Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease (4738)

Objective: To identify cerebrospinal fluid (CSF) biomarkers of AD linked to a diverse set of pathophysiological processes in the diseased brain. Background: Alzheimer’s disease (AD) features a complex web of pathological processes beyond amyloid accumulation and tau-mediated neuronal death. To meaningfully advance AD therapeutics, there is an urgent need for novel AD biomarkers that comprehensively reflect these underlying disease mechanisms. Design/Methods: Using multiplex proteomics, we analyzed the CSF proteomes of 40 subjects (controls=20, AD=20) and brain proteomes of 48 pathologically-confirmed control (n=10), asymptomatic AD (n=8), AD (n=10), and other neurodegenerative cases. Integrative statistical analyses were used to identify proteins differentially expressed in AD CSF with strong links to co-expression networks in the diseased brain. Using high-throughput proteomics, these results were validated in 96 independent CSF samples from control, asymptomatic AD (AsymAD), and AD individuals. Results: We identified >3,500 proteins across the 40 CSF samples and >12,000 proteins across the 48 postmortem brain tissues. Co-expression network analysis of the brain tissues resolved 44 protein co-expression modules, nearly half of which significantly correlated with AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain-linked fluid markers representing a variety of cortical functions. Neuron-enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial-enriched myelination and immunity panels were highly increased in both the brain and CSF. Analysis of our CSF validation cohort replicated these panel abundance changes. Remarkably, several panel markers were significantly altered in AsymAD spinal fluid and appeared to stratify subpopulations within this cohort. Conclusions: These brain-linked CSF biomarker panels represent a promising step toward a physiologically comprehensive tool that could meaningfully enhance the prognostic and therapeutic management of AD. Disclosure: Dr. Higginbotham has nothing to disclose. Dr. Ping has nothing to disclose. Dr. Dammer has nothing to disclose. Dr. Duong has nothing to disclose. Dr. Zhou has nothing to disclose. Dr. Gearing has nothing to disclose. Dr. Johnson has nothing to disclose. Dr. Hajjar has nothing to disclose. Dr. Lah serves on the advisory board for Humana.Dr. Levey has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Brightfocus Foundation, Alzheimer Drug Discovery Foundation, Burke Rehabilitation Institute, Rainbow Medical, Future Health Services LLC. Dr. Levey has received royalty, license fees, or contractual rights payments from Millipore. Dr. Levey has received research support from Abbvie, Genetech, Cognito Therapeutics, Biogen, Merck, Esai, and Novartis. Dr. Seyfried has nothing to disclose.