Genome-wide association studies (GWAS) have identified >80 Alzheimer’s disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer’s Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.

全基因组关联研究 （GWAS） 已确定 >80 阿尔茨海默病和相关痴呆症 （ADRD） 相关遗传位点。然而，大多数先前研究中使用的临床结果掩盖了潜在神经病理学的复杂性。在这里，我们对 11 种 ADRD 相关的神经病理学内表型进行了 GWAS，参与者来自以下三个来源：国家阿尔茨海默病协调中心、宗教秩序研究和 Rush 记忆与衰老项目，以及成人思想变化研究（n = 7,804 名尸检参与者总数）。我们确定了 8 个独立的显著相关位点，其中 4 个是新的（COL4A1 、 PIK3R5 、 LZTS1 和 APOC2）。单独测试已知的 ADRD 基因座，在假发现率调整后，19 个基因座与至少一种神经病理学显著相关。遗传共定位分析确定了多效性效应和数量性状位点。APOC2 附近两个部位的大脑皮层甲基化与脑淀粉样血管病有关。包括神经病理学内表型的研究是了解遗传性 ADRD 风险机制的重要步骤。