Identification of NPTX2 as a prognostic biomarker of Alzheimer’s disease through a longitudinal CSF proteomics study in ADNI subjects
Bibliographic record
Abstract
Abstract Background Many biomarkers have been identified which are relevant to studies of Alzheimer’s disease (AD), especially pertaining to the evolution of amyloid plaque, tau tangle pathology and loss of brain tissue. There remains, however, the need for additional biomarkers that reflect pathologic processes affecting neuronal function during pre‐clinical and prodromal stages, to help accelerate drug development efforts. Method A retrospective investigation of longitudinal changes in concentrations of five analytes (CgA, NPTX2, VGF, SCG2, FABP3) was performed in CSF of ADNI subjects. Rates of longitudinal change in these candidate proteins were compared between: a) Cognitively normal subjects (CN; n = 76) versus subjects with mild cognitive impairment (MCI; n = 111) at baseline; b) Subjects categorized as p‐Tau181/Aβ1‐42 ratio positive versus negative at baseline; and c) ‘Progressors’, i.e., subjects who progressed from CN to MCI or MCI to Dementia within a predefined period versus subjects categorized as ‘non‐progressors’. Following a pre‐specified analysis plan involving mixed‐effects linear models adjusting for relevant covariates, the association between changes in each analyte’s concentration and subjects’ clinical progression was quantified. Result NPTX2, a protein involved in synaptic function, showed the strongest association with baseline clinical diagnosis of MCI, and a positive p‐Tau181/Aβ1‐42 ratio – the biomarker profile indicative of AD. Differences in the rates of decline in NPTX2 concentration between subjects classified as CN and MCI as well as between p‐Tau181/Aβ1‐42 ratio positive and negative subjects were highly significant (p=0.008 and p<0.0001 resp.), suggesting a complex interaction between the rate of decline in subjects at various stages along the disease continuum. Of the five analytes, only the rates of change in NPTX2 concentrations differed between progressors and non‐progressors (mean difference: 0.08 ± 0.02 ng/mL/year); p = 0.0004), further validating the association of changes in NPTX2 concentration and clinical prognosis. Additional exploratory analyses indicated the presence of a correlation between NPTX2 rates of change and declining cognition measured by MMSE (coef. = 0.3, p = 0.02), and Adas‐Cog 13 (coef. = ‐0.3, p = 0.01). Conclusion These results suggest that NPTX2 concentration may serve as a prognostic biomarker of accelerated cognitive decline in at least a subset of individuals with AD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".