Cerebrospinal Fluid (CSF) Proteomic Signature in Preclinical and Clinical AD: Role of Adhesion Molecules.

Background: Although Amyloid-beta and Tau are the hallmarks of Alzheimer’s Disease (AD), other protein pathways such as endothelial dysfunction may be involved and may precede cognitive symptoms. Our objective was to characterize the cerebrospinal fluid (CSF) proteomic profiles focusing on cardiometabolic-related protein pathways in individuals on the AD spectrum. Methods: We performed CSF and plasma-targeted proteomics (276 proteins) from 354 participants of the Brain Stress Hypertension and Aging Program (BSHARP), of which 8% had preclinical AD, and 24% had MCI due to AD. We instituted a bioinformatic pipeline to generate data-driven protein modules, used “Hub” and "Critical” proteins within each module to describe protein signatures for each AD stage and then assessed their associations with clinical and biological AD traits. Finally, we completed pathway enrichment analysis to get insight into pathways that might be implicated in AD pathogenesis. Results: The 276 measured proteins clustered into five modules that were associated with CSF Amyloid-β42, Tau, and pTau. (all p-value <0.05). A CSF protein AD signature was characterized by elevated levels of CSF Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecule 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2(SCARB2), Plasminogen Activator, Urokinase (PLAU). (all <0.05) We also found a significant difference in the CSF/Plasma ratio for the proteins associated with Cognitive Status and the Tau/Aβ42 ratio (TAR) in the CSF. Pathway enrichment analysis revealed that cell adhesion and endothelial dysfuncton(all p-value <0.05) were key mechanisms involved in AD pathogenesis, especially in the preclinical stage. Conclusion: Our results suggest a proteomic signature in the CSF of individuals with preclinical AD that is driven by adhesion molecules and might be implicated in the pathogenesis of AD. Future studies investigating these pathways may provide insights into novel AD biomarkers and therapeutic targets.