Parkinson’s Protein Linked to Faster Alzheimer’s Progression in Women

Alzheimer’s brain changes progressed up to 20 times faster in women with Alzheimer’s and alpha-synuclein co-pathology compared with men, a cohort study showed.

In participants across the Alzheimer’s disease continuum, a significant interaction emerged between positive alpha-synuclein status, sex, and time on tau accumulation (β=0.061, 95% CI 0.030-0.093, P<0.001).

Compared with all other groups, women with positive alpha-synuclein had the fastest tau accumulation with a standardized uptake value ratio (SUVr) of 0.066/year (95% CI 0.043-0.089, P<0.001), reported Elijah Mak, PhD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.

Faster progression was not seen in men. Tau accumulation in men with positive alpha-synuclein was 0.003 SUVr/year (95% CI -0.015 to 0.020), the researchers reported in JAMA Network Open.

The findings suggest that when alpha-synuclein — a protein associated with Parkinson’s and other Lewy body diseases — accumulates alongside Alzheimer’s pathology, it may drive faster Alzheimer’s progression in women.

This opens a new direction to better understand women and dementia, Mak observed.

“The findings may explain why some women experience more aggressive dementia progression,” Mak told MedPage Today. “Individuals with both pathologies may benefit from different treatment strategies, potentially combination therapies targeting both Alzheimer’s disease and Lewy bodies in future.”

Co-pathology frequently occurs in Alzheimer’s, but its contribution to sex differences in disease progression is unclear. Studies also have shown that Alzheimer’s progresses differently in women.

By 2060, Alzheimer’s disease is projected to affect 13.8 million Americans, and nearly two-thirds will be women.

“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-author Kejal Kantarci, MD, also of the Mayo Clinic, said in a statement. “Co-pathologies may impact the disease process.”

Mak and colleagues evaluated longitudinal tau PET data from 415 participants in the Alzheimer’s Disease Neuroimaging Initiative collected between 2015 and 2023, with a median follow-up of 1.23 years. Participants were across the Alzheimer’s continuum at baseline: they had dementia, mild cognitive impairment, or were cognitively unimpaired.

The researchers stratified participants based on cerebrospinal fluid alpha-synuclein seed amplification assay status and sex. The mean age of the cohort was 72 years; 53% were women and 17% had positive alpha-synuclein.

The primary outcome was a metatemporal composite SUVr of the bilateral entorhinal cortex, amygdala, fusiform gyrus, and inferior or middle temporal cortices, with cerebellar gray matter as the reference.

Several mechanisms may underlie the findings, Mak and co-authors said. “Estrogen depletion compromises neuroprotective autophagy and microglial regulation, leading to permissive environments for protein aggregation. Our group recently demonstrated that bilateral oophorectomy performed before the age of 46 years increases tau burden in women with elevated amyloid,” they wrote.

“Against this backdrop of depleted neuroprotection, we propose that alpha-synuclein pathology may represent a second hit amplifier that exploits these existing vulnerabilities likely through cross-seeding tau aggregation, as well as amplified neuroinflammation that drives tau phosphorylation,” they noted.

The study has several limitations, they acknowledged. Only 27 women had positive alpha-synuclein in this study and replication in independent cohorts with larger samples is essential, they stated. Alpha-synuclein pathology had a binary classification of positive or negative, and dose-dependent effects could not be assessed. The relatively short follow-up period also might not have captured delayed effects in men.

The researchers are now studying whether sex-specific effects also appear in patients with dementia with Lewy bodies, where alpha-synuclein is the primary disease driver rather than a co-existing pathology.