Genetic evidence suggests a protective role of immunoglobulin M in Alzheimer's disease.

INTRODUCTION: Immune dysfunction has been implicated in Alzheimer's disease (AD), but the roles of specific immunoglobulin classes remain unclear. METHODS: We integrated human genetics and plasma biomarker analyses to evaluate immunoglobulin G (IgG), IgA, and IgM in relation to AD. Two-sample Mendelian randomization analyses were conducted with multiple sensitivity analyses. Polygenic risk scores for immunoglobulin classes were developed in the All of Us Research Program and tested in the UK Biobank for associations with AD and dementia, and in two Wisconsin-based cohorts for associations with plasma amyloid beta (Aβ)42/40, phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). RESULTS: Higher genetically proxied IgM was consistently associated with lower AD risk, higher Aβ42/40, and lower p-tau217, but not with NfL or GFAP. No consistent associations were observed for IgG or IgA. DISCUSSION: IgM-related humoral immunity may play a protective role in AD and warrants exploration for early intervention and prevention.