 qualified AD-related web pages from different businesses, governments, and hospitals were obtained. The quality of the web pages was assessed using the DISCERN tool, and the readability of the web pages was assessed using a readability measurement website suitable for the Chinese language. The differences in readability …and quality between different types of web pages were investigated, and the correlation between quality and readability was analyzed. Results: The mean overall DISCERN score was 40.93±7.5. The government group scored significantly higher than the commercial and hospital groups. The mean readability score was 12.74±1.27, and the commercial group had the lowest readability score. There was a positive correlation between DISCERN scores and readability scores. Conclusions: This study presents an evaluation of the quality and readability of health information pertaining to AD in China. The findings indicate that there is a need to enhance the quality and readability of web pages about AD in China. Recommendations for improvement are proposed in light of these findings. Show more
Keywords: Alzheimer’s disease, internet, quality evaluation, readability evaluation
DOI: 10.3233/JAD-231339
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2024
Authors: Gale, Seth A.
Article Type: Article Commentary
Abstract: As the biological, biomarker-driven framework of Alzheimer’s disease (AD) becomes formalized through revised, consensus clinical criteria, clinicians will confront more and more patients in the earliest, asymptomatic stages of disease. The language and diction used by practitioners to characterize these early patients, whether they are diagnosed with AD, and how their condition is documented in medical and legal records have important implications for both their care and their medical-legal status outside of the health system. Investigation is needed urgently to better understand clinicians’ views and practices regarding early AD, as we adapt to new disease definitions in this unprecedented era …of care. Show more
Keywords: Alzheimer’s disease, asymptomatic Alzheimer’s disease, biomarkers, data privacy, language, legal liability, medical law, nosology, preclinical Alzheimer’s disease
DOI: 10.3233/JAD-240195
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2024
Authors: Horvath, Alexandra | Quinlan, Patrick | Eckerström, Carl | Åberg, N. David | Wallin, Anders | Svensson, Johan
Article Type: Research Article
Abstract: Background: Insulin-like growth factor-I (IGF-I) regulates myelin, but little is known whether IGF-I associates with white matter functions in subjective and objective mild cognitive impairment (SCI/MCI) or Alzheimer’s disease (AD). Objective: To explore whether serum IGF-I is associated with magnetic resonance imaging – estimated brain white matter volumes or cognitive functions. Methods: In a prospective study of SCI/MCI (n = 106) and AD (n = 59), we evaluated the volumes of the total white matter, corpus callosum (CC), and white matter hyperintensities (WMHs) as well as Mini-Mental State Examination (MMSE), Trail Making Test A and B (TMT-A/B), and …Stroop tests I–III at baseline, and after 2 years. Results: IGF-I was comparable in SCI/MCI and AD (113 versus 118 ng/mL, p = 0.44). In SCI/MCI patients, the correlations between higher baseline IGF-I and greater baseline and 2-year volumes of the total white matter and total CC lost statistical significance after adjustment for intracranial volume and other covariates. However, after adjustment for covariates, higher baseline IGF-I correlated with better baseline scores of MMSE and Stroop test II in SCI/MCI and with better baseline results of TMT-B and Stroop test I in AD. IGF-I did not correlate with WMH volumes or changes in any of the variables. Conclusions: Both in SCI/MCI and AD, higher IGF-I was associated with better attention/executive functions at baseline after adjustment for covariates. Furthermore, the baseline associations between IGF-I and neuropsychological test results in AD may argue against significant IGF-I resistance in the AD brain. Show more
Keywords: Alzheimer’s disease, attention, corpus callosum, executive function, insulin-like growth factor-I, magnetic resonance imaging, mild cognitive impairment, speed, subjective mild cognitive impairment, white matter hyperintensities
DOI: 10.3233/JAD-231026
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2024
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