Prevailing Antagonistic Risks in Pleiotropic Associations with Alzheimer’s Disease and Diabetes

Abstract

Background: The lack of efficient preventive interventions against Alzheimer’s disease (AD) calls for identifying efficient modifiable risk factors for AD. As diabetes shares many pathological processes with AD, including accumulation of amyloid plaques and neurofibrillary tangles, insulin resistance, and impaired glucose metabolism, diabetes is thought to be a potentially modifiable risk factor for AD. Mounting evidence suggests that links between AD and diabetes may be more complex than previously believed. Objective: To examine the pleiotropic architecture of AD and diabetes mellitus (DM). Methods: Univariate and pleiotropic analyses were performed following the discovery-replication strategy using individual-level data from 10 large-scale studies. Results: We report a potentially novel pleiotropic NOTCH2 gene, with a minor allele of rs5025718 associated with increased risks of both AD and DM. We confirm previously identified antagonistic associations of the same variants with the risks of AD and DM in the HLA and APOE gene clusters. We show multiple antagonistic associations of the same variants with AD and DM in the HLA cluster, which were not explained by the lead SNP in this cluster. Although the ɛ2 and ɛ4 alleles played a major role in the antagonistic associations with AD and DM in the APOE cluster, we identified non-overlapping SNPs in this cluster, which were adversely and beneficially associated with AD and DM independently of the ɛ2 and ɛ4 alleles. Conclusion: This study emphasizes differences and similarities in the heterogeneous genetic architectures of AD and DM, which may differentiate the pathogenic mechanisms of these diseases.