Abstract
Testosterone replacement for older men is increasingly common, with some observations suggesting a protective effect on cognitive function. We examined the association of endogenous testosterone with cognitive function among older men in a Mendelian randomization study using a separate-sample instrumental variable (SSIV) analysis estimator to minimize confounding and reverse causality. A genetic score predicting testosterone was developed in 289 young Chinese men from Hong Kong, based on selected testosterone-related single nucleotide polymorphisms (rs10046, rs1008805 and rs1256031). The association of genetically predicted testosterone with delayed 10-word recall score and Mini-Mental State Examination (MMSE) score was assessed at baseline and follow-up using generalized estimating equation among 4,212 older Chinese men from the Guangzhou Biobank Cohort Study. Predicted testosterone was not associated with delayed 10-word recall score (−0.02 per nmol/L testosterone, 95% confidence interval (CI) −0.06–0.02) or MMSE score (0.06, 95% CI −0.002–0.12). These estimates were similar after additional adjustment for age, education, smoking, use of alcohol, body mass index and the Framingham score. Our findings do not corroborate observed protective effects of testosterone on cognitive function among older men.
Highlights
Testosterone has attracted great interest as a therapy for older men in the last few years, especially in North America[1]
Among the 8,450 men in all 3 phases of the Guangzhou Biobank Cohort Study (GBCS), DNA was extracted from blood samples and used for single nucleotide polymorphism (SNP) testing for 4,262 men, with availability depending on phase of recruitment and other logistical concerns, but not on genetic profile or cognitive function
Men with SNPs tested had higher baseline delayed 10-word recall score (mean difference 0.22, 95% confidence interval (CI) 0.14–0.30) than men without SNP testing, but were not different in baseline Mini-Mental State Examination (MMSE), assessed from linear regression adjusted for age; small differences could occur by chance
Summary
Curvilinear association with verbal memory, which disappears in age subgroups; only associated with better verbal memory in the oldest age group, no association in other age groups. Optimal TT associated with better MMSE at baseline, no association with MMSE change or verbal memory. No association with modified mental state examination (3MS), which includes MMSE. Prostate cancer patients receiving ADT had worse performance on visuomotor tasks compared to noncancer control groups. We used a separate-sample MR study design to assess the effect of endogenous peak testosterone on cognitive function in older men
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