The combination that may explain why women suffer more from Alzheimer's

BarcelonaA Mayo Clinic study has found that women experience brain changes associated with Alzheimer's disease up to 20 times faster than men, attributing this to an imbalanced presence of alpha-synuclein (α-synuclein), a protein also linked to Parkinson's disease. In an article published in JAMA, researchers did not observe this pattern in men when the same factors were considered. According to the study, this interaction could help explain why women account for the majority of Alzheimer's cases—between 60% and 70%—in countries like the United States, a trend also observed in Spain and South Korea, among others, and influenced by variables such as life expectancy, hormonal factors, and social influences.

"When we see that disease-related changes develop at drastically different rates [between the sexes], we can no longer approach Alzheimer's as if it behaves exactly the same way in everyone," says the study's lead author and Mayo Clinic neuroradiology expert, Kejal Kantarci. Researchers at this nonprofit healthcare organization set out to evaluate and determine whether having abnormal accumulations of certain proteins alters how Alzheimer's progresses, and if this effect differs between women and men. The goal: to lay the groundwork for more targeted clinical trial design and, ultimately, more personalized treatment strategies.

To provide context, the causes of Alzheimer's are still being studied, and it is often difficult to determine whether the signs observed are precursors or consequences of the disease. These include the accumulation of plaques of beta-amyloid protein or tau protein—which, when folded, creates a kind of clump that acts like knots, preventing communication between neurons. In some cases—and this is the focus of this new study—Alzheimer's patients also develop abnormal aggregation of α-synuclein, a protein more characteristic of Parkinson's disease and Lewy body dementia. While both thallus and α-synuclein occur naturally in the brain, in neurodegenerative diseases they can misfold and clump together, forming toxic deposits that disrupt communication between brain cells and contribute to cognitive decline.

Researchers at the Mayo Clinic tracked the progression of Alzheimer's disease in 415 participants from the Alzheimer's Disease Neuroimaging Initiative, a U.S. research consortium that monitors brain changes over time due to neurodegeneration. The team, led by Kantarci, subjected the participants to cerebrospinal fluid tests to detect abnormal α-synuclein, as well as repeated brain scans to measure changes in tau protein accumulation. According to this study, approximately 17% of the patients had abnormal α-synuclein levels. Within this cohort—those with both Alzheimer's-related pathology and α-synuclein abnormalities—women accumulated the tau protein at a significantly faster rate than men, despite the coexistence of the same protein changes. This finding aligns with existing documentation of the disease: women are twice as likely to develop it as men, and in those over 55, the prevalence is 7.1% in women and 3.3% in men. Given this new finding, researchers will now examine whether these sex-specific effects also appear in patients with Lewy body dementia, where α-synuclein is the main driver of the disease.

Low representation in trials

This research may help determine whether the observed difference between men and women is unique to Alzheimer's disease or reflects a broader sex-specific vulnerability to any neurodegenerative condition. "This opens up a completely new avenue for understanding why women bear a disproportionate burden of dementia," says Elijah Mak, a neuroimaging researcher at the Mayo Clinic and co-author of the article, adding, "If we could unravel the mechanisms behind this vulnerability, we could discover targets that..." Ace Alzheimer Center Barcelona points out that various biological and social factors interact behind this higher prevalence of Alzheimer's in women. In addition to certain genetic profiles, hormonal changes—such as decreased estrogen during menopause—or the more frequent use of certain medications can influence the risk of neurodegeneration. However, as has been the case with virtually all diseases, the female population is underrepresented in clinical trials: research conducted by this Catalan research center shows that women are 26% less likely to be selected to participate. For example, this is because in older age groups they tend to have lower levels of education due to the context in which they grew up, which makes it more difficult to administer standardized neuropsychological tests.