Alzheimer’s disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.

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We present an integrative proteomic strategy for the nomination and validation of proteins associated with cognitive resilience to Alzheimer's disease (AD). Correlation network analysis across distinct stages of AD was used to prioritize protein modules linked to resilience. Neuritin (NRN1), a hub protein in a module associated with synaptic biology, was identified as a top candidate of resilience and selected for functional validation in cultured neurons. NRN1 provided dendritic spine resilience against amyloid-β (Aβ), and NRN1 blocked Aβ-induced neuronal hyperexcitability. The impact of exogenous NRN1 on the proteome of cultured neurons was assessed and integrated with the AD brain network. This revealed over-lapping synapse-related biology that linked NRN1-induced changes in cultured neurons with human pathways associated with AD resilience. Collectively, this highlights the utility of integrating the proteome from human brain and model systems to prioritize therapeutic targets that mediate resilience to AD.

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