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 distinct brain atrophy patterns (using brain parenchymal fraction [BPF]) differentially predict functional performance and decline in Alzheimer's disease (AD), and are independently moderated by (1) a key AD genetic risk marker (apolipoprotein E [APOE]), (2) sex, and (3) high-risk group (women APOE ɛ4 carriers).

Methods

We used a 2-year longitudinal sample of AD patients (baseline N = 170; mean age = 71.3 [9.1] years) from the Sunnybrook Dementia Study. We applied latent class analysis, latent growth modeling, and path analysis. We aimed to replicate our findings (N = 184) in the Alzheimer's Disease Neuroimaging Initiative.

Results

We observed that high brain atrophy class predicted lower functional performance and steeper decline. This association was moderated by APOE, sex, and high-risk group. Baseline findings as moderated by APOE and high-risk group were replicated.

Discussion

Women APOE ɛ4 carriers may selectively be at a greater risk of functional impairment with higher brain atrophy.

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.

The Hispanic/Latino population is one of the largest and most diverse ethnoracial groups in the United States at high risk for dementia. We examined cognitive constructs and associations with subsequent hippocampal volume (HV) and white matter hyperintensity volume (WMHV). Participants were from the Hispanic Community Health Study/Study of Latinos-Magnetic Resonance Imaging Study (n = 2029). We examined confirmatory factor analysis and longitudinal invariance using neurocognitive scores at Visits 1 (2008-2011) and 2 (2014-2018) and path analyses. We obtained a longitudinally invariant two-factor episodic memory (EM) and working memory (WM) construct. Lower EM profile at both visits was associated with greater WMHV and smaller HV at Visit 2. Lower WM profile at both visits was associated with larger WMHV and smaller HV at Visit 2. Neurocognitive profiles were associated with subsequent neurodegeneration in a sample of Hispanics/Latinos. Identifying neurocognitive risk profiles may lead to early detection and intervention, and significantly impact the course of neurodegeneration.

Highlights

Cognitive profiles predict brain integrity up to 10 years later.We observed two-factor latent memory constructs and longitudinal invariance.These findings were observed in a Hispanic/Latino cohort.