Adhesion molecules provide an endothelial protein signature in preclinical and clinical Alzheimer's disease and predict clinical progression.

BACKGROUND: Cardiometabolic and inflammatory pathways may play important roles in Alzheimer's disease (AD) pathogenesis contributing to neuronal dysfunction even in the absence of cognitive symptoms. Our objective is to characterize proteomic signatures of these pathways in AD. METHODS: We perform CSF and plasma-targeted proteomics using Olink's highly sensitive proximity extension assay from 354 participants, of which 4.2% had preclinical AD, and 19.5% had prodromal AD. Using data-driven bioinformatic pipeline, we describe proteomic signatures based on various AD traits. RESULTS: The 276 measured proteins cluster into five modules that are associated with AD biomarkers and disease traits. We identify an AD signature in the CSF characterized by elevated levels of Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecules 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2 (SCARB2), and Plasminogen Activator Urokinase (PLAU) that was detectable even in preclinical AD. This signature also predicts clinical disease progression. Independent validation (n = 75) suggests that CSF adhesion molecules showed significant positive correlation with CSF Aβ-42: (R2 ranged: 0.05-0.44) and pTau (R2 ranged: 0.15-0.70). CONCLUSIONS: Our results identify a signature centered around CSF vascular adhesion proteins that associates with AD pathology and disease progression, with elevation detectable even in the preclinical stage, warranting further mechanistic investigation. Alzheimer’s disease is a brain disorder that slowly destroys memory and thinking skills, eventually affecting a person’s ability to carry out daily activitie. Alzheimer’s disease develops gradually over many years before symptoms appear. Increasing evidence suggests that changes in blood vessel function contribute to early brain injury. The aim of this study was to identify protein patterns linked to these processes across different stages of Alzheimer’s disease. We measured hundreds of proteins in blood and spinal fluid using a sensitive laboratory method and applied statistical analyses to identify consistent patterns. We found a group of proteins related to vascular function and inflammation that were elevated even in people with symptom-free, early Alzheimer’s disease and were associated with later disease progression. These findings suggest that vascular and inflammatory changes begin early and may help improve early detection and guide future prevention or treatment strategies.