A plasma‐based protein signature combining NPTXR, ACHE, and p‐tau217 predicts progression to symptomatic Alzheimer's disease

INTRODUCTION: We recently identified a plasma-based seven-protein model with strong performance for Alzheimer's disease (AD) classification. Here, we evaluated whether these proteins, alone or combined with plasma phosphorylated tau 217 (p-tau217), predict progression from cognitively unimpaired to symptomatic AD. METHODS: Using longitudinal data from Knight-ADRC (Alzheimer's Disease Research Center) with replication in Alzheimer's Disease Neuroimaging Initiative (ADNI), we modeled time to progression using Cox regression. Models included p-tau217, the seven-protein panel, and their combination. RESULTS: The p-tau217 alone showed similar progression prediction (hazard ratio [HR] = 4.08) than the seven-protein model (HR = 4.85). Integrating the seven-protein model with ptau217 significantly improved risk, identifying a high-risk group (HR = 11.15) with two intermediate-risk groups. Simplified models retained prognostic value, with top-performing ratios, Complexin-2/Synaptic vesicle membrane protein VAT-1 homolog (CPLX2/VAT1) and Acetylcholinesterase/Neuronal pentraxin receptor (ACHE/NPTXR) also lead to a significantly better risk stratification than p-tau217 alone. DISCUSSION: Integrating p-tau217 with targeted plasma proteins enables graded risk stratification and identifies individuals at highest risk of progression, supporting clinically scalable approaches for early risk assessment.