Anyone who’s ever gone through menopause knows the unpleasantness of the unrelenting hot flashes, brain fog, and other symptoms that crop up. Hormone replacement therapy (HRT) was, when it was first introduced in the 1960s, supposed to be a safe antidote for these inconveniences, one that was eventually prescribed to millions of women as a way to remain “feminine forever.”
For the most part, the treatment delivered on its promise, mitigating the most frustrating effects of menopause — but even the best remedies come with risks. There’s some evidence that HRT may increase the chance of developing Alzheimer’s, but the connection between the two is complex and still poorly understood. Here’s a look at what we do know and why not all women on HRT may be at risk.
Can hormone-replacement therapy cause Alzheimer’s?
A recent study conducted in Denmark determined that hormone therapy led to an increased risk of Alzheimer’s and other forms of dementia. Researchers analyzed the medical records of more than 60,000 women and found that those using hormones were 24 percent more likely to develop the neurodegenerative diseases than those who weren’t. Those findings are in line with other studies that have found a similar link.
But published that same day, in the same journal as the Danish study, researchers from the Mayo Clinic and Harvard Medical School issued an op-ed titled “A Causal Link Remains Unlikely.” They argue that the study can’t say for certain whether it’s the hormones or the symptoms the hormones are supposed to target that’s the culprit.
This discordance perfectly captures the maddening nature of the field. (To add to the confusion, some research — including one robust 2021 survey — suggests that HRT actually does live up to its original intent, providing a “protective effect” against dementia.) Researchers haven’t pinpointed what’s really to blame, leaving the many women relying on the treatment, or considering it, twisting in the wind. But they do seem to be inching closer.
There’s some evidence that what matters most when it comes to HRT and Alzheimer’s is when it’s administered. An influential 2002 study called the Women’s Health Initiative found that the participants who exhibited the greatest cognitive decline were the ones who began hormone therapy well after they’d started menopause. That’s supported by an interesting study released earlier this year by researchers at Massachusetts General Hospital. They looked specifically at tau tangles, abnormal protein clusters considered a hallmark of Alzheimer’s, and found that women who had delayed HRT for five to 10 years had significantly more tau in their brains. This wasn’t the case for women who started HRT soon after experiencing menopause.
Can menopause cause Alzheimer’s?
Some experts suspect that The Change is really what’s causing the high rates of Alzheimer’s in women. (About two-thirds of the Alzheimer’s population is female, and 60 percent of patients are postmenopausal.) And there’s research out there that backs them up. A study published last year found a correlation between hot flashes and white matter hyperintensities, small lesions in the brain thought to be a risk factor for dementia.
Scientists are also looking at how menopause makes it so much harder for women to get a good night’s rest, and whether that disruption in their sleep could lead to cognitive decline. When we sleep, “fluids essentially wash around the brain clearing away debris and proteins” like tau, Rachel Buckley, Ph.D., an author of the Mass General study, tells us. “If you’re constantly waking up through the night, and not going through your full cycle of sleep, you may be at a greater risk of accumulating these disease proteins,” he says.
Depression, another common symptom of menopause and a possible risk factor for dementia, could play a role too. As could the weight gain many women experience in middle age, Dr. Buckley says.
“So there’s really a myriad of things that need to be considered beyond just hormone therapy,” she says. “It’s something we’ve seen echoed many times: Timing is critical for hormone therapy,” Rachel Buckley, Ph.D., an author of the study, tells us.
It’s not clear why this gap between onset and treatment seems to matter so much, Dr. Buckley says. One theory is that when estrogen levels drop as a result of menopause, the body compensates for that estrogen, a chemical that keeps the brain active, by finding other biological pathways to fuel the organ. So when the hormone is reintroduced, “it causes the body to sort of go haywire because it’s become so used to relying on other mechanisms,” she says.
