Dementia risk jumps in older women with diabetes, high estrogen

By Anne Harding

High estrogen levels after menopause may predict dementia risk, especially among women with diabetes, new findings show.

Diabetic women with the highest estradiol (E2) levels had a 14-fold increased risk of incident dementia over a four-year period compared to those with lower E2 levels, Dr. Pierre-Yves Scarabin of Inserm in Paris, France and colleagues wrote in Neurology, online January 29.

"It was long believed that estrogens were good for women's health especially for (the) heart and brain," Dr. Scarabin told Reuters Health via email. The findings, along with other recent research, challenge this dogma, he added. "Findings from animal models do not necessarily apply to women!"

Dr. Scarabin and his colleagues note that while the decline in estrogen at menopause has been thought to account for cognitive decline as women age, clinical trials have not shown that estrogen therapy improves cognitive function. Two other studies (one by Geerlings et al in 2003 and another by Ravaglia et al in 2007) have linked higher endogenous E2 levels to an increased risk of vascular dementia and Alzheimer's disease.

"Although unexpected, these results are consistent with recent data supporting a deleterious effect of high E2 levels on frailty, cardiovascular disease, and all-cause mortality among postmenopausal women," the researchers write.

In the current study, Dr. Scarabin and his team looked at endogenous total E2, bioavailable E2, and total testosterone and all-cause dementia risk using data from the Three-City Study, a prospective population-based study of 5,644 postmenopausal women aged 65 and older. They compared the 132 women who developed dementia over a four-year period to a random subcohort of 562 women who did not develop dementia and were not using hormone therapy.

The researchers found a J-shaped relationship between total E2 and dementia risk, with women in the first quartile being 2.2 times more likely to develop dementia than those in the third quartile, and women in the fourth quartile at a 2.4-fold increased risk.

Among diabetic women in the fourth E2 quartile, dementia risk was 14.2 times higher compared to diabetic women in the second and third quartiles. For women without diabetes, the risk associated with high estradiol was 1.9-fold greater.

Similar results were found for bioavailable E2. Adjusting for several markers of inflammation and blood coagulation did not affect the results, and there was no relationship between total testosterone and dementia risk.

When the investigators excluded women with cognitive impairment at baseline as well as women who developed dementia during the first two years of follow-up, the relationship between low E2 levels and dementia disappeared, although the high E2-dementia link persisted. This suggests that reverse causation may account for the link between low E2 and dementia, Dr. Scarabin and his team say.

"Brain infarcts, microvascular pathologies, inflammation, and alteration in glucose, insulin, and amyloid metabolism may underlie the increased dementia risk in subjects with diabetes," they write. "Given that high E2 is also associated with a range of mechanisms involved in atherothrombosis such as enhanced inflammation and blood coagulation, it is plausible that higher endogenous E2 together with diabetes promote a set of unfavorable vascular processes to increase risk of dementia in postmenopausal women."

Future studies should investigate whether it's possible to reduce women's dementia risk by lowering their E2 levels, Dr. Scarabin said. "Women with both diabetes and 'hyperestrogenicity' could be a target for future prevention studies," he said.

SOURCE: http://bit.ly/1exT29B

Neurology 2014.

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