Summary: Nearly two-thirds of people with Alzheimer’s disease are women, and new research points to a major reason why. A Mayo Clinic study published in JAMA Network Open found that when the Parkinson’s-related protein alpha-synuclein accumulates alongside Alzheimer’s pathology, tau-related brain changes in women progressed up to 20 times faster. This accelerating interaction was not observed in men, suggesting a sex-specific vulnerability that could change how we screen for and treat Alzheimer’s in women.
The discovery highlights a previously underappreciated interaction between two misfolded proteins — tau and alpha-synuclein — and suggests that coexisting proteinopathies can dramatically alter the course of neurodegeneration in a sex-dependent way. These findings emphasize the need for more precise, sex-aware approaches to diagnosis, monitoring, and clinical trial design for Alzheimer’s disease.
Key Facts
- The 20X Effect: Women with both abnormal tau (Alzheimer’s) and abnormal alpha-synuclein showed up to a 20-fold faster progression of tau accumulation compared with women without alpha-synuclein copathology.
- Sex-Specific Vulnerability: Men with the same combination of protein changes did not show the same rapid acceleration, indicating important biological differences in how male and female brains respond to misfolded proteins.
- Alpha-Synuclein’s Role: Although alpha-synuclein is central to Parkinson’s disease and Lewy body dementia, it often appears as a copathology in Alzheimer’s and can substantially worsen outcomes for women.
- Imaging and Biomarkers: Researchers combined advanced tau PET brain imaging with cerebrospinal fluid (CSF) testing for alpha-synuclein using seed amplification assays, tracking changes across time in 415 participants.
- Implications for Precision Medicine: The work supports the idea that Alzheimer’s is heterogeneous and that screening for alpha-synuclein in women may improve prognosis estimation and trial enrollment strategies.
Source: Mayo Clinic
Major finding: Alzheimer’s-related tau accumulation progressed up to 20 times faster in women who also had abnormal levels of alpha-synuclein, according to a Mayo Clinic analysis published in JAMA Network Open. The same pattern did not appear in men.
Kejal Kantarci, M.D., a neuroradiologist at the Mayo Clinic and senior author of the study, uses advanced neuroimaging to follow Alzheimer’s progression. She emphasizes that recognizing sex-specific differences is essential for designing targeted clinical trials and developing personalized treatment strategies.
“When disease-related changes unfold at dramatically different rates across groups, we cannot treat Alzheimer’s as a single, uniform condition,” Dr. Kantarci said. “Copathologies such as alpha-synuclein may meaningfully modify the disease process, and that effect appears to be especially pronounced in women.”
Alzheimer’s disease is primarily defined by accumulation of tau protein in the brain. Many individuals on the Alzheimer’s continuum also develop abnormal clumping of alpha-synuclein — the protein characteristic of Lewy body diseases like Parkinson’s disease and dementia with Lewy bodies. Both tau and alpha-synuclein are normally present in the brain, but in neurodegenerative disease they can misfold and form deposits that disrupt neuronal communication and promote cognitive decline.
To explore whether alpha-synuclein copathology changes the trajectory of tau accumulation and whether that effect differs by sex, the researchers analyzed longitudinal data from 415 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants underwent cerebrospinal fluid testing for alpha-synuclein using a seed amplification assay and serial tau positron emission tomography (PET) scans to measure accumulation over time. About 17% of participants tested positive for abnormal alpha-synuclein.
Results showed that among people with both Alzheimer’s-related pathology and abnormal alpha-synuclein, women accumulated tau substantially faster than men with the same coexisting protein changes. Elijah Mak, Ph.D., the study’s first author and a Mayo Clinic neuroimaging researcher, noted that the finding opens a new avenue for understanding why women carry a disproportionate burden of dementia.
“If we can identify the biological mechanisms behind this sex-specific vulnerability, we may discover novel therapeutic targets,” Dr. Mak said. The team is now assessing whether similar sex-specific interactions occur in dementia with Lewy bodies, where alpha-synuclein is the primary pathology rather than a copathology, to determine whether the effect reflects a broader vulnerability across neurodegenerative diseases.
These findings have practical implications for clinical trials. The investigators estimated that trials targeting tau pathology in cognitively impaired individuals with an 18-month follow-up would require far fewer alpha-synuclein–positive women to detect a 25% treatment effect compared with alpha-synuclein–negative women, highlighting how biomarker stratification by sex could make trials more efficient and informative.
Key Questions Answered:
A: Not necessarily. Proteins such as alpha-synuclein can misfold in the brain without producing classic Parkinson’s symptoms. This study indicates that when alpha-synuclein appears in an Alzheimer’s brain, it can accelerate tau accumulation—particularly in women—thereby speeding cognitive decline.
A: The exact reasons are not yet clear. Potential explanations include hormonal influences, sex differences in immune response to protein aggregates, or differences in brain clearance mechanisms. Further research is needed to identify the biological drivers of this sex-specific vulnerability.
A: Yes. Cerebrospinal fluid testing using seed amplification assays can detect abnormal alpha-synuclein. The study suggests that such testing may be particularly informative for predicting disease trajectory in women and for selecting participants for biomarker-driven clinical trials.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal article was reviewed in full by editorial staff.
- Additional context was provided by the newsroom team to clarify implications for research and clinical practice.
About this Alzheimer’s disease and Parkinson’s disease research news
Author: Emily DeBoom
Source: Mayo Clinic
Contact: Emily DeBoom, Mayo Clinic
Image: Image 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 (summary)
Title: Sex-Specific Associations of α-Synuclein Pathology With Tau Accumulation
Importance: Sex differences are increasingly recognized as modifiers of Alzheimer’s disease and related dementias. Women often exhibit a greater tau burden and faster cognitive decline than men. Although alpha-synuclein copathology commonly coexists with Alzheimer’s disease, its role in driving sex differences in progression has not been clear.
Objective: To determine whether alpha-synuclein positivity, measured by cerebrospinal fluid seed amplification assay, is differentially associated with tau accumulation in women versus men across the Alzheimer’s disease continuum.
Design, Setting, and Participants: The cohort study used longitudinal tau PET data from the Alzheimer’s Disease Neuroimaging Initiative collected between 2015 and 2023, with a median follow-up of 1.23 years. Participants were stratified by CSF alpha-synuclein SAA status and sex and included individuals who were cognitively unimpaired as well as those with mild cognitive impairment or dementia at baseline.
Exposure: CSF alpha-synuclein status determined by seed amplification assay and categorized as SAA negative or SAA positive.
Main Outcomes and Measures: Tau burden quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region. Linear mixed-effects models tested interactions among SAA status, sex, and time on longitudinal tau accumulation, adjusting for baseline age, cognitive status, APOE ε4 carrier status, and study site. Sample size estimates were computed to assess trial design implications.
Results: Among 415 participants (mean age 72.3 years; 220 women, 53%; 69 SAA positive, 17%), there was a significant interaction between SAA status, sex, and time on tau accumulation. Women who were SAA positive exhibited the fastest tau accumulation (0.066 SUVr per year), and the interaction remained significant after adjustment. Sample size modeling suggested that trials targeting tau pathology could be more efficient when stratifying by SAA status and sex.
Conclusions and Relevance: In this cohort across the Alzheimer’s continuum, alpha-synuclein copathology was associated with faster tau accumulation in women compared with men. These results support sex-specific interpretation of alpha-synuclein biomarkers and could inform future trial design and personalized approaches to treatment.