α-synuclein positivity is associated with decline in brain microstructure in the Alzheimer’s disease spectrum

α-Synuclein co-pathology is common in Alzheimer's disease (AD) and is associated with faster cognitive decline, yet its impact on brain structural integrity remains unclear. We examined the extent to which α-synuclein pathology influences brain microstructural changes using diffusion tensor imaging in participants stratified by cognitive impairment status. Participants from the Alzheimer’s Disease Neuroimaging Initiative with available CSF α-synuclein SAA results, diffusion MRI, and AD biomarkers were analyzed. Subjects were classified as cognitively unimpaired (CU) or cognitively impaired (CI) and as SAA-positive (SAA +) or negative (SAA-). Fractional anisotropy (FA) and mean diffusivity (MD) values were extracted from white and gray matter regions-of-interest after multi-scanner harmonization using ComBat. Linear regression models were used to assess cross-sectional associations between SAA status and AD pathologic burden (CSF p-tau181/Aβ42 ratio) controlling for age and sex for CUs. Those models were performed for CI with additional adjustment for diagnostic stage (MCI vs dementia). For longitudinal data, similar models were performed using mixed-effects models including time and various interactions with time. False discovery rate correction across regions-of-interest was applied for all models. Cross-sectionally, α-synuclein positivity was associated with microstructural injury in temporo-limbic gray and white matter regions exclusively in CI participants, with effects persisting even after controlling for Alzheimer's disease pathologic burden. The influence of α-synuclein on microstructure was more pronounced longitudinally, such that CI SAA + participants showed greater and widespread white matter deterioration, remaining after AD pathologic burden adjustment. In CU individuals, higher levels of AD pathology were associated with longitudinal decline in white matter integrity only when α-synuclein co-pathology was present. Our findings demonstrate that α-synuclein copathology shapes brain microstructural decline in a stage-dependent manner in people on the AD spectrum. These results support combination therapy strategies informed by α-synuclein status and advance precision medicine approaches to neurodegeneration. Limitations included the lack of validation in an independent dataset, relatively short follow-up duration, and use of a binary SAA classification.