Alzheimer’s disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.

阿尔茨海默病 (AD) 尚无经过证实的因果和可改变的危险因素，也没有有效的干预措施。我们报告了一项全表组关联研究 (PheWAS)，研究了英国生物银行研究中 334,968 名参与者的 AD 遗传倾向，并按年龄分层。我们还研究了 AD 遗传倾向对先前涉及的风险因素的影响。我们在 HUNT 研究中重复了这些分析。在孟德尔随机化 (MR) 框架中对 PheWAS 命中和先前涉及的风险因素进行跟踪，以确定每个风险因素对 AD 风险的因果影响。早在 39 岁时，AD 的较高遗传风险就与病史以及认知、生活方式、身体和血液测量相关。这些效应很大程度上是由APOE基因驱动的。后续的 MR 分析基本上是无效的，这意味着大多数这些关联可能是前驱疾病或选择偏倚的结果，而不是导致疾病的危险因素。