HRT may ward off Alzheimer`s risk in menopausal women

Washington: Measurable signs of accelerated biological ageing were seen in healthy menopausal women carrying a well-known genetic risk factor for Alzheimer`s disease, according to a new study.

However, in carriers who started hormone therapy at menopause and remained on that therapy, this acceleration was absent, the researchers said.

Hormone therapy for non-carriers of the risk factor, a gene variant called ApoE4, had no protective effect on their biological ageing.

"This shows that ApoE4 is contributing to ageing at the cellular level well before any outward symptoms of decline become apparent. Yet, estrogen appears to have a protective effect for middle-aged women who are carrying this genetic risk factor," said Natalie Rasgon, MD, PhD, professor of psychiatry and behavioral sciences at the Stanford University School of Medicine and director of the Stanford Center for Neuroscience in Women`s Health.

All people carry two copies of a gene called ApoE. (One copy is inherited from each parent). Like genes for eye or hair color, ApoE comes in more than one version. Many carry at least one copy of ApoE4, a version that puts them at substantially increased risk for late-onset Alzheimer`s disease in comparison with people who are not ApoE4 carriers.

"We know from numerous studies that ApoE4 is a major genetic risk factor for cognitive decline, Alzheimer`s disease and early mortality. We wanted to see whether an accelerated rate of biological ageing explained this risk," said first author Emily Jacobs, PhD, a postdoctoral fellow at Harvard Medical School.

Another co-author of the study is Elizabeth Blackburn, PhD, professor of biochemistry and biophysics at UCSF, who won the Nobel Prize in 2009 for her work elucidating the mechanism by which intracellular features called telomeres act as biological clocks.
Using telomere shortening as an index of biological ageing, the investigators drew blood samples from almost 70 healthy women, most of them between the ages of 45 and 65, who had been on hormone therapy since menopause. These women were randomly divided into two groups. One group remained on hormones, while the second group discontinued therapy.

Jacobs, Rasgon and their colleagues separated white blood cells from each sample, extracted the cells` DNA and measured the length of each woman`s telomeres at both time points. Then they calculated the change in telomere length that had taken place over the two-year period.

They found that ApoE4 carriers` telomeres were six times as likely as those of non-carriers to undergo significant shortening within the two-year study window. On average, the telomeres of ApoE4 carriers had shortened by an amount equivalent to what might be expected to take a decade, based on other studies of healthy women.

However, hormone therapy effectively zeroed out ApoE4`s negative influence on telomere length over time. Carriers who remained on this regimen showed no evidence of telomere shortening.

"Our take-home findings from this study were, first, that ApoE4 carriers are at greater risk of biological ageing, which is associated with negative health outcomes and, second, that if you were a postmenopausal ApoE4 carrier, being on estrogen therapy was a good thing for telomere length, an established measure of biological ageing at the cellular level," Rasgon said.

"This brings us a step closer to being able to identify which women will benefit the most from estrogen replacement therapy," she added.

The finding has been published online in PLOS ONE.