Search

Impaired episodic memory is the primary feature of early Alzheimer's disease (AD), but not all memories are equally affected. Patients with AD and amnestic Mild Cognitive Impairment (aMCI) remember pictures better than words, to a greater extent than healthy elderly. We investigated neural mechanisms for visual object recognition in 30 patients (14 AD, 16 aMCI) and 36 cognitively unimpaired healthy (19 in the "preclinical" stage of AD). Event-related brain potentials (ERPs) were recorded while participants performed a visual object recognition task. Hippocampal occupancy (integrity), amyloid (florbetapir) PET, and neuropsychological measures of verbal & visual memory, executive function were also collected. A right-frontal ERP recognition effect (500-700 ms post-stimulus) was seen in cognitively unimpaired participants only, and significantly correlated with memory and executive function abilities. A later right-posterior negative ERP effect (700-900 ms) correlated with visual memory abilities across participants with low verbal memory ability, and may reflect a compensatory mechanism. A correlation of this retrieval-related negativity with right hippocampal occupancy (r = 0.55), implicates the hippocampus in the engagement of compensatory perceptual retrieval mechanisms. Our results suggest that early AD patients are impaired in goal-directed retrieval processing, but may engage compensatory perceptual mechanisms which rely on hippocampal function., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Understanding the neurobiological underpinnings between established multimodal dementia risk factors and noninvasive blood-based biomarkers may lead to greater precision and earlier identification of older adults at risk of accelerated decline and dementia. We examined whether key vascular and genetic risk impact the association between cerebral amyloid burden and plasma aβ (amyloid β) 42/40 in nondemented older adults., Methods: We used nondemented older adults from the UCD-ADRC (University of California, Davis-Alzheimer's Disease Research Center) study ( n =96) and Alzheimer's Disease Neuroimaging Initiative ( n =104). Alzheimer's Disease Neuroimaging Initiative was examined as confirmatory study cohort. We followed a cross-sectional design and examined linear regression followed by mediation analyses. Vascular risk score was obtained as the sum of hypertension, diabetes, hyperlipidemia, coronary artery disease, and cerebrovascular disease. Apolipoprotein E ( APOE ) ε4+ risk was genotyped, and plasma aβ42 and aβ40 were assayed. Cerebral amyloid burden was quantified using Florbetapir-PET scans. Baseline age was included as a covariate in all models., Results: Vascular risk significantly predicted cerebral amyloid burden in Alzheimer's Disease Neuroimaging Initiative but not in the UCD-ADRC cohort. Cerebral amyloid burden was associated with plasma aβ 42/40 in both cohorts. Higher vascular risk increased cerebral amyloid burden was indirectly associated with reduced plasma aβ 42/40 in Alzheimer's Disease Neuroimaging Initiative but not in UCD-ADRC cohort. However, when stratified by APOE ε4+ risk, we consistently observed this indirect relationship only in APOE ε4+ carriers across both cohorts., Conclusions: Vascular risk is indirectly associated with the level of plasma aβ 42/40 via cerebral amyloid burden only in APOE ε4+ carriers. Nondemented older adults with genetic vulnerability to dementia and accelerated decline may benefit from careful monitoring of vascular risk factors directly associated with cerebral amyloid burden and indirectly with plasma aβ 42/40.

