Overview of the study design and analytical workflow. Plasma samples from cognitively unimpaired (CU) participants were analyzed to evaluate progression to symptomatic Alzheimer’s disease (AD), and additional analyses examined progression from mild cognitive impairment (MCI) to AD and cross-sectional disease severity. Plasma phosphorylated tau 217 (p-tau217) was combined with the previously established 7-protein panel to assess progression risk, followed by model simplification analyses evaluating individual proteins and two-protein ratios. Biomarkers were dichotomized using Gaussian mixture modeling, and associations with clinical progression were evaluated using Cox regression. Disease severity analyses used model-predicted scores to examine tertile enrichment and correlations with observed Clinical Dementia Rating (CDR) stage. The overall goal was to identify simplified plasma biomarker combinations with potential translational utility for AD risk stratification.
Abstract
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.
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This post is Copyright: | August 14, 2026
Neuro-Dementia