Proteomics of 2 postmortem Human Brain Regions for Identification of Cognitive Resilience Factors

We implemented an integrative systems-level analysis of multi-region postmortem human brain proteomics derived from the Religious Order and Rush Memory and Aging Project (ROSMAP) to identify proteins and pathways significantly altered in resilient cases. ROSMAP is an information-rich longitudinal cohort-based study in which participants enroll without dementia, undergo annual cognitive and clinical assessments and donate their brains at death (12). Multiplex tandem mass tag mass spectrometry (TMT-MS)-based proteomic data was implemented for a correlation network analysis. Data from an independent brain proteome wide association study (PWAS) of cognitive trajectory was integrated with the brain network to robustly prioritize protein communities associated with cognitive resilience. This revealed proteins linked to synaptic biology and cellular energetics. Neuritin (NRN1) was prioritized as a hub that co-expressed with a community of proteins with high correlation to cognitive stability in life and is known for important roles in synaptic maturation and stability.