Introduction: We examine whether the association between key plasma biomarkers (amyloid β [aβ] 42/40, total tau (t-tau), neurofilament light [NfL]) and cognitive trajectories (executive function [EF] and episodic memory [EM]) is mediated through neurodegeneration., Methods: All participants were recruited from the University of California, Davis-Alzheimer's Disease Research Center ( n  = 473; baseline age range = 49-95 years, 60% women). We applied an accelerated longitudinal design to test latent growth models for EF and EM, and path and mediation analyses. Age was centered at 75 years, and all models were adjusted for sex, education, and ethnicity., Results: HV differentially mediated the association aβ 42/40 and NfL on EF and EM level and change. Hippocampal volume (HV) did not mediate the association between t-tau and cognitive performance., Discussion: Neurodegeneration as represented with HV selectively mediates the association between key non-invasive plasma biomarkers and cognitive trajectories in an ethnoracially and clinically diverse community-based sample., Competing Interests: All authors report no disclosures relevant to the manuscript. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Cognitive impairment, including dementia, is frequently under-detected in primary care. The Consortium for Detecting Cognitive Impairment, including Dementia (DetectCID) convenes three multidisciplinary teams that are testing novel paradigms to improve the frequency and quality of patient evaluations for detecting cognitive impairment in primary care and appropriate follow-up., Objective: Our objective was to characterize the three paradigms, including similarities and differences, and to identify common key lessons from implementation., Methods: A qualitative evaluation study with dementia specialists who were implementing the detection paradigms. Data was analyzed using content analysis., Results: We identified core components of each paradigm. Key lessons emphasized the importance of engaging primary care teams, enabling primary care providers to diagnose cognitive disorders and provide ongoing care support, integrating with the electronic health record, and ensuring that paradigms address the needs of diverse populations., Conclusion: Approaches are needed that address the arc of care from identifying a concern to post-diagnostic management, are efficient and adaptable to primary care workflows, and address a diverse aging population. Our work highlights approaches to partnering with primary care that could be useful across specialties and paves the way for developing future paradigms that improve differential diagnosis of symptomatic cognitive impairment, identifying not only its presence but also its specific syndrome or etiology.

Background: Impairment in daily functioning is a clinical hallmark of dementia. Difficulties with "instrumental activities of daily living" (IADL) seem to increase gradually over the course of Alzheimer's disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD., Methods: In a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging-Alzheimer's Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized., Results: The rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = - 0.32 [- 0.55, - 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (- 1.06 [- 1.27, - 0.85], p < .001) and nearly two SD units per year in stage 4+ (1.93 [- 2.19, - 1.67], p < .001). Overall, results were similar between community-based and memory clinic study cohorts., Conclusions: Our results suggest that the rate of functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive NIA-AA clinical stage. These results imply that incremental changes in function are a meaningful measure for early disease monitoring. Combined with the low-cost assessment, this advocates the use of these functional questionnaires for capturing the effects of early AD-related cognitive decline on daily life.

Introduction: Composite scores based on psychometrically rigorous cognitive assessments are well suited for early diagnosis and disease monitoring., Methods: We developed and cross-validated the Brain Health Assessment-Cognitive Score (BHA-CS), based on a brief computerized battery, in 451 cognitively normal (CN) and 399 cognitively impaired (mild cognitive impairment [MCI] or dementia) older adults. We investigated its long-term reliability and reliable change indices at longitudinal follow-up (N = 340), and the association with amyloid beta (Aβ) burden in the CN subgroup with Aβ positron emission tomography (N = 119)., Results: The BHA-CS was accurate at detecting cognitive impairment and exhibited excellent long-term stability. Reliable decline over one year was detected in 75% of participants with dementia, 44% with MCI, and 3% of CN. Among CN, the Aβ-positive group showed worse longitudinal performance on the BHA-CS compared to the Aβ-negative group., Discussion: The BHA-CS is sensitive to cognitive decline in preclinical and prodromal neurodegenerative disease., Competing Interests: No authors reported competing interests relevant to this study. Dr. La Joie has received research funding from the Alzheimer's Association. Dr. Rabinovici has received consulting fees or speaking honoraria from GE Healthcare, Axon Neurosciences, Merck, Eisai, Roche, and Genentech; grants from Avid Radiopharmaceuticals, Eli Lilly and Company, GE Healthcare, Life Molecular Imaging; and research funding from the National Institutes of Health (NIH), the Rainwater Charitable Foundation, and the Alzheimer's Association. Dr. Miller has received research funding from the NIH; serves as Medical Director for the John Douglas French Foundation; Scientific Director for the Tau Consortium; Director/Medical Advisory Board of the Larry L. Hillblom Foundation; Scientific Advisory Board Member for the National Institute for Health Research Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia (UK); and Board Member for the American Brain Foundation (ABF). Dr. Tomaszewski Farias has received research funding from the NIH. Dr. Kramer has received research funding from the NIH and the Larry L. Hillblom Foundation and royalties from Pearson Education, Inc. Dr. Rankin has received research funding from the NIH, Quest Diagnostics, the Rainwater Charitable Foundation, the Weill Family Foundation, and the Marcus Foundation. Dr. Possin has received research funding from the NIH, Quest Diagnostics, the Global Brain Health Institute, the Merck Foundation, and the Rainwater Charitable Foundation. No other disclosures were reported., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)