Summary: Women make up nearly two-thirds of Alzheimer’s patients, and researcher may have just discovered a massive reason why. A new study found that when the protein alpha-synuclein (typically associated with Parkinson’s) clumps together alongside Alzheimer’s pathology, brain changes in women progressed up to 20 times faster.
Surprisingly, this “accelerator” effect was not seen in men. The discovery suggests that the interaction between tau and alpha-synuclein creates a unique, high-speed vulnerability in the female brain, potentially redefining how we screen for and treat Alzheimer’s in women.
Key Facts
- The 20X Factor: In women with both tau (Alzheimer’s) and alpha-synuclein (Parkinson’s) abnormalities, brain degeneration occurred 20 times faster than in those without the co-pathology.
- Sex-Specific Vulnerability: Men with the same protein clumping did not experience the same rapid acceleration, indicating a profound biological difference in how female brains handle “misfolded” proteins.
- Alpha-Synuclein’s Role: While primary to Parkinson’s and Lewy Body dementia, this protein often appears as a “silent passenger” in Alzheimer’s patients, significantly worsening the prognosis for women.
- Imaging Breakthrough: Mayo Clinic researchers used advanced brain imaging and cerebrospinal fluid testing from 415 participants to track these protein interactions over time.
- Precision Medicine: The findings highlight that Alzheimer’s is not a “one-size-fits-all” disease and that women may require different screening for Lewy Body proteins to accurately predict their disease trajectory.
Source: Mayo Clinic
Alzheimer’s-related brain changes progressed up to 20 times faster in women who also had abnormal levels of a Parkinson’s-related protein, according to a Mayo Clinic study published in JAMA Network Open. The same pattern was not observed in men.
The findings suggest that when alpha-synuclein — a protein linked to Parkinson’s disease — accumulates alongside Alzheimer’s pathology, it may drive faster disease progression in women. That interaction could help explain a long-standing disparity: women make up nearly two-thirds of people living with Alzheimer’s disease in the U.S.
Kejal Kantarci, M.D., a Mayo Clinic neuroradiologist and senior author of the study, uses advanced brain imaging to track Alzheimer’s progression.
“Recognizing these sex-specific differences could help us design more targeted clinical trials and ultimately more personalized treatment strategies,” Dr. Kantarci says.
“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. Co-pathologies may impact the disease process.”
Alzheimer’s disease is marked by the buildup of tau protein in the brain. Many people along the Alzheimer’s disease continuum also develop abnormal clumping of α-synuclein, a protein associated with Lewy body diseases such as Parkinson’s disease and dementia with Lewy bodies.
Tau and α-synuclein occur naturally in the brain. In neurodegenerative diseases, however, these proteins can misfold and clump together, forming abnormal deposits. This pathological buildup disrupts communication between brain cells and contributes to cognitive decline.
Researchers set out to determine whether having both abnormal protein buildups alters how the disease progresses and whether that effect differs between women and men.
To investigate, the team analyzed data from 415 participants in the Alzheimer’s Disease Neuroimaging Initiative, a national research consortium that tracks brain changes over time.
Participants underwent cerebrospinal fluid testing to detect abnormal α-synuclein and repeated brain imaging to measure changes in tau accumulation. About 17% of participants showed evidence of abnormal α-synuclein.
Among participants with both Alzheimer’s-related pathology and α-synuclein abnormalities, women accumulated tau dramatically faster than men with the same coexisting protein changes.
Elijah Mak, Ph.D., first author of the study and a Mayo Clinic neuroimaging researcher, studies how multiple brain pathologies interact and drive disease progression.
“This opens an entirely new direction for understanding why women bear a disproportionate burden of dementia,” Dr. Mak says. “If we can unravel the mechanisms behind this vulnerability, we may uncover targets we haven’t considered before.”
The researchers are now examining whether these sex-specific effects also appear in patients with dementia with Lewy bodies, where α-synuclein is the primary disease driver rather than a coexisting pathology.
The work will help determine whether the observed difference is unique to Alzheimer’s disease or reflects a broader sex-specific vulnerability across neurodegenerative conditions.
For a complete list of authors, disclosures and funding, review the study.
Key Questions Answered:
A: Not necessarily. These proteins can “misfold” in the brain even if you don’t have a full Parkinson’s diagnosis. This study shows that when these proteins (alpha-synuclein) show up in an Alzheimer’s brain, they act like fuel on a fire—specifically in women—speeding up the loss of brain function.
A: This is the million-dollar question researchers are now racing to answer. It could be linked to hormonal differences, how the female immune system reacts to “clumped” proteins, or different wiring in the brain’s waste-clearance systems. This discovery is the first step in unlocking that mystery.
A: Yes. Doctors can use cerebrospinal fluid (CSF) tests to detect abnormal alpha-synuclein levels. This research suggests that for women, these tests could be crucial for determining how quickly the disease might progress and which clinical trials would be most effective.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease and Parkinson’s disease research news
Author: Emily DeBoom
Source: Mayo Clinic
Contact: Emily DeBoom – Mayo Clinic
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Sex-Specific Associations of α-Synuclein Pathology With Tau Accumulation” by Elijah Mak, Angela J. Fought, Heather J. Wiste, Scott A. Przybelski, Robert I. Reid, Christopher G. Schwarz, Matthew L. Senjem, Prashanthi Vemuri, Clifford R. Jack Jr., Val J. Lowe, Ronald C. Petersen, Walter A. Rocca, Bradley F. Boeve, and Kejal Kantarci. JAMA Network Open
DOI:10.1001/jamanetworkopen.2026.0461
Abstract
Sex-Specific Associations of α-Synuclein Pathology With Tau Accumulation
Importance
Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though α-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear.
Objective
To test whether α-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum.
Design, Setting, and Participants
This cohort study used longitudinal tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid α-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline.
Exposure
Cerebrospinal fluid α-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive.
Main Outcomes and Measures
Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E ε4 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment.
Results
Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P < .001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year; P < .001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women.
Conclusions and Relevance
In this cohort study of participants across the Alzheimer disease continuum, α-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of α-synuclein biomarkers and trial design.
