Mr Shea Andrews, Genome Diversity & Health, Genome Sciences Department, The John Curtin School of Medical Research, ANU.
Background: Recent genome wide associations studies have identified novel SNPs, beyond APOE, that increase risk for developing Alzheimer’s disease (AD). Due to the phenotypic similarity between Alzheimer’s disease and cognitive decline, these variants are good candidates for assessing the association of genetic factors with cognitive decline. This study examines the role of AD risk variants, individually and as a composite risk score, in cognitive decline using a comprehensive cognitive assessment.Methods: Participants were 1,689 cognitively normal older (age 60-64) Australians of European ancestry from the Personality and Total Health (PATH) Through Life Project. All participants were assessed at baseline and at 4 year intervals for a period of 8 years for the five following cognitive measures; perceptual speed; episodic memory; working memory; vocabulary and; global cognition. Participants were genotyped for 11 AD risk SNPs; rs3764650 (ABCA7), rs744373 (BIN1), rs9296559 (CD2AP), rs34813869 (CD33), rs11136000 (CLU), rs3818361 (CR1) rs11767557 (EPHA1), rs4938933 (MS4A4A), rs670139 (MS4A4E), rs6109332 (MS4A6A) and rs3851179 (PICALM) using the TaqMan OpenArray system. Multilevel Models were used to assess the associations between the individual genetic risk factors, weighted and unweighted genetic risk scores with cognitive decline. All models were adjusted for sex, education and symptoms of depression.Results: APOE e4 carriers had a faster rate of decline in episodic memory and global cognition; ABCA7-rs3764650G carriers had a lower episodic memory scores at baseline; CR1-rs3818361A carriers experienced a faster rate of decline in global cognition; MS4A4E-rs6109332T carriers had a higher vocabulary score at baseline and a slower rate of decline for episodic memory and global cognition; and the weighted GRS was associated with faster rates of decline in episodic memory and global cognition. The remaining SNPs were not significantly associated with cognitive performance on any of the cognitive measures.Conclusions: Three nonAPOE AD risk SNPs; ABCA7-rs3764650, CR1-rs3818361 and MS4A4E-rs6109332, and a weighted GRS were associated with cognitive performance in a large cohort of community dwelling individuals. Identifying associations between individual genetic risk factors or their combined influence as a risk score with cognitive decline may help in screening for people with elevated risk and be useful for developing intervention and treatment strategies.