Cross-cohort CSF proteomics identifies non-tau signatures in amyloid-positive Alzheimer's disease

An observational proteomic analysis of 60 Beijing patients and 875 ADNI participants identified eight reproducible CSF protein signals, including four non-tau proteins. The non-tau panel added modest explanatory value for cognition beyond tau, but gains were not stable after accounting for diagnosis and clinical characteristics.

Eight CSF protein signals reproduced across two amyloid-positive cohorts.
Four non-tau proteins retained associations after adjustment for CSF pTau-217.
Incremental cognitive information was not stable in diagnosis-conditioned models.
Plasma pTau-217 alone met expression thresholds across all three contrasts.

Researchers used the NULISAseq CNS Disease Panel to profile cerebrospinal fluid (CSF) from 60 amyloid-positive Beijing patients with Alzheimer's disease and 875 amyloid-positive Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. The observational analysis compared protein expression across three amyloid–tau–neurodegeneration (ATN) contrasts, requiring a false discovery rate below 0.05 and an absolute log2 fold change of at least 0.5. Investigators also examined ADNI plasma, cognitive correlations and models assessing non-tau proteins beyond tau biomarkers.

Eight CSF proteins met the cross-cohort criteria in at least one matched contrast: pTau-217, pTau-181, pTau-231, MAPT, SMOC1, MDH1, VSNL1 and FABP3. All 12 associations involving the four non-tau proteins retained their direction and statistical support after adjustment for CSF pTau-217. Tau biomarkers had the strongest cognitive correlations. Adding the four non-tau proteins after tau increased cross-validated R² by 0.0101–0.0265 across three cross-sectional cognitive outcomes in models without diagnosis. Models accounting for diagnosis showed no stable increment beyond tau and clinical characteristics. In plasma, only pTau-217 met both expression thresholds across all three contrasts.

These findings support a reproducible CSF molecular signature extending beyond tau, rather than established clinical utility for the additional proteins. Cognitive analyses were cross-sectional, and incremental information depended on model specification. Independent validation is needed before considering the panel for biological stratification; this assessment is based on the abstract, with full text unavailable.

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Alzheimer's & Dementia: Cross‐cohort NULISAseq identifies tau‐anchored CSF and plasma‐specific signatures across the amyloid‐positive Alzheimer's disease ↗

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