Large-scale proteomic analyses of incident Alzheimer's disease reveal new pathophysiological insights and potential therapeutic targets.

Pathophysiological evolutions in early-stage Alzheimer's disease (AD) are not well understood. We used data of 2923 Olink plasma proteins from 51,296 non-demented middle-aged adults. During a follow-up of 15 years, 689 incident AD cases occurred. Cox-proportional hazard models were applied to identify AD-associated proteins in different time intervals. Through linking to protein categories, changing sequences of protein z-scores can reflect pathophysiological evolutions. Mendelian randomization using blood protein quantitative loci data provided causal evidence for potentially druggable proteins. We identified 48 AD-related proteins, with CEND1, GFAP, NEFL, and SYT1 being top hits in both near-term (HR:1.15-1.77; P:9.11 × 10-2.78 × 10) and long-term AD risk (HR:1.20-1.54; P:2.43 × 10-3.95 × 10). These four proteins increased 15 years before AD diagnosis and progressively escalated, indicating early and sustained dysfunction in synapse and neurons. Proteins related to extracellular matrix organization, apoptosis, innate immunity, coagulation, and lipid homeostasis showed early disturbances, followed by malfunctions in metabolism, adaptive immunity, and final synaptic and neuronal loss. Combining CEND1, GFAP, NEFL, and SYT1 with demographics generated desirable predictions for 10-year (AUC = 0.901) and over-10-year AD (AUC = 0.864), comparable to full model. Mendelian randomization supports potential genetic link between CEND1, SYT1, and AD as outcome. Our findings highlight the importance of exploring the pathophysiological evolutions in early stages of AD, which is essential for the development of early biomarkers and precision therapeutics.