2026 American Academy of Neurology Abstract Website

Objective:

To identify molecular pathways linking vesicular transport and immune dysregulation in brains with mixed Alzheimer’s disease pathology (ADP) and Lewy-related pathology (LRP).

Background:

Mixed dementia involving ADP and LRP is common but remains poorly understood at the molecular level. Dysregulation of vesicular transport and immune signaling may underlie the convergence of these disease processes.

Design/Methods:

RNA sequencing and proteomic profiling were performed on brain tissue from medial frontal gyrus (MFG), superior temporal gyrus (STG), and cerebrospinal fluid (CSF) from a cohort of 92 subjects, including those with Alzheimer's disease (AD, n=23), Lewy body dementia (LBD, n=23), mixed AD/LBD (n=26), and controls (n=20). Differential expression, principal component, and pathway enrichment analyses identified shared and distinct molecular signatures across disease groups.

Results:

Transcriptomic analysis revealed distinct gene expression patterns for each pathology, with mixed cases showing overlapping activation of immune, vesicle trafficking, and chromatin remodeling pathways. In the STG, the strongest protein-level differences were related to synaptic organization and vesicular transport. Integrative network analyses highlighted coordinated dysregulation of immune and vesicle-associated processes across modalities.

Conclusions:

Combined transcriptomic and proteomic evidence suggests that interplay between vesicular transport and immune-related pathways contributes to mixed Alzheimer’s–Lewy body pathology. These findings provide a molecular framework for biomarker development and therapeutic exploration in mixed dementias.