Abstract

Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are among the leading causes of dementia, yet it remains unclear why certain brain cells are especially vulnerable to disease pathology while neighboring cells remain relatively unaffected. Understanding this selective cellular vulnerability is critical for informing future therapeutic strategies.

This project will leverage advanced spatial transcriptomic and proteomic technologies to characterize molecular changes in situ at single-cell resolution within intact human brain tissue, preserving tissue architecture and neuropathological context that are not captured by standard single-cell genomics approaches. By directly linking molecular changes to hallmark disease pathology, including tau aggregates and amyloid plaques, we aim to identify the molecular signatures that distinguish vulnerable from resilient cells. Comparing AD, FTLD-tau, and Long COVID will further reveal biological alterations that are shared across diseases, as well as those unique to each condition.

The long-term goal of this research is to define the molecular and cellular basis of selective cellular vulnerability, particularly to disease pathology, in neurodegenerative diseases and establish a molecular framework that will inform future therapeutic target discovery. Support from the Larry L. Hillblom Foundation will help launch my independent research program, integrating molecular neuropathology with single-cell spatial multi-omics to advance our understanding of aging-related neurodegenerative diseases.