Breaking Silos: A Bidirectional Human Framework Linking Vascular Dysfunction and Tauopathy Across Dementias

Dr. Elahi proposes to investigate how cerebrovascular disease and tau pathology work together to drive neurodegeneration in Alzheimer’s disease (AD). While vascular disease and tau tangles commonly occur together in aging brains, it remains unclear whether damaged blood vessels promote tau pathology, whether tau pathology damages the brain’s vasculature, or whether both processes reinforce one another. To address this, Dr. Elahi will leverage a rare inherited small vessel disease (CADASIL) as a simplified human model to disentangle these relationships without the confounding effects of amyloid pathology. Using postmortem human brain tissue, the team will compare vascular and tau pathology across CADASIL, AD, progressive supranuclear palsy (PSP), and healthy control brains to identify the cellular and molecular pathways linking vascular dysfunction to tau accumulation.

The project combines advanced human brain analyses with innovative stem cell-based models to determine how vascular dysfunction contributes to neuronal injury. In Aim 1, the team will generate a detailed cellular atlas of vascular and tau pathology by integrating digital pathology, single-nucleus sequencing, and spatial imaging to identify vascular changes that are most closely associated with tau accumulation. Aim 2 will use human induced pluripotent stem cell-derived neurons, glia, and vascular cells in both microfluidic and three-dimensional multicellular models to test whether vascular dysfunction directly causes tau-mediated neuronal damage and whether tau pathology, in turn, promotes harmful changes in blood vessels. Together, these studies aim to define the bidirectional relationship between vascular disease and tau pathology and identify new therapeutic targets for Alzheimer’s disease and related dementias.