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.

中文翻译：

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CD2AP 基因座与阿尔茨海默病家族史中年人认知功能的关联

摘要 一级家族史是阿尔茨海默病 (AD) 的既定危险因素。我们在 AD 父母的 315 名后代中调查了晚发性 AD 风险位点与认知功能的关联。参与者是来自以色列阿尔茨海默病预防登记处 (IRAP) 研究的认知正常的犹太人，年龄在 40-65 岁之间。这些基因座内的 22 个单核苷酸多态性 (SNP) 和 APOE E4 等位基因被纳入最终分析，并且还计算了多基因风险评分 (PRS)。使用线性回归（假设加性遗传模型），我们发现仅位于 CD2 相关蛋白 (CD2AP) 基因附近的 SNP rs9473117 与全局认知存在显着关联。控制人口统计变量（年龄、性别、受教育年限和血统），晚发性 AD 风险等位基因 C 与较低的整体认知功能相关 (p = 0.0005)，并且经受住了多重比较的阈值。在调整其他特征（APOE E4 状态以及心血管因素）后，结果基本保持不变（分别为 p=0.0003 和 p=0.0005）。在检查特定认知领域的二次分析中，rs9473117 与情景记忆（p = 0.005）、语言（p = 0.009）和工作记忆/注意力（​​p = 0.018）类似，但与执行功能无关（p = 0.27）。同样，在调整 APOE E4 状态和心血管因素后，结果相似。PRS 与全球认知功能或四个领域中的任何一个都无关。我们的研究结果表明 CD2AP 基因座对中年人的认知功能有贡献，在有 AD 家族史的个体中。需要进一步的验证，包括纵向研究。