Abstract
INTRODUCTION
ATN-stratified cerebrospinal fluid (CSF) proteomic signals may partly reflect classifier tau immunoassays; reproducible non-tau signals and CSF–plasma differences remain unclear.
METHODS
We profiled CSF from 60 A+ Beijing patients with Alzheimer’s disease (AD) and 875 A+ Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants using the NULISAseq CNS Disease Panel. Differential expression was assessed using a false discovery rate (FDR) < 0.05 and |log2FC|≥0.5 across three ATN contrasts. We also analyzed ADNI plasma, protein–cognition correlations, tau-adjusted associations, and nested models comparing non-tau proteins with tau biomarkers.
RESULTS
Eight CSF proteins met the cross-cohort criterion within at least one matched contrast: pTau-217, pTau-181, pTau-231, MAPT, SMOC1, MDH1, VSNL1, and FABP3. NULISA tau correlated with INNOTEST (ρ = 0.75–0.85) and Elecsys (ρ = 0.65–0.68). T and N classifications agreed for 94.6% of ADNI participants (κ = 0.880); after adjustment for CSF pTau-217, all 12 associations involving the four non-tau proteins retained their direction and FDR support. In CSF, Elecsys p-tau181 and NULISA tau-family analytes had the strongest cognitive correlations (mean |ρ| = 0.35 and 0.29–0.34, respectively), followed by FABP3 (0.24). Adding the four-protein block after tau increased cross-validated R2 across all three cross-sectional outcomes in models without diagnosis (+0.0101 to +0.0265), most clearly for the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, 13-item version (ADAS-Cog13); diagnosis-conditioned models showed no stable increment beyond tau and clinical characteristics. In plasma, pTau-217 was the only analyte that met both thresholds in all three contrasts.
DISCUSSION
CSF NULISAseq identified a reproducible tau-associated signature across A+ cohorts that extended beyond the tau family. The four non-tau proteins extend the molecular profile associated with tau-defined disease state and merit further evaluation for biological stratification in independent cohorts.
Highlights
Eight cerebrospinal fluid (CSF) proteins replicated across cohorts in matched ATN contrasts.
The non-tau CSF proteins were SMOC1, MDH1, FABP3, and VSNL1.
Non-tau signals retained direction and false discovery rate (FDR) support after adjusting for CSF pTau-217.
Four-protein ΔR2 was positive before diagnosis adjustment but smaller afterward.
pTau-217 was the only plasma analyte to meet both thresholds in all three contrasts.
Authors and Affiliations
Lan Ding¹˒², Menghan Zheng², Simiao Wang², Wenying Liu², Yumei Liang², Siqi Xie², Ting Yang², Dandan Sheng², Shuheng Wang², Jianpeng Sheng¹, Jianping Jia¹˒²˒³˒⁴˒⁵˒⁶, and the Alzheimer’s Disease Neuroimaging Initiative
¹ Chinese Institutes for Medical Research, Beijing (CIMR), Capital Medical University, Beijing, P. R. China
² Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, P. R. China
³ Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P. R. China
⁴ Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, P. R. China
⁵ Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, P. R. China
⁶ Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, P. R. China