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Abstract Details

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer's Disease
Aging, Dementia, and Behavioral Neurology
P5 - Poster Session 5 (8:00 AM-9:00 AM)
10-001

To identify cerebrospinal fluid (CSF) biomarkers of AD linked to a diverse set of pathophysiological processes in the diseased brain.

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. 

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.  
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.  

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. 

Authors/Disclosures
Lenora A. Higginbotham, MD (Emory University)
PRESENTER 		The institution of Dr. Higginbotham has received research support from NIH/NINDS . The institution of Dr. Higginbotham has received research support from Bright Focus Foundation. The institution of Dr. Higginbotham has received research support from Â鶹´«Ã½Ó³»­. Dr. Higginbotham has received intellectual property interests from a discovery or technology relating to health care.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Erik C. Johnson, MD, PhD (The Emory Clinic - Neurology) No disclosure on file
Ihab Hajjar Ihab Hajjar has nothing to disclose.
James J. Lah, MD, PhD (Emory Brain Health Center) Dr. Lah has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Diagnostics. The institution of Dr. Lah has received research support from Roche.
Allan I. Levey, MD, PhD (Dept of Neurology Emory University) Dr. Levey has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genuv. Dr. Levey has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Cognito Therapeutics. Dr. Levey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Levey has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Karuna Pharmaceuticals. Dr. Levey has received stock or an ownership interest from NextSense. The institution of Dr. Levey has received research support from NIH. The institution of Dr. Levey has received research support from Biogen. The institution of Dr. Levey has received research support from Esai. The institution of Dr. Levey has received research support from Â鶹´«Ã½Ó³»­. The institution of Dr. Levey has received research support from State of Georgia. The institution of Dr. Levey has received research support from Novartis. The institution of Dr. Levey has received research support from Genentech. Dr. Levey has received intellectual property interests from a discovery or technology relating to health care. Dr. Levey has received personal compensation in the range of $500-$4,999 for serving as a NAPA Avisory Committee Co-Chair with US Dept of Health and Human Services.
No disclosure on file