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Could a longer reproductive period put women at greater risk for Alzheimer disease?

New study suggests that a longer exposure to endogenous estrogen is associated with increased levels for Alzheimer disease biomarkers

Estrogen has been thought to play a role in a woman's risk of developing Alzheimer disease (AD). A new study has taken a different approach to identifying risk factors for AD by examining the association between a woman's reproductive life span as an indicator of endogenous estrogen exposure and levels of cerebrospinal fluid biomarkers. Study results are published online in Menopause, the journal of The North American Menopause Society (NAMS).

Alzheimer disease represents 60% to 70% of all dementia diagnoses, making it the most common form of dementia. Approximately two-thirds of those with AD are women. This is not surprising, because age is the greatest known risk factor for AD, and women tend to live longer than men.

The incidence of AD is rising quickly because of the aging population, so multiple studies have been undertaken to identify other risk factors, especially those that may explain any sex differences. Prior studies have shown a link between both higher and lower estradiol blood levels and risk of dementia, whereas others have identified no associations. Some studies have shown that hormone therapy after menopause can increase the risk of dementia, but others have documented a decreased risk. Similarly, cognitive decline has been linked with both longer and shorter reproductive periods.

Despite all the conflicting evidence, few, if any, studies have examined the association between estrogen and biomarkers for AD in cerebrospinal fluid, the clear body fluid found within the tissues surrounding the brain and spinal cord. In this new study, a small sampling of women who were free of dementia and underwent natural menopause were followed for 25 years. Based on the results from the cerebrospinal fluid samples, researchers concluded that a longer reproductive life was associated with increased levels of AD biomarkers in the preclinical phase of the disease; however, they suggested that larger studies should be conducted to confirm these findings.



The aim of the study was to examine the association between reproductive period, as an indicator of endogenous estrogen, and levels of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD).


A population-based sample of women from Gothenburg, Sweden was followed from 1968 to 1994 (N = 75). All women had natural menopause and were free from dementia. Information on reproductive period (age at menarche to age at menopause) was obtained from interviews from 1968 to 1980. Lumbar puncture was performed from 1992 to 1994 and CSF levels of Aβ42, Aβ40, P-tau, and T-tau were measured with immunochemical methods. Linear regression models adjusted for potential confounders were used to analyze the relationship between reproductive period and CSF biomarkers for AD.


Longer reproductive period was associated with lower levels of Aβ42 (β = -19.2, P = 0.01), higher levels of P-tau (β = 0.03, P = 0.01), and lower ratio of Aβ42/Aβ40 (β = -0.02, P = 0.01), while no association was observed for T-tau (β = 0.01, P = 0.46). In separate analyses, examining the different components of reproductive period, earlier age at menarche was associated higher levels of P-tau (β = -0.07, P = 0.031) and lower ratio of Aβ42/Aβ40 (β = 0.05, P = 0.021), whereas no association was observed with Aβ42 (β = 31.1, P = 0.11) and T-tau (β = -0.001, P = 0.98). Furthermore, no association was observed between age at menopause and CSF biomarkers for AD.


Our findings suggest that longer exposure to endogenous estrogen may be associated with increased levels of AD biomarkers in the preclinical phase of AD. These findings, however, need to be confirmed in larger samples.


Jenna Najar 1, Tore Hällström, Anna Zettergren, Lena Johansson, Erik Joas, Madeleine Mellqvist Fässberg, Henrik Zetterberg, Kaj Blennow, Silke Kern, Ingmar Skoog. Reproductive period and preclinical cerebrospinal fluid markers for Alzheimer disease: a 25-year study. Menopause 2021 Jul 2. doi: 10.1097/GME.0000000000001816. Online ahead of print

Content updated 29 July 2021

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