Dissociable influences of <i>APOE</i> ε4 and polygenic risk of AD dementia on amyloid and cognition.

Abstract

To investigate the effects of genetic risk of Alzheimer disease (AD) dementia in the context of β-amyloid (Aβ) accumulation. We analyzed data from 702 participants (221 clinically normal, 367 with mild cognitive impairment, and 114 with AD dementia) with genetic data and florbetapir PET available. A subset of 669 participants additionally had longitudinal MRI scans to assess hippocampal volume. Polygenic risk scores (PRSs) were estimated with summary statistics from previous large-scale genome-wide association studies of AD dementia. We examined relationships between <i>APOE</i> ε4 status and PRS with longitudinal Aβ and cognitive and hippocampal volume measurements. <i>APOE</i> ε4 was strongly related to baseline Aβ, whereas only weak associations between PRS and baseline Aβ were present. <i>APOE</i> ε4 was additionally related to greater memory decline and hippocampal atrophy in Aβ+ participants. When <i>APOE</i> ε4 was controlled for, PRS was related to cognitive decline in Aβ+ participants. Finally, PRSs were associated with hippocampal atrophy in Aβ- participants and weakly associated with baseline hippocampal volume in Aβ+ participants. Genetic risk factors of AD dementia demonstrate effects related to Aβ, as well as synergistic interactions with Aβ. The specific effect of faster cognitive decline in Aβ+ individuals with higher genetic risk may explain the large degree of heterogeneity in cognitive trajectories among Aβ+ individuals. Consideration of genetic variants in conjunction with baseline Aβ may improve enrichment strategies for clinical trials targeting Aβ+ individuals most at risk for imminent cognitive decline.