Disclosures: Najar reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.
July 07, 2021
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Higher Alzheimer’s disease biomarkers linked to longer reproductive life span in women

Disclosures: Najar reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.
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Longer exposure to endogenous estrogen is associated with increased levels of Alzheimer’s disease biomarkers in women, according to a study published in Menopause.

In a long-term population-based study of women in Sweden, longer reproductive life span was associated with increased levels of biomarkers during the preclinical phase of Alzheimer’s disease.

Older woman feeling better
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“Our finding that longer reproductive period was associated with preclinical biomarkers for Alzheimer’s disease is in line with results from the same study reporting that longer reproductive period was associated with increased risk for dementia and a clinical diagnosis of Alzheimer’s disease, in women followed over 44 years, from 1968 to 2012,” Jenna Najar, MD, PhD, researcher in the Institute of Neuroscience and Physiology at the University of Gothenburg in Sweden, and colleagues wrote. “Further support comes from the Rotterdam Study reporting an increased risk of dementia in women with higher serum estradiol levels and longer reproductive period. Moreover, our findings are also consistent with results from neuroimaging studies.”

Researchers analyzed data from the Prospective Population Study of Women from Gothenburg, Sweden. Participants born in 1908, 1914, 1918 and 1922 were enrolled in the study in 1968 and 1969, and had reexaminations from 1974 to 1975, 1980 to 1981 and 1992 to 1994. In the final follow-up, women were invited to have an extensive neuropsychiatric examination and lumbar puncture in which levels of cerebrospinal fluid biomarkers were collected. There were 75 women with natural menopause and no dementia included in the analysis (median age, 52 years at baseline). Information on age at menarche and menopause were obtained through semi-structured interviews. Data on covariates were obtained at baseline through interviews and self-examination.

Researchers used two models to analyze the relationship between reproductive life span and cerebrospinal fluid biomarker levels. The first model used reproductive period and birth year as covariates for all biomarkers. In the second model, the covariates for amyloid-beta 42 were birth year, oral contraceptive use, waist-to-hip ratio and education; covariates for phosphorylated tau (p-tau) were birth year, psychological stress, smoking status and education; for total tau (t-tau), the covariates were birth year and psychological stress; and for amyloid-beta 42/40 ratio, the covariates were birth year, waist-to-hip ratio and psychological stress.

In the first model, a longer reproductive life span was associated with lower levels of amyloid-beta 42 (beta = –14.5; P = .048) and a lower amyloid-beta 42/40 ratio (beta = –0.2; P = .0084). In the second model, a longer reproductive life span was associated with lower levels of amyloid-beta 42 (beta = –19.2; P = .011), a lower amyloid-beta 42/40 ratio (beta = –0.02; P = .011) and higher levels of p-tau (beta = –0.03; P = .011). There were no associations between reproductive life span length and t-tau levels.

In a secondary analysis with crude models adjusted for birth year, earlier age at menarche was associated with higher levels of p-tau (beta = –0.07; P = .031) and a lower amyloid-beta 42/40 ratio (beta = 0.5; P = .021). There were no associations between age at menopause and any biomarkers. A strong correlation was observed between age at lumbar puncture and birth year, reducing the possibility that the associations in the study were driven by different ages during lumbar puncture.

“These results add to the understanding of the association between indicators of endogenous estrogen and Alzheimer’s disease,” the researchers wrote. “This may be one explanation for the higher lifetime risk of Alzheimer’s disease in women compared to men. The findings, however, need to be confirmed in larger samples.”