Abstract INTRODUCTION The association of testosterone and cognitive decline is inconclusive, and its joint effect with neurofilaments light chain (NfL) remains largely unknown. METHODS A total of 581 non‐demented older men in the Shanghai Aging Study were included. Blood total testosterone (TT), free testosterone (FT), and NfL were measured at baseline. The relationships between TT, FT, TT/FT‐NfL, and cognitive decline were explored by Cox regression models. RESULTS During a median follow‐up of 6.7 years, there was an inverse association between TT/FT and cognitive decline (TT, trend p = 0.004, Q1 vs Q4, hazard ratio [HR] = 4.39, 95% confidence interval [CI] = 1.60 to 12.04; FT, trend p = 0.002, Q1 vs Q4, HR = 5.29, 95% CI = 1.50 to 16.89). Compared to participants with high TT/FT‐low NfL, those with low TT/FT‐high NfL had significantly higher risks of cognitive decline (TT, HR = 5.10, 95% CI = 1.11 to 23.40; FT, HR = 6.14, 95% CI = 1.34 to 28.06). DISCUSSION Our findings suggest that the combination of testosterone and neurodegenerative markers may provide reliable predictive insights into future cognitive decline. Highlights Testosterone is inversely associated with cognitive decline in older men. There is a joint effect of testosterone and NfL on cognitive decline. Sex hormone and neurodegeneration may synergistically contribute to cognitive deterioration.

Joint effect of testosterone and neurofilament light chain on cognitive decline in men: The Shanghai Aging Study