Clinical Manifestations.

Abstract

Alzheimer's disease (AD) is characterised biologically by beta-amyloid (Aβ) plaques and tau tangles, but autopsy studies reveal that most older adults also present with cerebrovascular disease (CVD) markers. Effects of biological AD on cognition in the context of concurrent CVD remain unclear. In older adults with CVD pathology, this study sought to determine ante-mortem cognitive trajectories associated with Aβ/tau positivity or negativity (+/-) at autopsy. Participants aged 65-95 classified as cognitively unimpaired at baseline from the National Alzheimer's Coordinating Center database, with ≥1 follow-up between 2005-2015, and available autopsy/APOE data were included (N = 924). Autopsy indicated that all participants had at least one of six CVD pathology markers. Participants were classified into four groups (A-T-, A+T-, A-T+, A+T+) based on semiquantitative Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque staging and Braak staging. Linear mixed models including group × time interactions assessed rate of change in Preclinical Alzheimer's Cognitive Composite scores, episodic memory, and executive function. Interactions between age, sex, APOE ε4 × time and the interval between death/the final study visit were included as covariates. A+T+ adults demonstrated significantly faster cognitive decline on all outcomes in the ∼10 years preceding death compared to A-T-, A+T-, and A-T+ adults (Table 1, Figure 1, d = 0.15 - 0.39). At final visit prior to death, a greater proportion of A+T+ adults (36%) received a dementia diagnosis compared to A-T+ (14%) or A+T- (15%) (p <.001). When analyses were restricted to exclude dementia diagnoses, significantly faster decline on all outcomes (p's <.001, d = 0.06 - 0.36) was similarly observed in A+T+ adults compared to A-T-, A+T- and A-T+ adults (Figure 2). Cognitive trajectories were equivalent between A-T- and A+T- for all outcomes (p's >.55). ln older adults with CVD pathology, A+T+ at autopsy was associated with greater cognitive decline over 10 years preceding death compared to A+T-, A-T+, and A-T- older adults. Faster cognitive decline in this group in the context of low final visit dementia diagnoses may suggest that post-mortem A+T+ is associated with a steep trajectory of cognitive decline ante-mortem, but that dementia progression is not inevitable.