The Association between Polygenic Hazard and Markers of Alzheimer's Disease Following Stratification for APOE Genotype.

Abstract

Research indicates that polygenic indices of risk of Alzheimer's disease are linked to clinical profiles. Given the "genetic centrality" of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers. A polygenic hazard score (PHS) was extracted from 784 non-demented participants recruited in the Alzheimer's Disease Neuroimaging Initiative and stratified by APOE ε4 status. Datasets were split into sub-cohorts defined by clinical (unimpaired/MCI) and amyloid status (Aβ+/Aβ-). Linear models were devised in each sub-cohort and for each APOE-ε4 status to test the association between PHS and memory, executive functioning and grey-matter volumetric maps. PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aβ+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 Aβ+ participants. The link between polygenic hazard and neurocognitive variables varies depending on APOE-ε4 allele status. This suggests that clinical phenotypes might be influenced by complex genetic interactions.