Patients with late-onset Alzheimer’s disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with major depressive disorder (MDD) have an increased prevalence of LOAD. This suggests shared etiologies and intersecting pathways between LOAD and MDD. We performed pleiotropy analyses using LOAD and MDD GWAS data sets from the International Genomics of Alzheimer’s Project (IGAP) and the Psychiatric Genomics Consortium (PGC), respectively. We found a moderate enrichment for SNPs associated with LOAD across increasingly stringent levels of significance with the MDD GWAS association (LOAD|MDD), of maximum four and eightfolds, including and excluding the APOE-region, respectively. Association analysis excluding the APOE-region identified numerous SNPs corresponding to 40 genes, 9 of which are known LOAD-risk loci primarily in chromosome 11 regions that contain the SPI1 gene and MS4A genes cluster, and others were novel pleiotropic risk-loci for LOAD conditional with MDD. The most significant associated SNPs on chromosome 11 overlapped with eQTLs found in whole-blood and monocytes, suggesting functional roles in gene regulation. The reverse conditional association analysis (MDD|LOAD) showed a moderate level, ~sevenfold, of polygenic overlap, however, no SNP showed significant association. Pathway analyses replicated previously reported LOAD biological pathways related to immune response and regulation of endocytosis. In conclusion, we provide insights into the overlapping genetic signatures underpinning the common phenotypic manifestations and inter-relationship between LOAD and MDD. This knowledge is crucial to the development of actionable targets for novel therapies to treat depression preceding dementia, in an effort to delay or ultimately prevent the onset of LOAD.

迟发性阿尔茨海默病 (LOAD) 患者经常表现出合并的神经精神症状，其中抑郁和焦虑最为常见，重度抑郁症 (MDD) 患者的 LOAD 患病率增加。这表明 LOAD 和 MDD 之间存在共同的病因和交叉通路。我们分别使用国际阿尔茨海默病基因组学项目 (IGAP) 和精神病基因组学联盟 (PGC) 的 LOAD 和 MDD GWAS 数据集进行了多效性分析。我们发现与 LOAD 相关的 SNP 在与 MDD GWAS 关联 (LOAD|MDD) 越来越严格的显着性水平上适度富集，最大四倍和八倍，分别包括和不包括APOE区域。不包括APOE的关联分析-region 确定了对应于 40 个基因的大量 SNP，其中 9 个是已知的 LOAD 风险基因座，主要位于包含SPI1基因和MS4A的染色体 11 区域基因簇，其他基因是新的多效性风险基因座，负载条件为 MDD。11 号染色体上最显着的相关 SNP 与在全血和单核细胞中发现的 eQTL 重叠，表明在基因调控中的功能作用。反向条件关联分析 (MDD|LOAD) 显示中等水平，约七倍的多基因重叠，然而，没有 SNP 显示出显着关联。通路分析复制了先前报道的与免疫反应和内吞作用调节相关的 LOAD 生物通路。总之，我们对支持常见表型表现的重叠遗传特征以及 LOAD 和 MDD 之间的相互关系提供了见解。这些知识对于开发可操作的靶点来治疗痴呆症之前的抑郁症的新疗法至关重要，