In Women with Alzheimer's, a Parkinson's Protein Accelerates Brain Decline Up to 20-Fold

Women account for nearly two-thirds of people living with Alzheimer's disease in the United States. That disparity has been attributed to women's longer average lifespan, hormonal differences, and other factors - but the underlying biology has never been fully explained. A Mayo Clinic study published in JAMA Network Open adds a specific and striking piece to that puzzle: when women have both Alzheimer's-related pathology and abnormal levels of a protein associated with Parkinson's disease, their disease progresses up to twenty times faster than in men with the same co-pathology.

Twenty times. Not 20 percent. Not double. That magnitude demands explanation, and the researchers are careful to note they do not yet have one. But the observation itself is important enough to change how the field thinks about Alzheimer's in women.

Two proteins, one brain

Alzheimer's disease is defined by the accumulation of tau protein in the brain. As tau builds up in characteristic tangles, neurons lose function and cognitive decline follows. What the Mayo study examined is what happens when a second abnormal protein is also present: alpha-synuclein, the protein that clumps pathologically in Parkinson's disease and dementia with Lewy bodies.

Both tau and alpha-synuclein occur naturally in the brain. Both can misfold and aggregate in disease. Their co-occurrence in the same brain is not unusual - autopsy studies have found alpha-synuclein abnormalities in a substantial fraction of Alzheimer's patients. What had not been systematically characterized, at least not in living patients tracked over time, was whether that co-pathology changes the pace of Alzheimer's progression - and whether it does so differently in women and men.

The study design

The Mayo team analyzed data from 415 participants in the Alzheimer's Disease Neuroimaging Initiative, a national research consortium that tracks brain changes in participants over years using repeated imaging and cerebrospinal fluid testing. Participants underwent CSF testing to detect abnormal alpha-synuclein and repeated brain imaging to measure changes in tau accumulation over time. About 17% of the sample showed evidence of abnormal alpha-synuclein.

Among participants who had both Alzheimer's pathology and alpha-synuclein abnormalities, women accumulated tau dramatically faster than men with the same co-pathology. The up-to-20-fold difference represents the range of the effect observed across participants and imaging timepoints - not every woman progressed at the maximum rate, but the accelerated trajectory in women compared to men was consistent and statistically robust.

Men with the same combination of pathologies did not show the same acceleration. The same pattern was not observed in men. That sex-specific finding is the study's most striking result and the one that demands the most follow-up.

Why this might be happening

The researchers do not yet know the mechanism. Several possibilities are worth considering. Hormonal differences - particularly the decline in estrogen associated with menopause - have been hypothesized to affect how the brain handles abnormal protein aggregates. It is possible that estrogen provides some protection against alpha-synuclein's acceleration of tau spread, and that its loss leaves women more vulnerable to the interaction.

It is also possible that biological sex differences in brain structure, immune function, or the cellular machinery for clearing misfolded proteins create different environments for protein aggregation. Alpha-synuclein and tau are known to interact physically - each can seed the aggregation of the other - and it is conceivable that this seeding process operates more efficiently in the female brain environment, for reasons that are not yet characterized.

"Recognizing these sex-specific differences could help us design more targeted clinical trials and ultimately more personalized treatment strategies," said Kejal Kantarci, the study's senior author and a Mayo Clinic neuroradiologist. "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."

What comes next

The Mayo team is now examining whether the same sex-specific pattern appears in patients with dementia with Lewy bodies, where alpha-synuclein is the primary driver rather than a co-pathology. If the sex-specific acceleration appears there too, it would suggest a broader biological vulnerability in women to the interaction between these two proteins - not something unique to Alzheimer's disease specifically.

The practical implications depend on what future research establishes about mechanism. If the acceleration is driven by an identifiable biological pathway, it may become a treatment target. If it is predictable from biomarkers - alpha-synuclein levels combined with sex - it could inform prognosis and trial enrollment decisions right away. Clinical trials for Alzheimer's treatments have historically enrolled men and women in roughly equal numbers, with results averaged across both. If women with co-pathology progress much faster, sex-stratified analysis becomes not just good scientific practice but potentially essential for detecting or missing treatment effects.

The study was published in JAMA Network Open. Elijah Mak, PhD, is first author and a Mayo Clinic neuroimaging researcher. Media contact: Emily DeBoom, deboom.emily@mayo.edu.