Hip Bone Marrow Adiposity as a Risk Factor for Alzheimer's Disease: Insights From Mendelian Randomization Analysis

Abstract Background The bone–brain axis has emerged as a critical framework linking skeletal metabolism to neurodegeneration. Within this axis, bone marrow adipose tissue (BMAT) represents a unique fat depot with distinct endocrine and hematopoietic functions, yet its contribution to Alzheimer's disease (AD) remains unclear. Methods We conducted a two‐sample Mendelian randomization (MR) analysis using genome‐wide association study (GWAS) summary statistics to assess the causal effects of six fat depots—abdominal subcutaneous, visceral, spinal, femoral head, total hip, and femoral diaphysis fat—on AD risk. Mediation analysis was further performed to evaluate whether femoral neck bone mineral density (BMD) mediates these associations. Results Among the six depots, only total hip BMAT showed a significant causal association with AD risk (OR = 1.28, 95% CI: 1.09–1.51, p = 0.003). Total hip BMAT was inversely related to femoral neck BMD ( β = –0.43, 95% CI: –0.61 to –0.24, p < 0.001), whereas no causal relationship was detected between BMD and AD (OR = 1.01, 95% CI: 0.89–1.15, p = 0.849), excluding bone loss as a mediator. Conclusions This study provides the first genetic evidence that excessive hip BMAT increases the risk of AD, supporting the bone–brain axis hypothesis. These findings highlight BMAT as a novel target for understanding and potentially preventing AD.