“What’s particularly interesting is that they found an association between hormone therapy and biological measures,” in addition to actual symptoms, says Jill M. Daniel, PhD, the Dohanich Professor in Brain Science and a professor of psychology at the Tulane University Brain Institute in New Orleans, who wasn’t involved in the research. Biological measures are physical signs of Alzheimer’s disease in the brain, rather than symptoms like memory problems.
While the findings suggest estrogen treatment may help preserve late-life brain health for some women, experts say it’s too soon to recommend hormone therapy for Alzheimer’s prevention.
Researchers Looked at Brain Changes, Biomarkers, and Dementia Diagnoses
Researchers analyzed records from two large Alzheimer’s databases with information from more than 21,000 women. They specifically focused on women who reported taking systemic estrogen-only therapy during at least one study visit; women who had used estrogen plus progestin were excluded from the main analysis.
Estrogen-only hormone therapy is typically recommended for women who’ve had a hysterectomy, says lead study author Jennifer L. Bruno, PhD, an instructor of psychiatry and behavioral sciences at Stanford Medicine in California. Women with an intact uterus generally need a progestogen along with estrogen to protect the uterine lining.
Brain autopsy results were available for about 2,700 women, including about 250 estrogen-only hormone therapy users. Smaller groups had blood or spinal fluid biomarker tests, brain imaging, or memory testing. In the main autopsy analysis, researchers accounted for factors tied to dementia risk, including age, education, genetic predisposition to Alzheimer’s, race, and high blood pressure.
Women Who Used Estrogen Had Fewer Brain Changes Linked to Alzheimer’s
The clearest finding came from the autopsy data. After adjusting for other risk factors, women who took estrogen-only hormone therapy had 35 percent lower odds of having more advanced Alzheimer’s-related changes in their brains.
Key findings included:
- About 18 percent of hormone therapy users had no signs of Alzheimer’s disease in the brain at autopsy, compared with about 10 percent of nonusers.
- About 40 percent had high levels of Alzheimer’s-related brain changes, compared with about 51 percent of nonusers.
- Hormone therapy users had 39 percent lower odds of a clinical dementia diagnosis and lower odds of measurable memory problems compared with nonusers.
“For the subset of women who have had a hysterectomy, our results suggest that estrogen-only hormone therapy may have a protective association with Alzheimer’s-related brain changes,” says Dr. Bruno says.
Timing of Hormone Therapy Is an Important Missing Piece
In the research databases, study subjects first reported taking estrogen in their 70s. Today, hormone therapy isn’t generally recommended at such an advanced age. Instead, doctors typically start women on hormones much closer to menopause, often in the late forties or early fifties.
Dr. Daniel says it would be especially useful to know when the women in the study actually started treatment, plus how long they’d used estrogen therapy and their hormone therapy history before entering the studies.
Previous research has raised the possibility of a “critical window” for estrogen treatment to positively affect the brain, and that this may depend partly on how close to menopause the hormone therapy begins.
“If, in fact, most of the women in this study initiated hormone therapy during this critical window, the findings suggest that prolonged use is not detrimental and may offer benefits for brain aging,” Daniel says.
Does the New Research Align With Previous Studies?
How Estrogen May Affect the Brain
When the brain is healthy, it regularly breaks down and clears away a protein called beta-amyloid. But in people with Alzheimer’s, amyloid plaques accumulate, leading to brain cell damage. Laboratory research suggests estrogen may affect how beta-amyloid is processed in the brain, making it less likely to clump into plaques.
In the new study, estrogen users had more favorable amyloid measures in blood and spinal fluid, but there were no significant differences in amyloid brain scans and several other biomarkers.
Strengths and Limitations of the Study
A major strength of the new trial is that researchers approached the question from several angles — dementia diagnoses, biomarkers, and brain tissue at autopsy. The association with fewer Alzheimer’s-related brain changes also remained after researchers accounted for several dementia risk factors, differences in who underwent autopsy, and coexisting vascular brain changes.
However, subjects were mostly white and highly educated, meaning the findings may not apply to women from other backgrounds. Because this was an observational study, women who used estrogen may have differed from nonusers in unmeasured ways, including baseline health or frequency of doctor visits.
Bruno says the findings highlight the need for prospective clinical trials, meaning women would be randomized to receive either hormone therapy or a placebo, and then followed over time to see how outcomes differ. Ideally, these trials would enroll women around the age of menopause who’ve had a hysterectomy and can safely take estrogen-only therapy, says Bruno.
Should Women Take Hormone Therapy to Lower Dementia Risk?
For now, the study is more useful for guiding future research than for changing how women take hormone therapy.
“These findings do not change current clinical recommendations,” says coauthor Jacob Shaw, MD, a former C-Brain Lab scholar at Stanford Medicine and a resident physician at Massachusetts General Hospital in Boston.
“At this point, there is not enough evidence to recommend hormone therapy specifically to reduce one’s risk of dementia, especially in women undergoing natural menopause,” Daniel says.
For women who want to lower their dementia risk in midlife, Daniel recommends focusing on factors supported by stronger evidence:
- Manage chronic health conditions.
- Exercise regularly.
- Eat a healthy diet.
- Stay socially and intellectually engaged.
“Midlife is not too late to make meaningful changes that may reduce our risk of dementia later in life,” Daniel says.
