Alzheimer’s Biomarkers Tied to Endogenous Estrogen Exposure in Women

Longer exposure to endogenous estrogen was linked to higher levels of Alzheimer’s disease biomarkers in cognitively normal older women, a 25-year study showed.

A longer reproductive period — age at menarche to age at menopause — was associated with lower cerebrospinal fluid (CSF) levels of amyloid-beta 1-42 (Aβ42), higher levels of phosphorylated tau (p-tau), and a lower ratio of Aβ42 and amyloid-beta 1-40 (Aβ42/Aβ40), reported Jenna Najar, MD, PhD, of the University of Gothenburg in Sweden, and co-authors, in Menopause.

Women have a higher risk of Alzheimer’s disease than men, and “for a long time, this sex difference in Alzheimer’s risk was thought to be explained only by the fact that women live longer than men,” Najar told MedPage Today. “However, evidence shows that the sex difference in longevity could not explain all of the differences in dementia risk between men and women.”

Estrogen has been suggested as a potential explanation, but “as far as we know, no previous study has examined the relation between length of reproductive period and levels of CSF markers of Alzheimer’s disease,” Najar noted.

The relationship between sex hormones, especially estrogen, and dementia risk is unclear, observed Rachel Buckley, PhD, of Massachusetts General Hospital in Boston, who wasn’t involved with the study.

“While clinical trials have either shown greater dementia risk, or no risk, in women on hormone therapy, observational studies have provided evidence both for and against the protective effect of estrogen,” Buckley told MedPage Today.

This study’s findings “were quite surprising in that a longer reproductive period was associated with worse outcomes for Alzheimer’s biomarkers of amyloid and phosphorylated tau,” she continued. “Although women have been shown to have higher levels of tau than men across many brain regions — our work has found this time and again across multiple cohorts — this is one of the first to suggest that a longer reproductive period might underlie this differential level of risk.”

Other research has shown that age at menopause is associated with higher levels of amyloid, lower levels of glucose metabolism, and smaller brain volumes on MRI, Buckley added. “I think the story is still unfolding on the sex biological mechanisms underlying risk for Alzheimer’s disease, particularly from the perspective of pathological markers of tau,” she said.

In their analysis, Najar and colleagues looked at 75 dementia-free women from a population-based sample in Gothenburg, who were followed from 1968 to 1994. All the women had natural menopause. Reproductive period information came from interviews conducted from 1968 to 1980. CSF assessments came from lumbar punctures performed from 1992 to 1994.

Median age at baseline exam (the first exam after menopause) was 52, and median age at lumbar puncture was 74. Mean length of reproductive period was 35.4 years, with mean ages of 14 at menarche and 49.4 at menopause.

A longer reproductive period was associated with lower levels of CSF Aβ42 (β -19.2, P=0.01), higher levels of p-tau (β 0.03, P=0.01), and a lower Aβ42/Aβ40 ratio (β -0.02, P=0.01). No association was seen for total tau (β 0.01, P=0.46).

Earlier age at menarche was associated with higher levels of p-tau (β -0.07, P=0.031) and lower Aβ42/Aβ40 ratio (β 0.05, P=0.021), but not with Aβ42 (β 31.1, P=0.11) or total tau (β -0.001, P=0.98). No associations emerged between age at menopause and Alzheimer’s CSF biomarkers.

The findings need to be confirmed in larger samples, the researchers noted. “Many studies are underpowered to examine the impact of sex hormones and reproductive history on Alzheimer’s pathology, predominantly because studies have not been designed specifically to test these questions,” Buckley pointed out.

“Over time, and with increasing levels of interest in this area of research, I’m hoping we will see large meta-analyses on differing components of reproductive history and the menopause transition in association with Alzheimer’s disease risk,” she said.

Another area gaining attention is the relationship between testosterone levels and Alzheimer’s biomarkers, with recent evidence suggesting that lower levels of testosterone also may be related to higher levels of p-tau, Buckley added.

“What is absolutely clear is that, as a result of different reproductive changes throughout life, women are impacted by the disease differently than men, and this likely has ramifications for drug treatment in Alzheimer’s disease clinical trials,” she said.

Last Updated July 08, 2021