LEPR and Alzheimer disease: More recently, a large-scale Mendelian randomization study using genome-wide association data demonstrated that genetically predicted higher leptin levels were significantly associated with a reduced risk of AD (OR 0.838, 95% CI 0.741–0.948, p = 0.005), whereas soluble LepR levels showed no significant association; notably, this protective effect was attenuated after adjustment for insulin sensitivity index (ISI) but remained independent of body mass index (BMI), with no evidence of reverse causation, pleiotropy, or heterogeneity observed, supporting the robustness of the findings [306].