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 – from age at menarche to age at menopause – has been associated with lower cerebrospinal fluid (CSF) levels of beta-amyloid 1-42 (A), 42), higher levels of phosphorylated tau (p-tau) and a ratio of Aβ42 and amyloid-beta 1-40 (Aβ42 / Aβ40), reported Jenna Najar, MD, PhD, 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 it was thought that this gender difference in Alzheimer’s risk was only due to the fact that women live longer than men. men, ”Najar said. MedPage today. “However, the evidence shows that the difference in longevity between the sexes could not explain all of the differences in dementia risk between men and women.”

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

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

“While clinical trials have shown either a higher risk of dementia or no risk, in women on hormone therapy, observational studies have provided evidence for both the protective effect of estrogen,” Buckley said. . MedPage today.

The results of this study “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 tau levels than men in many areas of the brain – our work has found this time and again in multiple cohorts – this is one of the first to suggest that a longer breeding period could 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 still unfolds on the biological sexual mechanisms underlying Alzheimer’s disease risk, particularly from the perspective of pathological markers of tau,” she said.

In their analysis, Najar and colleagues examined 75 dementia-free women from a sample population in Gothenburg, who were followed from 1968 to 1994. All of the women had natural menopause. Information on the breeding season came from interviews conducted from 1968 to 1980. CSF assessments were from lumbar punctures performed from 1992 to 1994.

The median age at the initial examination (the first examination after menopause) was 52 years and the median age at the lumbar puncture was 74 years. The average length of the reproductive period was 35.4 years, with an average age of 14 years at menarche and 49.4 years at menopause.

A longer reproduction 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 observed for total tau (β 0.01, P= 0.46).

An earlier age at menarche was associated with higher levels of p-tau (β -0.07, P= 0.031) and a 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 association was found between age at menopause and Alzheimer’s CSF biomarkers.

The results need to be confirmed in larger samples, the researchers noted. “Many studies are insufficient to examine the impact of sex hormones and reproductive history on Alzheimer’s disease, primarily because the studies were not designed specifically to test these questions,” Buckley pointed out.

“Over time, and with increasing interest in this area of ​​research, I hope we will see large meta-analyzes on different components of reproductive history and menopausal transition in association with risk. Alzheimer’s disease, ”she said.

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

“What is absolutely clear is that due to different reproductive changes throughout life, women are affected by the disease differently from men, and this probably has ramifications for drug treatment in clinical trials. on Alzheimer’s disease, ”she said.

Last updated on July 08, 2021