Female Reproductive Factors and Risk of Mild Cognitive Impairment and Dementia: The HUNT Study

Background: More women are living with dementia than men worldwide and there is a need to investigate causes for this female preponderance. While reproductive factors have been investigated as risk factors, the results are conflicting. We aim to clarify this using a large cohort with a long observation time, adjusting for multiple health and lifestyle variables and encompassing a wider range of cognitive impairment. Objective: To study the association between menopause age, menarche age and risk of and risk of mild cognitive impairment (MCI) and dementia. Setting: The Trondelag Health study (HUNT), a longitudinal population health study in Norway (1984-2019). Participants: Women who were >= 70 years in 2017-2019 were assessed for cognitive impairment. Measurements: Data on menopause age and menarche age were obtained from questionnaires. Diagnosis of MCI or dementia was set using a standardised procedure by a diagnostic group of nine physicians. Multinomial logistic regression was used to study the association between menopause age, menarche age and risk of MCI and dementia with adjustment for birth year, education, smoking, ApoE4, number of children, diabetes, body mass index, alcohol use and physical inactivity. Results: We evaluated 5314 women where 900 (16.9%) had dementia, and 1747 (32.8%) had MCI. Multiple adjusted relative risk ratio (RRR) and 95% confidence intervals (CI) for dementia were: 0.96(95%CI 0.95-0.98) (p<0.001) for menopause age, 0.97(95%CI 0.94-0.99) (p=0.007) for natural menopause age (excluding hysterectomy and/or oophorectomy<55 years) and 0.97(95%CI 0.95-0.99) (p<0.001) for reproductive span (menopause age minus menarche age). Menopause age <45years was associated with a 56% higher risk compared to mean menopause age 50 years. We found no significant associations between menarche age and dementia and no associations with MCI. Conclusions: Older menopause age and longer reproductive span corresponding to longer oestrogen exposure were associated with a lower dementia risk. Future studies should explore therapeutical options to offset this risk in women.