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