HRT May Protect Against Alzheimer’s for High-Risk Women

    • February 13, 2013

A new study by Robert Wood Johnson Foundation (RWJF) Health & Society Scholar (2010-2012) Emily Goard Jacobs, PhD, is the first to find that hormone replacement therapy (HRT) may have a direct effect on a genetic marker for dementia and biological aging.

Previous studies have found that longer exposure to endogenous estrogen over a woman’s lifetime results in longer telomeres. Telomere length is a measure of biological aging. Other studies have also shown that estrogen, even HRT, protects the connection between brain cells and neurons, to some degree. “Telomeres also show a striking difference between genders,” Jacobs explained. “Women have consistently longer telomeres than men and estrogen exposure might help explain this difference.”

True Power of Estrogen a Mystery

But like other aspects of the hormone replacement therapy debate, significant questions remain about whether hormones, taken in the years just after menopause, can protect all women from the damage that comes with time.

Jacobs and her team decided that one way to answer this question was to gauge the impact of estrogen on the telomeres of women with the APOE-e4 gene allele. People with APOE-e4 have roughly four times the risk of developing Alzheimer’s disease than someone without the gene. “We know that APOE-e4 is a major genetic risk factor for Alzheimer’s disease and early mortality,” Jacobs said.

Seeking the answer through telomeres made sense because, Jacobs said, “telomere length [longer is better] is an emerging biomarker of aging.” Telomeres can predict how long you live, how well you age or whether you will be susceptible to certain diseases.

Telomeres are at the tip of every DNA-filled chromosome—“think of the plastic cap at the end of a shoelace,” Jacobs said. Each time a cell divides, telomeres shorten, which is a normal part of life. But many factors, including oxidative stress, inflammation, and psychological stress (such as being a victim of child abuse) may hasten telomere shortening and thus the aging process.

The Hormone Effect

“For our study, we followed 63 post-menopausal women (the mean age was 57) who had been on hormone replacement therapy since menopause. The women were randomly divided into two groups. One group remained on hormone therapy and one group went off,” Jacobs said.

“We found that the APOE-e4 carriers lost considerably more telomeres [435.15 base pairs] during the two-year study than the non-carriers. But hormone therapy protected against telomere loss in the APOE-e4 group. Carriers who remained on hormone therapy had longer telomeres at the end of the study [by approximately 320 base pairs] than the carriers who went off hormone therapy,” Jacobs added.

The research, supported by RWJF and published in the article, “Accelerated Cell Aging in Female APOE-e4 Carriers: Implications for Hormone Therapy Use,” in the journal, PLOS One, (February 13), revealed surprising results for the women who did not carry the APOE-e4 gene. For them, stopping hormone therapy actually resulted in longer telomeres at the end of the study. The telomeres of the non-APOE-e4 carriers who remained on hormone therapy did not change during the two-year study period. Hormone therapy was only protective for the APOE-e4 carrier group.

Lots More to Learn

“That was the biggest surprise,” Jacobs said. “The impact of hormone therapy on cell aging is probably dependent on your genotype.” She also noted that there were limitations to the study that made it difficult to understand the unexpected findings in the non-carrier group. “We did not have a big enough sample to look at sub-groups of women to determine how different hormonal formulations impact telomere shortening. Not all estrogen preparations are made the same way or processed in the same way by the body.”

Yet for women at very high risk for Alzheimer’s, this early work may provide some helpful answers about how to approach hormone therapy. “For APOE-e4 carriers,” Jacobs said, “hormone therapy may be protective. For other women, the rest of the story has yet to be told.”

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