Abstract
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.
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This post is Copyright: | August 24, 2026
Neuro-Dementia