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

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.