Mayo Clinic Study links alpha-synuclein protein to faster Alzheimer’s progression in women

UAE—New research from the Mayo Clinic has revealed a striking biological difference in how Alzheimer’s disease progresses in women and men, potentially opening new avenues for more personalized approaches to dementia research and treatment.

Published in JAMA Network Open, the study found that Alzheimer ’s-related brain changes progressed up to 20 times faster in women who also had abnormal levels of alpha-synuclein, a protein commonly associated with Parkinson’s disease and other Lewy body disorders.

Researchers did not observe the same accelerated progression in men with similar protein abnormalities.

Investigating the role of coexisting brain pathologies

Alzheimer’s disease is characterized by the accumulation of tau protein in the brain, which gradually damages nerve cells and impairs memory and cognitive function.

However, many patients also develop abnormal deposits of alpha-synuclein, a protein more commonly linked to Parkinson’s disease and dementia with Lewy bodies.

Although both proteins occur naturally in the brain, they can misfold and clump together during neurodegenerative disease. These abnormal deposits disrupt communication between neurons and contribute to the progressive decline in cognitive abilities.

Researchers sought to determine whether the coexistence of tau and alpha-synuclein pathology influences the rate at which Alzheimer’s disease progresses and whether the effect differs between women and men.

According to the research team, understanding these interactions could help explain why women account for nearly two-thirds of Alzheimer’s disease cases in the United States.

Analysis of more than 400 participants

To explore the relationship, investigators analyzed data from 415 participants enrolled in the Alzheimer’s Disease Neuroimaging Initiative, a large research consortium that tracks brain changes over time.

The participants underwent cerebrospinal fluid testing to detect abnormal alpha-synuclein and repeated brain imaging scans to measure tau protein accumulation.

Approximately 17% of the participants showed evidence of abnormal alpha-synuclein. Among those individuals, women experienced significantly faster tau accumulation than men with the same protein abnormalities.

The study identified women with positive alpha-synuclein findings as having the most rapid disease-related brain changes.

Kejal Kantarci, senior author of the study and a neuroradiologist at Mayo Clinic, said the findings underscore the importance of recognizing biological differences in disease progression.

“Recognizing these sex-specific differences could help us design more targeted clinical trials and ultimately more personalized treatment strategies,” she said.

“When we see disease-related changes unfolding at dramatically different rates, we cannot keep approaching Alzheimer’s as though it behaves exactly the same way in everyone.”

Implications for future research

The findings also have implications for the design of future clinical trials.

Researchers reported that women with both Alzheimer’s pathology and abnormal alpha-synuclein accumulated tau at a rate that may make it easier to detect the effects of experimental therapies in smaller study populations.

Elijah Mak, the study’s first author and a neuroimaging researcher at Mayo Clinic, noted that the results highlight a previously underappreciated factor that may contribute to women’s higher burden of dementia.

Researchers are now extending their investigations to patients with dementia with Lewy bodies, a condition in which alpha-synuclein serves as the primary disease driver.

By examining whether similar sex-related differences emerge in those patients, the team hopes to determine whether the observed vulnerability is unique to Alzheimer’s disease or reflects a broader pattern across neurodegenerative disorders.

The study adds to a growing body of evidence suggesting that sex-specific biological mechanisms play an important role in brain health and disease progression, reinforcing the need for precision medicine approaches in Alzheimer’s research and treatment development.