Association of the CD2AP locus with cognitive functioning among middle-aged individuals with a family history of Alzheimer's disease.

First-degree family history is an established risk factor for Alzheimer's disease (AD). We investigated the association of late-onset AD risk loci with cognitive functioning among 315 offspring of AD patients. Participants were cognitively normal Jewish individuals, aged 40-65 years, from the Israel Registry for Alzheimer's Prevention (IRAP) study. Twenty-two single-nucleotide polymorphisms (SNPs) within these loci and the APOE E4 allele were included in the final analyses, and a polygenic risk score was also calculated. Using linear regression (assuming an additive genetic model), we found a significant association only for SNP rs9473117, located near the CD2-associated protein (CD2AP) gene, with global cognition. Controlling for demographic variables (age, sex, years of education, and ancestry), the late-onset AD risk allele C was associated with lower global cognitive functioning (p = 0.0005), and withstood correction for multiple testing. After adjusting for additional characteristics (APOE E4 status and then also for cardiovascular factors), the results remained essentially unchanged (p = 0.0003 and p = 0.0005, respectively). In secondary analyses examining specific cognitive domains, rs9473117 was similarly associated with episodic memory (p = 0.005), language (p = 0.009), and working memory/attention (p = 0.018) but not with executive functions (p = 0.27). Again, the results were similar after adjusting for APOE E4 status and cardiovascular factors. The polygenic risk score was not associated with global cognitive functioning or with any of the 4 domains. In conclusion, our findings suggest a contribution of the CD2AP locus to cognitive functioning in middle-aged individuals with a parental history of AD. Further validations, including in longitudinal studies, are required.