The association between polygenic hazard and markers of Alzheimer’s disease following stratification for APOE genotype

Background: Research indicates that polygenic indices of risk of Alzheimer’s disease are linked to clinical profiles.

Objective: Given the “genetic centrality” of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers.

Methods: 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.

Results: 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.

Conclusion: 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.