ABSTRACT: Alzheimer's disease (AD) and ischemic stroke (IS) are an immense socioeconomic burden worldwide. There is a possibility that shared genetic factors lead to their links at epidemiological and pathophysiological levels. Although recent genome-wide association studies (GWAS) have provided profound insights into the genetics of AD and IS, no shared genetic variants have been identified to date. This prompted us to initiate this study, which sought to identify shared pathways linking AD and IS. We took advantage of large-scale GWAS summary data of AD (17,008 AD cases and 37,154 controls) and IS (10,307 cases and 19,326 controls) to conduct pathway analyses using genetic pathways from multiple well-studied databases, including GO, KEGG, PANTHER, Reactome, and Wikipathways. Collectively, we discovered that AD and IS shared 179 GO categories (56 biological processes, 95 cellular components, and 28 molecular functions); and the following pathways: six KEGG pathways; two PANTHER pathways; four Reactome pathways; and one in Wikipathways pathway. The more fine-grained GO terms were mainly summarized into different functional categories: transcriptional and post-transcriptional regulation, synapse, endocytic membrane traffic through the endosomal system, signaling transduction, immune process, multi-organism process, protein catabolic metabolism, and cell adhesion. The shared pathways were roughly classified into three categories: immune system; cancer (NSCLC and glioma); and signal transduction pathways involving the cadherin signaling pathway, Wnt signaling pathway, G-protein signaling and downstream signaling mediated by phosphoinositides (PIPs). The majority of these common pathways linked to both AD and IS were supported by convincing evidence from the literature. In conclusion, our findings contribute to a better understanding of common biological mechanisms underlying AD and IS and serve as a guide to direct future research.
