Women who used estrogen-only menopausal hormone therapy were less likely to show the brain changes associated with Alzheimer’s disease, according to a new Stanford Medicine study published in the journal Neurology.
Researchers examined data from 21,462 participants, including autopsy results from 258 women who had reported using estrogen-only menopausal hormone therapy and about 2,701 women who reported no use of menopausal hormone therapy. The researchers looked directly for Alzheimer’s-related amyloid plaques and neurofibrillary tangles, two defining features of the disease.
The women who had used estrogen-only therapy had 35% lower odds of Alzheimer’s pathology. They also had 39% lower odds of a lifetime clinical dementia diagnosis, while data from living participants showed better memory performance and greater ability to function independently among estrogen-only users.
Study Focused on Estrogen-Only Therapy
Many of the women receiving estrogen-only therapy had undergone hysterectomies. Women without a uterus can generally receive estrogen without the progestin used to protect the uterine lining in women who still have a uterus.
The researchers said the distinction is important because earlier research often combined different hormone formulations, making it difficult to determine whether estrogen itself was associated with cognitive outcomes.
The study also examined blood and cerebrospinal fluid biomarkers, which supported the findings from the autopsied brains.
“Our study is unique in that we looked at all the standards of Alzheimer’s diagnosis, including the gold-standard outcome: Alzheimer’s-associated hallmarks in autopsied brains,” said senior author Hadi Hosseini, Ph.D., an associate professor of psychiatry and behavioral sciences at Stanford, according to Stanford Medicine News Center.
The researchers said estrogen may have several effects that could help explain the findings, including effects on amyloid processing, tau proteins, synaptic function, neuroinflammation and the blood-brain barrier.
Findings Do Not Establish Cause and Effect
The researchers cautioned that the study was observational and therefore cannot establish that estrogen therapy prevents Alzheimer’s disease or dementia.
Women who used hormone therapy could have differed from nonusers in ways the study could not fully measure, including their underlying health and interactions with the healthcare system. The researchers adjusted for several known factors, including age, education, race, hypertension and APOE4 status, but said observational research has limitations.
The study also cannot be generalized to all forms of menopausal hormone therapy. The analysis did not establish the effects of estrogen-plus-progestin treatment, and topical estrogen users were not included in the analysis. Researchers also lacked complete information about when participants began therapy, the specific formulations they used and how long they remained on treatment.
Findings Revisit Earlier Hormone Therapy Research
The findings contrast with concerns raised by earlier studies, particularly the Women’s Health Initiative and its subsequent memory study, which associated estrogen-plus-progestin therapy with increased dementia risk when treatment was initiated at older ages.
Researchers said differences in hormone formulations, participants’ ages when treatment began, routes of administration, and study outcomes may help explain why research on hormone therapy and dementia has produced conflicting results.
More recent research has suggested that menopausal hormone therapy may have different effects depending on when treatment begins. The Stanford researchers noted that the women in the current study tended to be older, meaning the findings could potentially underestimate an association seen when therapy is started during or soon after menopause.
Still, the study does not change current clinical recommendations or establish that women should begin hormone therapy to prevent Alzheimer’s disease.
“These results add meaningful, first-of-their-kind pathological evidence to a genuinely controversial area — but they are a signal for further study, not a reason to start or stop MHT for brain health,” said Jennifer Bruno, Ph.D., an instructor in psychiatry and behavioral sciences at Stanford and a study co-author, per Fox News.
The researchers said prospective studies following women before, during, and after menopause, while tracking brain imaging and blood and cerebrospinal fluid biomarkers, could help determine whether the timing and type of hormone therapy affect later Alzheimer’s risk.
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