Sex Hormones and Risk of Incident Dementia in Men and Postmenopausal Women

ABSTRACT Background Dementia poses a major global public health challenge, with its risk varying by sex. Women were nearly twice as likely to have Alzheimer's and other forms of dementia compared to men. Although testosterone levels are believed to influence cognitive function in older adults, existing studies have reported inconsistent findings, leaving the relationship between sex hormones and dementia unclear. Methods We used data from UK Biobank. Serum total testosterone and sex hormone binding globulin (SHBG) were measured by immunoassay. Serum free testosterone was calculated using vermeulen method. The incident dementia and Alzheimer's disease (AD) was recorded from hospital inpatient data. Cox proportional hazards regression was conducted to assess the association between sex hormones and dementia, adjusted for age and other variables. Restricted cubic spline models were employed to quantify dose–response relationships. Result A total of 186,296 men (mean age: 56.68 years, SD: 8.18) and 126,109 postmenopausal women (mean age: 59.73 years, SD: 5.78) were included. After 12.0 (IQR: 11.0−13.0)‐year follow‐up, 3874 (2.08%) male participants and 2523 (2.00%) female participants developed dementia. Men in the highest quintile of free testosterone levels had a reduced risk of all‐cause dementia (HR: 0.63, 95%CI: 0.56−0.71) and AD (0.49, 0.60−0.72) compared to those in the lowest quintile. Conversely, men in the highest quintile of SHBG levels had an increased risk of all‐cause dementia (1.47, 1.32−1.64) and AD (1.32, 1.11−1.58) compared to those in the lowest quintile. Among postmenopausal women, those in the fourth quintile of free testosterone levels exhibited a lower risk of all‐cause dementia (0.84, 0.78−0.95) and AD (0.76, 0.63−0.91). Higher SHBG was linked to an increased incidence of all‐cause dementia (1.35, 1.28−1.55) and AD (1.52, 1.25−1.85) in menopausal women. Conclusion Our findings revealed that higher SHBG and lower free testosterone concentrations seem to be associated with higher incidence of all‐cause dementia and AD and further studies must be done to determine causality.