Scientists identify why women face doubled Alzheimer’s risk

Researchers have identified two biological factors – chromosomes and menopause – that may help explain why women are around twice as likely as men to develop Alzheimer’s disease.

The findings could contribute to more targeted strategies for preventing and treating Alzheimer’s in women, who account for nearly two-thirds of those affected in the US. One in three older Americans dies with Alzheimer’s or another form of dementia.

The work adds to growing evidence that neurological diseases affect men and women differently, with implications for sex-specific approaches to brain health in later life.

Scientists from Harvard Medical School and Mass General Brigham point to differences in chromosomes. Women have two X chromosomes, compared with one X and one Y in men. Chromosomes are DNA structures that carry genes involved in various biological functions and physical traits.

“Epidemiologically, we see that for almost all neurological diseases, there are differences in how many biological women and men are affected,” said Anna Bonkhoff, resident and research fellow in neurology at Harvard Medical School and Mass General Brigham.

“There’s a tendency, for example, in multiple sclerosis and migraine for more females to be affected, while it’s the contrary for brain tumours and Parkinson’s. Just based on these numbers, you get the feeling that something needs to underlie these differences in terms of the biology.”

Some genes associated with Alzheimer’s have been found on the X chromosome. Research also suggests that women with Alzheimer’s may live longer than men with the disease, possibly due to protective effects from their second X chromosome. Many genes involved in immune function and brain structure are located on the X chromosome, leading to differences in gene activity between sexes.

“A lot of genes for the immune system and regulating brain structure are located on the X chromosome, so the dosages differ to certain degrees between men and women. That seems to have an effect,” Bonkhoff said.

Menopause is the second factor researchers are examining. It usually begins in a woman’s 40s or 50s, when the ovaries stop producing hormones such as oestrogen and progesterone, which are known to influence brain function.

“Menopause is part of the puzzle, probably one of the bigger ones,” Bonkhoff said. “I’m not saying it’s the only one – ageing is relevant by itself, and there’s a lot of interesting research looking at what ageing does to the immune system that seems to have implications for cognitive changes.”

Separate research by Rachel Buckley, associate professor of neurology at Harvard Medical School, found that women who received hormone replacement therapy (HRT) after age 70 had significantly higher levels of tau protein in the brain. Tau is a hallmark of Alzheimer’s disease, with its accumulation in brain cells linked to cognitive decline.

While HRT can relieve menopausal symptoms such as hot flushes, the US Centers for Disease Control and Prevention states it may increase the risk of conditions including heart attack, stroke, breast cancer, blood clots and gall bladder disease in some women.

“We work with a lot of secondary data that already exists, and that’s great but there are limitations to what we can do with it,” Buckley said. “We’re trying to see if we can set up a new study design where we can really look at the time of menopause, what is changing in the blood, what is changing in the brain, what is changing in cognition, and how that might be associated with later life risk.”

Understanding these sex-based differences could help inform new approaches to dementia prevention, particularly for women considering HRT during or after menopause. The findings suggest that personalised strategies based on biological sex may be key to protecting brain health in later life.