Abstract
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.