α-synuclein pathology is associated with faster tau accumulation in women

1. α-synuclein pathology was associated with faster tau accumulation in women than men.

Evidence Rating Level: 2 (Good)

Sex differences play an important role in Alzheimer’s disease, as women often show greater tau burden and faster cognitive decline than men. Although misfolded α-Synuclein frequently occurs in Alzheimer’s disease, it is unclear whether this copathology is differentially associated with disease progression by sex. This study thus examined whether α-synuclein pathology is differentially associated with tau accumulation in women and men across the Alzheimer’s disease continuum. This cohort study used data from the Alzheimer’s Disease Neuroimaging Initiative collected between 2015 and 2023 and included participants who were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline. Cerebrospinal fluid α-synuclein status was determined by cerebrospinal fluid seed amplification assay (SAA) and dichotomized as SAA negative or SAA positive. The primary outcome was tau burden measured as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest from positron emission tomography (PET) imaging. In total, 415 participants were included (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), with a median (IQR) follow-up of 1.23 (0.00-3.84) years. A 3-way interaction was found between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P < .001), indicating that the rate of tau accumulation over time differed by both SAA status and sex. Tau accumulation was fastest for women with positive SAA compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year). Overall, this study found that α-synuclein pathology was associated with faster tau accumulation in women than men, highlighting the importance of sex-specific interpretation of α-synuclein biomarkers in Alzheimer’s disease. 

Click here to read this study in JAMA Network Open

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