Multi-omics identification of haptoglobin as a novel target for increased Alzheimer's disease risk associated with obesity through inhibiting the phagocytosis of Aβ by disease-associated microglia.

INTRODUCTION: Obesity may increase Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear. METHODS: We investigated this link through global epidemiology, Mendelian randomization (MR), transcriptomics, clinical cohort validation, and mechanistic exploration. RESULTS: High body mass index (BMI)-attributable AD disability-adjusted life years and deaths increased 4-fold from 1990-2021, with projections indicating a tripling by 2050. MR analyses found that elevated BMI was genetically related to increased AD risk. Haptoglobin (HP) was identified as a core mediator between them. HP expression was correlated with plasma AD biomarkers and cognitive scores. Mechanistically, HP localized to plaque-associated microglia and suppressed microglial amyloid beta (Aβ) phagocytosis and DNAX activating protein of 12 kDa (Dap12)/Spleen tyrosine kinase (Syk) pathway with modulating disease-associated microglial transcriptional programs. CONCLUSION: This study identified HP as a strong candidate mediator linking obesity to AD pathogenesis through inhibiting the phagocytosis of Aβ by microglia.