A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEɛ4 Carriers

Article type: Research Article

Authors: Sapkota, Shraddha^{a; *} | Dixon, Roger A.^{a; b}

Affiliations: [a] Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada | [b] Department of Psychology, University of Alberta, Edmonton, Canada

Correspondence: [*] Correspondence to: Shraddha Sapkota, PhD, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, M6-192, Toronto, ON, M4N 3M5 Canada. Tel.: +1 416 480 6100 ext. 85420; E-mail: [email protected].

Abstract: Background:Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk. Objective:We organize three possible combinations into a “network” of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer’s disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein). Method:We use an accelerated longitudinal design (n = 634; age range = 55–95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ɛ4+ versus ɛ4–). Results:APOE ɛ4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOE ɛ4 carriers with low AD-GRS. Conclusions:APOE ɛ4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differentially predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.

Keywords: Alzheimer’s disease, Apolipoprotein E, cognitive aging, executive function, genetic risk, Victoria Longitudinal Study

DOI: 10.3233/JAD-170909

Journal: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 887-900, 2018