Ryan G. Palaganas, Dimitrios N. Sidiropoulos, Meaghan Morris, Genevieve Stein-O’Brien
Neurodegenerative diseases (NDDs) are a global health crisis affecting 15% of the population, with projections indicating this burden will double within two decades. Despite having shared molecular hallmarks, co-occurring proteinopathies, predictable progression patterns, and overlapping genetic risk variants, what causes specific NDDs to manifest in a particular individual or even a particular cell type is unknown. Thus, systems biology approaches are necessary to decipher the molecular, cellular, and environmental interactions driving pathogenesis. Multi-omics spatial profiling preserves tissue architecture while mapping cellular phenotypes and molecular interactions at subcellular resolution. Systems biology integration of these modalities will facilitate the identification of underlying causes of neuronal vulnerability, protein aggregation mechanisms, and disease progression patterns, accelerating targeted therapeutic development across NDDs.