Greicius said he makes sure to counsel women about their increased risk when they are carriers of the APOE4 gene.
“Increasingly, I make sure to weave that into my conversation, because we have a lot of data now supporting that differential risk with APOE4 in men and women,” he said.
3. The jury is still out on how hormone therapy might relate to dementia.
The presence of the estrogen binding site near the APOE4 gene isn’t the only reason to think that estrogen might be involved in Alzheimer’s. There are receptors for the hormone scattered throughout the brain, and the period around menopause — when estrogen levels in women plummet — coincides with when Alzheimer’s-associated changes in the brain are thought to begin accumulating.
“This could all be coincidental,” said Henderson, who has spent much of his career looking at the interplay between estrogen and dementia. “But there is a fair amount of observational evidence that the loss of estrogen at menopause might be associated with Alzheimer’s disease several decades later.”
So, does hormone replacement therapy, which boosts levels of estrogen, prevent dementia?
When the Women’s Health Initiative results came out in the early 2000s, early data from a sub-study suggested that certain hormone therapies could do the reverse, raising dementia risk. But more recent trials — especially those in which estrogen replacement was started earlier — have not shown the same risk.
“Unfortunately, we’re not sure about the impacts of hormone replacement right now,” Henderson said. “By and large, most clinical trials don’t show much cognitive benefit or harm either way.”
Both Henderson and Greicius say dementia risk probably shouldn’t be driving the HRT decision, even in women at heightened risk of Alzheimer’s.
“I don’t recommend menopausal hormone therapy to prevent dementia, but if a woman is already taking it for other reasons, I don’t think the dementia risk should scare her off,” Henderson said.
4. More research is needed before clinicians treat Alzheimer’s differently in women and men.
For most of medical research history, animal model studies were conducted predominantly in males, and early human trials weren’t much better. Female hormone cycles were seen as a variable that made results harder to interpret.
“Ninety-nine percent of mouse studies in Alzheimer’s disease were conducted in male mice only,” Greicius said. “Which seems laughable now.”
Today, more women are included in Alzheimer’s research studies, but Henderson said most studies aren’t designed to analyze results by sex, making it hard to know whether drugs have a different impact. In part, that hesitation is because if a study clearly illustrated different effects in men and women, it might complicate how the drugs are advertised or prescribed, Henderson said.
“Pharmaceutical companies are supposed to do this, but some don’t because they don’t want it to affect their marketing down the road,” he said.
After clinical trial results are published, he adds, analysis sometimes reveals small differences, such as with lecanemab, the drug recently approved by the U.S. Food and Drug Administration for mild Alzheimer’s. The published data suggested women might benefit less than men do from the drug. More research is needed to show whether that is the case, since the trial wasn’t designed to answer that question.
For now, Henderson and Greicius say they will continue to treat Alzheimer’s the same in men and women — until a time comes when well-designed trials conclude they should do otherwise.
5. The same lifestyle interventions are recommended in men and women — but the effects could be different.
The good news is that most of what’s known about reducing Alzheimer’s risk applies equally to women and men: exercise regularly, manage blood pressure, stay socially and cognitively engaged, get enough sleep, and don’t smoke. None of that advice changes based on sex.
But Henderson notes that because men and women tend to live differently, the same risk factors often play out differently in practice. Where people work, what they eat, how much they exercise, how much air pollution they’re exposed to — all of these vary systematically between men and women, and all have been linked to dementia risk.
“It’s not just biological differences that could explain why women may get more Alzheimer’s,” he said, “but lifestyle differences too.”
That means that the gap in Alzheimer’s rates between women and men isn’t entirely in their DNA; it’s shaped by factors that can change. Women today are more educated and health-aware than previous generations, and there’s already evidence that’s making a difference: Dementia rates have been declining in recent decades.
“The modifiable risk factors for dementia — things like blood pressure, exercise, staying socially engaged — if we can move the needle on those, we should be able to reduce the burden of Alzheimer’s,” Henderson said. “And women stand to gain from that.”