Association of Alzheimer's Disease Genetic Risk Loci with Cognitive Performance and Decline: A Systematic Review

The association of Apolipoprotein E (APOE) with late-onset Alzheimer's disease (LOAD) and cognitive endophenotypes of aging has been widely investigated. There is increasing interest in evaluating the association of other LOAD risk loci with cognitive performance and decline. The results of these studies have been inconsistent and inconclusive. We conducted a systematic review of studies investigating the association of non-APOE LOAD risk loci with cognitive performance in older adults. Studies published from January 2009 to April 2018 were identified through a PubMed database search using keywords and by scanning reference lists. Studies were included if they were either cross-sectional or longitudinal in design, included at least one genome-wide significant LOAD risk loci or a genetic risk score, and had one objective measure of cognition. Quality assessment of the studies was conducted using the quality of genetic studies (QGenie) tool. Of 2,466 studies reviewed, 49 met inclusion criteria. Fifteen percent of the associations between non-APOE LOAD risk loci and cognition were significant. However, these associations were not replicated across studies, and the majority were rendered non-significant when adjusting for multiple testing. One-third of the studies included genetic risk scores, and these were typically significant only when APOE was included. The findings of this systematic review do not support a consistent association between individual non-APOE LOAD risk and cognitive performance or decline. However, evidence suggests that aggregate LOAD genetic risk exerts deleterious effects on decline in episodic memory and global cognition.