Circulating adipokines level and the risk of neurodegenerative diseases: a two‑sample mendelian randomization study and proteomic analysis

BACKGROUND: Observational studies have suggested associations between circulating adipokines and neurodegenerative diseases, but the causal nature of these relationships remains unclear. This study evaluated the causal effects of adipokines on neurodegenerative diseases using Mendelian randomization (MR) and validated key findings through proteomic analysis. METHODS: Two-sample MR was performed using genome-wide association study (GWAS) summary statistics for adiponectin (N = 39,883), leptin (N = 57,232), resistin (N = 21,758), and monocyte chemoattractant protein-1 (MCP-1; N = 21,758). Outcomes included Alzheimer’s disease (AD; N = 63,926), Parkinson’s disease (PD; N = 482,730), and amyotrophic lateral sclerosis (ALS; N = 36,052). The inverse-variance weighted (IVW) method was applied for primary causal estimates, with sensitivity analyses assessing pleiotropy and heterogeneity. Significant MR findings were further examined in a proteomic cohort. RESULTS: Higher genetically predicted adiponectin levels were significantly associated with a reduced risk of AD (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.65–0.96, p = 0.019). This association remained robust across multiple sensitivity analyses, with no evidence of horizontal pleiotropy or heterogeneity. By contrast, no causal relationships were identified for leptin, resistin, or MCP-1 with the risk of AD, PD, or ALS. Complementing the genetic findings, proteomic analysis further revealed that plasma adiponectin levels were downregulated in mild cognitive impairment patients who experienced cognitive deterioration compared with those showing cognitive improvement. CONCLUSION: The findings provide genetic evidence supporting a potential protective role of adiponectin in AD, with the proteomic results offering complementary, directionally consistent support. Adiponectin may represent a potential biomarker and therapeutic target for AD.