Associations Between Age at Menopause, Vascular Risk, and 3-Year Cognitive Change in the Canadian Longitudinal Study on Aging

Background and Objectives Mounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition. Methods We used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes, smoking, and obesity. Cognition was measured with a global cognitive composite at baseline and 3-year follow-up. Linear models tested independent and interactive associations of age at menopause, vascular risk, and HT history with cognition at 3-year follow-up, adjusting for baseline cognition, baseline age, years of education, and test language (English/French). Results We included 8,360 postmenopausal female participants (mean age at baseline = 65.0 +/- 8.53 years, mean age at menopause = 50.1 +/- 4.62 years) and 8,360 age-matched male participants for comparison. There was an interaction between age at menopause and vascular risk, such that earlier menopause and higher vascular risk were synergistically associated with lower cognitive scores at follow-up (beta = 0.013, 95% CI 0.001-0.025, p = 0.03). In stratified analyses, vascular risk was associated with lower cognitive scores in female participants with earlier menopause (menopausal ages 35-48 years; beta = -0.044, 95% CI -0.066 to -0.022, p < 0.001), but not average (ages 49-52 years; beta = -0.007, 95% CI -0.027 to 0.012, p = 0.46) or later menopause (ages 53-65 years; beta = 0.003, 95% CI -0.020 to 0.025, p = 0.82). The negative association of vascular risk with cognition in female participants with earlier menopause was stronger than the equivalent association in age-matched male participants. HT history did not further modify the synergistic association of age at menopause and vascular risk with follow-up cognition (beta = -0.005, 95% CI -0.032 to 0.021, p = 0.69). Discussion Endocrine and vascular processes may synergistically contribute to increased risk of cognitive decline in female adults. These findings have implications for the development of sex-specific dementia prevention strategies.