Alzheimer disease (AD) is a common and costly neurodegenerative disorder. A large proportion of AD risk is heritable, and many genetic risk factors have been identified. The objective of this study was to test the hypothesis that cumulative genetic risk of known AD markers contributed to odds of dementia in a population-based sample.

In the US population-based Health and Retirement Study (waves 1995–2014), we evaluated the role of cumulative genetic risk of AD, with and without the APOE 4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, and cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.

In the European ancestry sample (n = 8,399), both AD polygenic score excluding the APOE genetic region (odds ratio [OR] = 1.10; 95% confidence interval [CI]: 1.00–1.20) and the presence of any APOE 4 alleles (OR = 2.42; 95% CI: 1.99–2.95) were associated with the odds of dementia relative to normal cognition in a mutually adjusted model. In the African ancestry sample (n = 1,605), the presence of any APOE 4 alleles was associated with 1.77 (95% CI: 1.20–2.61) times higher odds of dementia, whereas the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97–1.30).

Cumulative genetic risk of AD and APOE 4 are both independent predictors of dementia in European ancestry. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.

阿尔茨海默病 (AD) 是一种常见且代价高昂的神经退行性疾病。很大一部分 AD 风险是可遗传的，并且已经确定了许多遗传风险因素。本研究的目的是在基于人群的样本中检验已知 AD 标志物的累积遗传风险会导致痴呆几率的假设。

在美国基于人群的健康和退休研究（1995-2014 年浪潮）中，我们评估了 AD 的累积遗传风险（有和没有APOE 4等位基因）对痴呆状态（痴呆、无痴呆的认知障碍、临界认知障碍）的作用无痴呆，认知正常）。我们使用逻辑回归，考虑人口学协变量和遗传主成分，并按欧洲和非洲遗传血统对分析进行分层。

在欧洲血统样本 (n = 8,399) 中，不包括APOE遗传区域的 AD 多基因评分（优势比 [OR] = 1.10；95% 置信区间 [CI]：1.00-1.20）和任何APOE 4等位基因的存在（ OR = 2.42；95% CI：1.99-2.95）在相互调整的模型中与痴呆症相对于正常认知的几率相关。在非洲血统样本 (n = 1,605) 中，任何APOE 4等位基因的存在与 1.77 (95% CI: 1.20–2.61) 倍的痴呆几率相关，而排除APOE遗传区域的 AD 多基因评分不显着与正常认知相关的痴呆几率为 1.06 (95% CI: 0.97–1.30)。

AD 和APOE 4的累积遗传风险都是欧洲血统痴呆症的独立预测因子。这项研究提供了对痴呆多基因性质的重要见解，并证明了多基因评分在痴呆研究中的实用性。