The length of a woman’s reproductive period (age at menarche to age at menopause) may hold clues to Alzheimer disease (AD) risk, according to a study conducted in Sweden and published in Menopause.

Estrogen has been suggested as a possible reason why more women than men develop AD. The researchers examined long-term associations between reproductive period and levels of AD biomarkers found in cerebral spinal fluid. The biomarkers the researchers looked for were Aβ42, P-tau, T-tau, and ratio of Aβ42/Aβ40.

They used a population-based sample of women without dementia and followed them from 1968 to 1994. All women experienced natural menopause. Lumbar puncture was performed between 1992 and 1994. The 75 women participants were born in 1908, 1914, 1918, and 1922; all but 8 were born in 1918 or 1922.

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The researchers used 2 linear regression models to analyze the relationship between length of menses and AD biomarkers. In the first model, a longer reproductive period was associated with lower levels of Aβ42 (β, -14.5; R2, 0.04; P =.048) and a lower ratio of Aβ42/Aβ40 (β, -0.02; R2, 0.1; P =.0084).

In the second model, a longer reproductive period was associated with lower levels of Aβ42 (β, -19.2; R2, 0.1; P =.011), a lower ratio of Aβ42/Aβ40 (β, -0.02, R2, 0.1; P =.011), and higher levels of P-tau (β, -0.03; R2, 0.1; P =.011). The researchers found no associations between length of reproductive period and levels of CSF T-tau.

The researchers’ results do not support past studies that showed estrogen provides a neuroprotective benefit. The researchers did not find a significant association between age at menopause and AD biomarkers.

The study had limitations, including a small sample size and cumulative attrition. Only 10% of the total eligible sample underwent lumbar puncture. That sample could be generally younger and healthier than the general population; the group was younger, had higher-than-average education, and members were less likely to develop dementia compared with nonparticipants. The researchers also suspected some recall biases.

The study “may suggest that longer exposure to endogenous estrogen is associated with increased levels of AD biomarkers in the preclinical phase of AD,” the researchers concluded. “These results add to the understanding of the association between indicators of endogenous estrogen and AD. This may be one explanation for the higher life-time risk of AD in women compared to men.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Najar J, Hällström T, Zettergren A, et al. Reproductive period and preclinical cerebrospinal fluid markers for Alzheimer disease: a 25-year study. Menopause. Published online July 2, 2021. doi:10.1097/GME.0000000000001816