Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas, USA.
Jan and Dan Duncan Neurological Research Institute, Houston, Texas, USA.
Alzheimers Dement. 2021 May;17(5):831-846. doi: 10.1002/alz.12240. Epub 2020 Dec 7.
The strongest genetic risk factor for idiopathic late-onset Alzheimer's disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease-free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau- or β42-induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type-specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.
载脂蛋白 E（APOE）ɛ4 是特发性迟发性阿尔茨海默病（LOAD）最强的遗传风险因素，而 APOE ɛ2 等位基因是保护性的。然而，有些载脂蛋白 E ɛ4 携带者没有患病，而有些载脂蛋白 E ɛ2 携带者却患有 LOAD。我们比较了健康的 APOE ɛ4 携带者和 APOE ɛ2 阿尔茨海默病（AD）患者的外显子组，根据其预测的功能影响对编码变异进行优先级排序，并在这两个群体之间确定了 216 个具有差异突变负荷的候选基因。这些候选基因在 LOAD 大脑中明显失调，并且许多基因在果蝇中调节 tau 或 β42 诱导的神经退行性变。这些基因的变异与 AD 风险相关，即使在 APOE ɛ3 纯合子中也是如此，这表明其具有很强的风险分层预测能力。网络分析显示候选基因参与了包括突触生物学、树突棘修剪和炎症在内的特定于脑细胞类型的途径。这些 LOAD 的潜在修饰因子可能构成新的生物标志物，为潜在的治疗干预提供途径，并支持在更大的全外显子组测序队列可用时应用这种方法。
