A neglected piece of the Alzheimer’s puzzle has been getting increased scientific attention: why women are twice as likely as men to develop the disease.

One might be tempted to explain the disparity as a natural consequence of women living longer. But those studying the disease say that wouldn’t account for such a large difference, and they’re not precisely sure what would.

While many factors may be at play, researchers are zeroing in on two where the biological differences between women and men are clear: chromosomes and menopause.

Women have two X chromosomes, and men have an X and a Y. Differences between genes held on the X and Y chromosomes, researchers say, may give women an increased chance of developing Alzheimer’s.

Menopause, when production of the hormones estrogen and progesterone declines, is another clear difference between the sexes. Those hormones are widely known for their roles in the reproductive system, but estrogen also acts on the brain, researchers say.

Whatever’s at play is likely part of deeper neurological processes, researchers say, pointing to similar sex-related differences in other conditions. Multiple sclerosis and migraine, for example, are both more common in women. Parkinson’s disease, brain tumors, and epilepsy, by contrast, are more common in men. In some cases like migraine in women and Parkinson’s in men increased severity accompanies increased incidence.

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

The basic building blocks are genes, which in humans are arranged on 46 chromosomes, organized into 23 pairs. One of those pairs — XX in women and XY in men — contain the genes that define sex-based characteristics, differences that are key areas of exploration.

The X and Y chromosomes differ significantly, Bonkhoff said.

The X chromosome is rich in genes, while the Y chromosome has lost a significant number over the millennia. Having two X chromosomes, though, doesn’t mean that women have a double dose of the proteins and other gene products produced by those genes, because one of the X chromosomes is silenced.

That silencing, however, is imperfect, Bonkhoff said, leaving some genes on the silenced X chromosome active. Studies have shown that genes on the X chromosome are related to the immune system, brain function, and Alzheimer’s disease.

“We know that biological men and women differ by the number of X chromosomes,” said Bonkhoff, lead author of a recent review article in the journal Science Advances that examined sex-related differences in Alzheimer’s disease and stroke.

“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.” 

Source: https://news.harvard.edu/gazette/story/2025/07/why-are-women-twice-as-likely-to-develop-alzheimers-as-men/#:~:text=Women%20have%20two%20X%20chromosomes,clear%20difference%20between%20the%20sexes