Network analysis of mouse brain proteomes resolves molecular and cellular endophenotypes of aging and Aβ pathology

Aging and Alzheimer's disease (AD) pathology exert both shared and distinct effects on the brain, yet their relative contributions to molecular alterations remain poorly defined. Here we performed tandem mass tag proteomics across the lifespan in wild-type and 5xFAD mice and integrated these data with human brain proteomic networks to resolve aging- and amyloid-beta (Aβ-associated molecular programs. We quantified 8,535 proteins and identified 51 co-expression modules representing neuronal, mitochondrial, glial, vascular and proteostatic pathways. Aging emerged as the predominant driver of proteomic remodeling, with widespread alterations in RNA metabolism, protein translation, and neuronal pathways occurring independently of Aβ pathology. In contrast, Aβ selectively modified a subset of age-dependent processes, including suppression of mitochondrial ATP biosynthetic machinery and amplification of astrocytic and microglial activation states. These key aging and disease-related molecular signatures were highly conserved in human AD brain proteomes. Together, our findings establish aging as the primary determinant of brain proteome organization while revealing specific mechanisms through which Aβ pathology reshapes age-associated biological processes. Our results also highlight molecular mechanisms of human aging and AD pathology that can be modeled in mouse models.