Health
Why women are at higher risk of dementia than men
Why are women more susceptible to dementia yet live longer with the degenerative brain condition than men do? Here’s what the latest research says.
By Sabrina Rogers-Anderson
When you imagine your golden years, you probably hope you’ll be sharp as a tack and regale the younger generation with tales of your youth at every family reunion.
But with the rate of dementia set to double in Australia by 2058 (in large part due to our ageing population), your yarn-spinning glory days aren’t a given – especially if you’re a woman.
With 63% of Australians with dementia being female and the brain condition now the leading cause of death in Australian women, having two X chromosomes can put you at particular risk. But why?
Australian cognitive neuroscientist Dr Rachel Buckley, who runs her own research lab at Massachusetts General Hospital, Harvard University’s largest teaching hospital, has dedicated her career to answering this question.
“Alzheimer’s disease involves multiple types of proteins building up in the brain abnormally over time,” says Dr Buckley. “This has knock-on effects for your memory and thinking, and essentially kills off brain cells.
“The two hallmark proteins of Alzheimer's are beta-amyloid and tau. Beta-amyloid aggregates into plaques and tau aggregates into tangles. We still don't entirely know how these two pathologies play off one another because they build up in different areas of the brain at different times, but we know they coexist and tau is much more closely associated with dementia.
“Someone can have a head full of beta-amyloid and never progress to dementia. But if you have high tau and high beta-amyloid, your risk escalates a lot. So, there has been a lot of focus on the implications of having high levels of tau in the past 10 years. We’ve focused on trying to understand sex differences and have made some interesting findings.”
Even healthy women have higher levels of tau
In 2019, Buckley and her colleagues were the first to show that older women have higher levels of tau protein in the brain than men.
“At the same time, other researchers were finding higher levels of tau in [women’s] postmortem brains and other groups were seeing it in their cerebrospinal fluid too,” says Dr Buckley. “There was a lot of really interesting evidence.”
The finding that most fascinated Buckley and her colleagues was that not only did women with dementia have higher levels of tau, but so did healthy older women.
“Our first question was: when is this starting? Can we go into middle age and see it?” says Dr Buckley. “The next question was: is there something about reproductive history that's driving this sex difference? We thought menopause might have something to do with it.”
To investigate these questions, Buckley and her colleagues analysed data from the Wisconsin Registry for Alzheimer's Prevention (WRAP).
“Some of the study participants were imaged with amyloid PET scans and tau PET scans in their late 50s and early 60s, which is rare because most studies don’t do that until 65,” Dr Buckley explains.
“We found that these much younger, healthy women did show much higher levels of tau than men and that earlier age at menopause – below the age of 45 – seemed to be a major driver of these higher levels.”
The impact of hormone therapy on dementia
Buckley and her team were also keen to investigate whether menopausal hormone therapy (MHT) had an effect on tau levels and dementia risk.
Hormone therapy has been controversial since the landmark Women's Health Initiative (WHI) study erroneously reported that MHT increased the risk of breast cancer and heart disease in 2002. The WHI also found that hormone therapy had a negative impact on cognitive function.
When Buckley and her colleagues analysed the WRAP data, they were surprised to find that women who took hormone therapy had much higher levels of tau.
“That was so confusing,” says Dr Buckley. “We knew that women who underwent earlier menopause had higher levels of tau, which said to us that removing oestrogen from the body wasn’t a good thing. But then we discovered that women who took hormone therapy also had higher levels of tau. It didn’t make any sense.”
Then one of Dr Buckley’s colleagues, Dr Gillian Coughlan, had a lightbulb moment. “She figured it must have to do with the timing of hormone therapy,” explains Dr Buckley.
“In the Women's Health Initiative, the women who showed the poorest outcomes initiated hormone therapy use after the age of 65. The average age of menopause onset is 51, so that's about 14 years later. To restart your oestrogen system after all that time is probably going to do things you're not quite prepared for.
“When we looked at the length of time between [WRAP participants’] age of menopause and when they started hormone therapy use, the women who reported a delay of 5 to 10 years were the ones with higher levels of tau. Women who took hormone therapy around the age of onset or earlier didn’t show higher levels of tau. It really spoke to the idea of timing.”
While Buckley and her team have made some groundbreaking discoveries, their findings have raised several other questions. Is the issue only with the conjugated equine oestrogen (CEE) that was commonly used at the time of the WHI or all hormone therapy? To what extent does timing of hormone therapy play a role? Does surgical history, such as ovary removal or hysterectomy, have an influence?
“We're currently trying to put together different grants to investigate these questions because the data isn’t there in previous studies,” says Dr Buckley. “One thing we want to do is recontact the women who were 50 to 55 in the Women's Health Initiative and who are now 75 to 80. They’re at a critical time for dementia and no one has looked at them.
“The other thing we want to do is create a very detailed study of women going through menopause and collect everything we can think of, including blood, bone density, neuroimaging, genetics, proteomics, sleep and more. We want to measure these women between the ages of 40 to 55, and then again 10, 15 and 20 years later. Our plan is to follow their progression with a focus on neurodegenerative disease.”
Dr Buckley is excited that the recent mapping of Alzheimer's disease biomarkers in blood will open the door to further research opportunities. “Prior to that it was all head imaging, which was so expensive, and data was limited. We need to convince people that reproductive history, hormone therapy use and more information needs to be gathered to address our critical questions.”
The X chromosome may increase dementia risk
Another area of research Buckley’s team wants to tackle is the potential role the X chromosome plays in exacerbating the risk of dementia.
“There have been some really fascinating findings coming out of the University of California San Francisco,” says Dr Buckley. “The leader of the lab is Dr Dena Dubal and her work is focused on the X chromosome primarily in mouse models, but she’s also starting work on humans.
“We know that women are so resilient. They live longer, they live twice as long with dementia than men, they handle COVID better, they have less cancer. Evolutionary biologists have often made the argument that the second X chromosome gives women this superpower.
“The incredible thing Dena has started to look into is whether the X chromosome plays a role in Alzheimer's disease and her work in mouse models seems to suggest that the second X seems to have this same superpower. Male mouse models have much higher rates of death, so survival is much better in females, and there seem to potentially be lower levels of pathology related to these X chromosomes.
“The reason I love her work is because a lot of the [dementia] research up until this point seemed to point to a vulnerability in women, but there’s more to the story. We want to study this in humans. We want to look at gene expression on these X chromosomes and see how it’s associated with amyloid and tau, and how it might also impact change in cognition.
“Then we’ll try to figure out if we can take some of these gene targets and pass them through to other groups to see if they might be possible therapeutic targets for drug trials in the future.”
Feature image: iStock/adamkaz
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