Mayo Clinic researchers have found that misfolded aggregates of alpha-synuclein—a protein linked to Parkinson’s disease—are associated with a much faster accumulation of tau proteins in women with Alzheimer’s disease. In fact, these women accumulated tau aggregates more than 20 times faster compared to men diagnosed with Alzheimer’s who also tested positive for misfolded alpha-synuclein.
Published today in JAMA Network, these findings provide a potential explanation for the well-documented sex differences seen in Alzheimer’s disease. Women are currently estimated to be two to three times more likely to develop Alzheimer’s compared to men, often showing greater tau pathology and faster cognitive decline.
“Recognizing these sex-specific differences could help us design more targeted clinical trials and ultimately more personalized treatment strategies,” said Kejal Kantarci, MD, professor of radiology at Mayo Clinic and senior author of the study. “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.”
Misfolded alpha-synuclein had previously been linked to faster neurodegeneration and cognitive decline in Alzheimer’s patients. However, no other studies had looked at how sex differences influence these effects.
Kantarci and colleagues analyzed data from 415 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a longitudinal study evaluating biomarkers for Alzheimer’s clinical trials. Among them, 17% had tested positive for misfolded alpha-synuclein aggregates in the cerebrospinal fluid at baseline. Longitudinal PET scans evaluated the progression of tau aggregates over time, with a median follow-up time of one year.
Among men, the presence of aggregated alpha-synuclein did not make a difference in terms of disease progression. Among women, however, alpha-synuclein pathology was associated with a dramatic increase in tau accumulation, reaching more than 20-fold higher accumulation rates compared to men with the same pathology.
“This opens an entirely new direction for understanding why women bear a disproportionate burden of dementia,” said Elijah Mak, PhD, assistant professor of radiology at Mayo Clinic and lead author of the study. “If we can unravel the mechanisms behind this vulnerability, we may uncover targets we haven’t considered before.”
Furthermore, these findings could have significant implications for the development of precision medicine approaches targeting sex-specific differences, as well as for the design of clinical trials in Alzheimer’s disease. Based on their results, the researchers estimate that recruiting women with misfolded alpha-synuclein in an 18-month trial would require 75% fewer participants to find statistically significant effects.
The authors noted that the study also highlights potential diagnostic shortcomings in other neurodegenerative conditions where alpha-synuclein pathology is involved. For instance, dementia with Lewy bodies (DLB) is reported to be less common in women than men. However, these women with misfolded alpha-synuclein aggregates are much more likely to also develop Alzheimer’s, meaning DLB diagnoses may often be masked by the more obvious Alzheimer’s symptoms in women. This could be preventing female patients from receiving adequate treatment for DLB symptoms or result in their exclusion from relevant clinical trials.
Altogether, these findings showcase the importance of accounting for sex differences when interpreting alpha-synuclein and Alzheimer’s biomarkers, whether for clinical trial design or the development of targeted treatments.
