NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment

Abstract

Objective: This study examined whether cerebrospinal fluid (CSF) baseline levels of the synaptic protein NPTX2 predict time to onset of symptoms of mild cognitive impairment (MCI), both alone and when accounting for traditional CSF Alzheimer's disease (AD) biomarker levels. Longitudinal NPTX2 levels were also examined.

Methods: CSF was collected longitudinally from 269 cognitively normal BIOCARD Study participants (mean baseline age = 57.7 years; mean follow-up = 16.3 years; n = 77 progressed to MCI/dementia). NPTX2 levels were measured from 3 correlated peptides using quantitative parallel reaction monitoring mass spectrometry. Levels of Aβ₄₂ /Aβ₄₀ , p-tau₁₈₁ , and t-tau were measured from the same CSF specimens using Lumipulse automated electrochemiluminescence assays.

Results: In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio [HR] = 0.76, SE = 0.09, p = 0.023). This association was significant for progression within 7 years (p = 0.036) and after 7 years from baseline (p = 0.001). Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline AD biomarker levels (p < 0.01), and NPTX2 did not interact with the CSF AD biomarkers or APOE-ε4 genetic status. In linear mixed effects models, higher baseline p-tau₁₈₁ and t-tau levels were associated with higher baseline levels of NPTX2 (both p < 0.001) and greater rates of NPTX2 declines over time.

Interpretation: NPTX2 may be a valuable prognostic biomarker during preclinical AD that provides additive and independent prediction of MCI onset among individuals who are cognitively normal. We hypothesize that NPTX2-mediated circuit homeostasis confers resilience during the early phase of AD. ANN NEUROL 2023;94:620-631.

Figure 1.

Approximate timeline of BIOCARD study indicating the types of data collected each year.

Figure 2.

Scatterplots showing the correlation between CSF levels of the three quantotypic peptides for NPTX2 used in the current study, as measured by parallel reaction monitoring mass spectrometry (PRM-MS, y-axis, in pmol/ml) and levels of the same peptides measured by enzyme-linked immunosorbent assay (ELISA, x-axis, in pg/ml). The CSF samples used for the validation (N=35, including 11 with probable AD dementia and 24 cognitively normal participants, mean age=73.6 years, SD=6.4 years) were obtained from the University of California, San Diego Shirley Marcos Alzheimer’s Disease Research Center and the CSF collection methods have been described previously.

Figure 3.

Kaplan-Meier plots showing the proportion of participants who remain MCI symptom-free as a function of baseline level of CSF NPTX2 (as measured by the NPTX2 composite score) and baseline levels of (A) CSF Aβ₄₂/Aβ₄₀; (B) CSF p-tau₁₈₁; or (C) CSF t-tau. High vs. low levels of each CSF measure were based on the median.

Figure 4.

Adjusted estimates of longitudinal trajectories of NPTX2 composite score over time for (A) participants with high vs. low CSF p-tau₁₈₁ (high = upper tertile of the distribution; low=bottom two tertiles of the distribution); and (B) participants with high vs. low t-tau (high = upper tertile of the distribution; low = bottom two tertiles of the distribution).