Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aβ) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.

阿尔茨海默病 （AD） 是全球痴呆的主要原因。除了神经原纤维缠结和 β 淀粉样蛋白 （Aβ） 斑块外，在 AD 大脑中还可以观察到广泛的合并神经病理学特征。由于 AD 具有非常强的遗传背景并表现出广泛的表型异质性，本研究旨在调查共病和标志性神经病理病变的遗传基础。这是通过从 Leuven Brain Collection 的 325 个个体的低覆盖度全基因组测序数据中获得 75 个 AD 风险变异的基因型来实现的。与深度特征的神经病理学病变的关联测试显示，APH1B 外显子 1 中的 SNP rs117618017 与 tau 相关病理具有强烈且可能的直接影响。其次，除了复制众所周知的 APOE 与 AD 标志性神经病理学病变的关联外，还发现了 APOE 与粒细胞血管变性（坏死性凋亡的代理）之间的关系。此外，在 pTDP 病理学、 α-突触核蛋白病变和 pTau 相关病理学中检测到与 AD 风险基因的几个名义关联。这些发现在一项包含三个独立队列的荟萃分析中得到了证实。例如，我们复制了 TPCN1 （rs6489896） 和 LATE-NC 风险之间的先前关联。此外，我们鉴定了新的推定的 LATE-NC 连锁 SNP，包括位于 ANK3 上游的 rs7068231。我们发现了 BIN1 （rs6733839） 与 α-突触核蛋白病理之间的关联，并复制了 USP6NL （rs7912495） 与路易体病理之间的先前关联。此外，我们还发现 UMAD1 （rs6943429） 名义上与 Lewy 体病理相关。 总体而言，这些结果有助于更广泛地了解在大规模临床全基因组关联研究中发现的 AD 风险变异如何参与 AD 的病理机制，并表明这些研究中引入的下游消除表型异质性的重要性。