Revisiting the Effect of Leptin on Alzheimer Disease and Parkinson Disease: The Role of Insulin Sensitivity

Context Studies have indicated a link between leptin, Alzheimer disease (AD), and Parkinson disease (PD). However, the causal relationship among them remains not well established due to confounders and reverse causation.Objective This Mendelian randomization (MR) study was performed to evaluate the impact and potential mechanism of leptin and its soluble receptor on AD and PD.Methods Utilizing genome-wide association studies summary-level data, a comprehensive MR was conducted to assess the causal effect of leptin and soluble leptin receptor (sLEPR) on AD and PD. Additionally, we also explored the role of body mass index (BMI) and insulin sensitivity index (ISI) in using the multivariable MR. The primary analysis was performed using the inverse variance-weighted method.Results Pooled estimates showed that genetically proxied higher leptin levels was significantly associated with a decreased risk of AD (OR 0.838, 95% CI 0.741-0.948, P = .005), but not PD. In contrast, no significant associations were observed between sLEPR levels, AD, and PD. Moreover, the effect of leptin on AD was attenuated to null after adjustment of ISI (OR 0.879, 95% CI 0.758-1.018, P = .086), but not BMI. There was no causal impact of AD and PD on circulating levels of leptin and sLEPR, indicating the absence of reverse causation. Sensitivity analyses confirmed the robustness of these associations, with no obvious pleiotropy and heterogeneity.Conclusion The study offers evidence supporting a potential protective effect of leptin in AD, but not PD, via the enhancement of insulin sensitivity. Our findings underscore the distinct roles of leptin in AD and PD.