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

Abstract 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 parents. 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 (PRS) 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 the threshold for multiple comparisons. After adjusting for additional characteristics (APOE E4 status and then also for cardiovascular factors), 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, results were similar after adjusting for APOE E4 status and cardiovascular factors. The PRS was not associated with global cognitive functioning or with any of the four domains. Our findings suggest a contribution of the CD2AP locus to cognitive functioning already in middle age, in individuals with a family history of AD. Further validations, including in longitudinal studies, are required.