Alzheimer's Environmental and Genetic Risk Scores are Differentially Associated with General Cognitive Ability and Dementia Severity

We investigated the association of the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) and an Alzheimer disease (AD) genetic risk score (GRS) with cognitive performance.Methods:The ANU-ADRI (composed of 12 risk factors for AD) and GRS (composed of 25 AD risk loci) were computed in 1061 community-dwelling older adults. Participants were assessed on 11 cognitive tests and activities of daily living. Structural equation modeling was used to evaluate the association of the ANU-ADRI and GRS with: (1) general cognitive ability (g), (2) dementia-related variance in cognitive performance (δ), and (3) verbal ability (VA), episodic memory (EM), executive function (EF), and processing speed (PS).Results:A worse ANU-ADRI score was associated with poorer performance in "g" [β (SE)=-0.40 (0.02), P<0.001], δ [-0.40 (0.04), P<0.001], and each cognitive domain [VA=-0.29 (0.04), P<0.001; EM=-0.34 (0.03), P<0.001; EF=-0.38 (0.03), P<0.001; and PS=-0.40 (0.03), P<0.001]. A worse GRS was associated with poorer performance in δ [-0.08 (0.03), P=0.041] and EM [-0.10 (0.03), P=0.035].Conclusions:The ANU-ADRI was broadly associated with worse cognitive performance, including general ability and dementia severity, validating its further use in early dementia risk assessment.