BACKGROUND: Cognitive functioning can be negatively influenced by age, cardiovascular risk (CVR) and mental health challenges, and sex-hormones can have neuroprotective effects. Little is known about cognitive functioning in older transgender individuals receiving long-term gender-affirming hormone therapy (GHT). In a previous, smaller study, cognitive differences between transgender women and cisgender groups were minimal yet statistically significant. AIMS: This study assessed cognitive differences between larger samples of older transgender and cisgender individuals, and the contribution of CVR and mental/social health to these differences. METHODS: This cross-sectional study compared 73 transgender women and 39 transgender men (56-84 y) receiving long-term GHT (10-47 y) with matched (age
education level) cisgender women and men from the Longitudinal Aging Study Amsterdam on cognitive functioning assessed with neuropsychological tests. Mean z-scores per cognitive domain were calculated and analyzed using linear regression. Models were subsequently adjusted for CVR ((history of) cardiovascular disease
smoking) and mental/social health (anxiety
loneliness) factors. RESULTS: Transgender women had lower scores than cisgender women and men, respectively, on information-processing speed (b = -0.62, 95% CI -0.90 to -0.35
b = -0.33, 95%CI -0.60 to -0.05), episodic memory (b = -1.28, 95%CI -1.53 to -1.04
b = -0.77, 95%CI -1.01 to -0.52), and crystallized intelligence (b = -0.42, 95%CI -0.75 to -0.10
b = -0.41, 95%CI -0.75 to -0.08). Transgender men scored lower on episodic memory than cisgender women but scored equal to cisgender men (b = -0.43, 95%CI -0.79 to -0.08
b = -0.01, 95%CI -0.36 to 0.35). Mental/social health factors (particularly depressive symptoms) largely, and CVR factors slightly, explained cognitive differences between the trans- and cisgender groups. DISCUSSION: Small cognitive differences between transgender men and cisgender groups do not suggest adverse or beneficial long-term testosterone effects on cognitive functioning. However, transgender women had lower cognitive functioning than cisgender groups, which was largely explained by mental/social health. This warrants further research and clinical awareness of mental and cognitive health in older transgender individuals.