Why women bear the burden of dementia: Unraveling the sex gap

Nearly two-thirds of Americans diagnosed with Alzheimer’s disease are women, and they often experience faster cognitive decline than men. The reasons behind this sex gap have largely remained a mystery — until now.

Groundbreaking research led by Dr. Farida Sohrabji, Regents Professor and director of the Women’s Health in Neuroscience Program at Texas A&M University, observed that biological sex significantly increases the risk of stroke in older women, a condition that accelerates the onset and progression of dementia.

“In every decade after 50,” explained Sohrabji, “women are more likely to experience stroke compared to men, especially severe strokes. This significantly fuels the risk for cognitive impairment and eventual dementia, and is fundamental for future drug developments and personalized medicine.”

 A new approach to treatment

Sohrabji’s findings support a growing body of research in precision medicine, an approach that tailors medical care to individual characteristics, such as biological sex.

"Similar drugs don’t always work as effectively or the same across sexes. Even though the disease or condition may be the same, the effect of treatments on male and female brains may not be," Sohrabji said.

This insight is urgent for Alzheimer’s care, where women make up the majority of patients. For women 60 and over, the risk of developing Alzheimer’s is almost twice as likely as the risk of breast cancer.

“We already customize and personalize treatments for certain cancers,” Sohrabji said. “It’s fundamental that we do the same for stroke and dementia, and I believe it will lead to better outcomes overall.”

Why women bear the burden

Sohrabji’s lab set out to understand why women are disproportionately affected by dementia and Alzheimer’s disease.

One key discovery points to hormonal changes during menopause. As estrogen levels drop, the brains of women become more vulnerable to inflammation, damage and ultimately stroke — known contributors to dementia and Alzheimer’s.

“We found estrogen appears to protect against stroke,” she said. “In fact, in models where ovaries are removed, stroke outcomes worsened, yet were reversed with estrogen treatment.”

But the evidence is complex, and the relationship isn’t straightforward.

“We repeated the same study and used estrogen replacement to see if it would protect older female model populations. To our surprise, it did not,” Sohrabji explained. “Estrogen was actually toxic. It made the loss of brain tissue more severe, impairment more severe and when we followed them long term, they showed signs of clear neurodegeneration.”

The promise of sex-specific therapies

Based on these complex results, Sohrabji and her team explored whether a small peptide called IGF-1 (insulin-like growth factor), in combination with estrogen therapy, could improve outcomes for middle-aged female models, and their findings were groundbreaking.

Not only did the combination reverse the usually toxic effects of estrogen to this older group, but subsequent studies showed that IGF-1 treatment alone is sufficient to improve stroke outcomes.

“If you gave the subjects estrogen and IGF-1, you clearly see neuroprotective effects,” Sohrabji said. “In fact, IGF-1 treatment itself was one of the most neuroprotective molecules we have ever tested.”

In other work, the researchers tested a small, non-coding RNA molecule, and again, the results were striking.

Administering the agent both protected brain tissue and noticeably reduced long-term signs of cognitive decline.

“Our findings suggest the agent played a protective role in the process, and it was most effective in older female subjects compared to age-matched males,” Sohrabji said.

Sex differences matter in brain research

Sohrabji’s research represents a shift from one-size-fits-all treatments to tailored therapies, adding to a growing call in neuroscience and medicine in recognizing the importance of sex differences.

"These differences aren’t minor, they’re profound. It’s why we see women bear the burden of chronic diseases like dementia and Alzheimer’s," Sohrabji said.

By advancing sex-specific research, Sohrabji is championing a promising future where the burden of Alzheimer’s no longer falls hardest on women, and where therapies advance overall human health.

“As a basic scientist, and in my personal journeys, we follow our passions to improving human health and to solving these really important problems,” Sohrabji said.

Sohrabji’s research studies were published in the Journal of Neuroscience, Brain Behavior and Immunity, Neurobiology of Aging, and a recent preprint is available at BioRxiv.

For more information about Sohrabji, visit her faculty page.