A Subset of Cerebrospinal Fluid Proteins from a Multi-Analyte Panel Associated with Brain Atrophy, Disease Classification and Prediction in Alzheimer's Disease

Abstract

In this exploratory neuroimaging-proteomic study, we aimed to identify CSF proteins associated with AD and test their prognostic ability for disease classification and MCI to AD conversion prediction. Our study sample consisted of 295 subjects with CSF multi-analyte panel data and MRI at baseline downloaded from ADNI. Firstly, we tested the statistical effects of CSF proteins (n = 83) to measures of brain atrophy, CSF biomarkers, ApoE genotype and cognitive decline. We found that several proteins (primarily CgA and FABP) were related to either brain atrophy or CSF biomarkers. In relation to ApoE genotype, a unique biochemical profile characterised by low CSF levels of Apo E was evident in ε4 carriers compared to ε3 carriers. In an exploratory analysis, 3/83 proteins (SGOT, MCP-1, IL6r) were also found to be mildly associated with cognitive decline in MCI subjects over a 4-year period. Future studies are warranted to establish the validity of these proteins as prognostic factors for cognitive decline. For disease classification, a subset of proteins (n = 24) combined with MRI measurements and CSF biomarkers achieved an accuracy of 95.1% (Sensitivity 87.7%; Specificity 94.3%; AUC 0.95) and accurately detected 94.1% of MCI subjects progressing to AD at 12 months. The subset of proteins included FABP, CgA, MMP-2, and PPP as strong predictors in the model. Our findings suggest that the marker of panel of proteins identified here may be important candidates for improving the earlier detection of AD. Further targeted proteomic and longitudinal studies would be required to validate these findings with more generalisability.

Fig 1. Heatmap of baseline CSF proteins that were significantly associated with regional MRI measures, SPARE-AD score or CSF biomarkers in AD patients and MCI subjects (n = 207).

Fig 2. CSF proteins significantly associated with different ApoE gene polymorphisms (ε2 carriers, ε3 carriers, and ε4 carriers).

(A) CSF levels of ApoE protein between ApoE groups; (B) CSF levels of Interleukin-3 (IL-3) between ApoE groups and (C) CSF levels of Macrophage migration inhibitory factor (MIF) between ApoE groups. *These units refer to data before transformation.

Fig 3. ROC curves from disease classification models for differentiating between AD and CN individuals.

Fig 4. Predictive values from the combined CSF RFE subset CSF biomarker and regional MRI measures model for MCI to AD conversion prediction at several follow up timepoints.

(A) Predictive values of MCI-c progressing to AD at different follow up timepoints overlaid with predictive values of AD and CN individuals and (B) predictive values of MCI-nc at different follow up timepoints overlaid with predictive values of AD and CN individuals.