PI-007 - PROTEOMIC SIGNATURES IN THE CEREBROSPINAL FLUID (CSF) OF INDIVIDUALS WITH PRECLINICAL AND PRODROMAL ALZHEIMER'S DISEASE (AD): A KEY ROLE FOR ENDOTHELIAL AND ADHESION PROTEINS IN PRECLINICAL AD.

R. Neal¹, I. Ozobu¹, M. obideen¹, z. yang¹, I. Hajjar¹; ¹UT Southwestern Medical Center, Dallas, TX, USA.

Background: Alzheimer’s Disease (AD) is characterized by a progressive decline in cognitive function and the accumulation of Amyloid-beta and Tau related pathologies in the brain (hallmark of AD). Our current understanding of the pathogenesis of AD includes a preclinical phase where amyloid deposition is not associated with significant cognitive symptoms. However, the molecular mechanism(s) involved that precede the cognitive symptoms remain unknown.

Methods: To study the molecular mechanisms involved in the pathogenesis of AD, we conducted targeted proteomic analyses of 276 proteins. We used the cerebrospinal fluid (CSF) and plasma samples of 354 participants previously recruited to the Brain Stress Hypertension and Aging Program (BSHARP). We then applied a bioinformatic pipeline to generate data-driven protein modules and identified “Hub” and "Critical” proteins within each module that were associated with clinical and biological AD traits. The CSF proteomic profiles of individuals with normal cognition, preclinical AD, prodromal AD, and non-AD MCI were compared and differentially expressed “Critical” proteins were identified. Then a pathway enrichment analysis of those proteins was performed to gain a better understanding of the mechanisms through which they might be involved in the pathogenesis of AD.

Results: The 276 proteins clustered into five modules that were linked to AD clinical traits and associated with CSF Amyloid-β42, Tau, pTau, and The Tau/Aβ42 Ratio (TAR). (all p-value < 0.05). Differentially expressed “Critical” proteins based on TAR and cognitive status included (HGF, ICAM-1, VCAM-1, NRP-1, NRP-2, SCARB2, & PLAU). (all p-value < 0.05) The CSF/Plasma ratio of those proteins also significantly differed based on TAR & cognitive status. Pathway enrichment of those proteins using the Gene Ontology (GO) Biological Process identified a series of pathways related to cell-cell adhesion and protein phosphorylation. (all p-value < 0.05) Those pathways are known to be involved in the mechanisms of AD risk factors.

Conclusion: Our results suggest a proteomic signature in the CSF of individuals with preclinical AD that is driven by adhesion molecules and is implicated in the pathogenesis of AD cognitive impairment. Future studies investigating these proteins might provide some insights into novel AD therapeutic targets.