A plasma‐based protein signature combining NPTXR, ACHE, and p‐tau217 predicts progression to symptomatic Alzheimer's disease
Menghan Liu, Katherine Gong, Yike Chen, Gyujin Heo, Ying Xu, Jigyasha Timsina, Daniel Western, John Budde, John C. Morris, Giorgetti Marco, David M. Holtzman, Jeremiah Hinson, Scott Levin, Nicholas Ashton, Marisa Denkinger, Suzanne E. Schindler, Kausik Das, Muhammad Ali, Carlos CruchagaAbstract
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.