Neuroinflammation and Alzheimer's Disease: A Machine Learning Approach to CSF Proteomics

In Alzheimer's disease (AD), the contribution of pathophysiological mechanisms other than amyloidosis and tauopathy is now widely recognized, although not clearly quantifiable by means of fluid biomarkers. We aimed to identify quantifiable protein biomarkers reflecting neuroinflammation in AD using multiplex proximity extension assay (PEA) testing. Cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment due to AD (AD-MCI) and from controls, i.e., patients with other neurological diseases (OND), were analyzed with the Olink Inflammation PEA biomarker panel. A machine-learning approach was then used to identify biomarkers discriminating AD-MCI (n: 34) from OND (n: 25). On univariate analysis, SIRT2, HGF, MMP-10, and CXCL5 showed high discriminatory performance (AUC 0.809, p = 5.2 x 10(-4), AUC 0.802, p = 6.4 x 10(-4), AUC 0.793, p = 3.2 x 10(-3), AUC 0.761, p = 2.3 x 10(-3), respectively), with higher CSF levels in AD-MCI patients as compared to controls. These same proteins were the best contributors to the penalized logistic regression model discriminating AD-MCI from controls (AUC of the model 0.906, p = 2.97 x 10(-7)). The biological processes regulated by these proteins include astrocyte and microglia activation, amyloid, and tau misfolding modulation, and blood-brain barrier dysfunction. Using a high-throughput multiplex CSF analysis coupled with a machine-learning statistical approach, we identified novel biomarkers reflecting neuroinflammation in AD. Studies confirming these results by means of different assays are needed to validate PEA as a multiplex technique for CSF analysis and biomarker discovery in the field of neurological diseases.

Automated summary

In this study, novel protein biomarkers reflecting neuroinflammation in Alzheimer's disease were identified using a high-throughput multiplex CSF analysis coupled with machine-learning. These biomarkers, including SIRT2, HGF, MMP-10, and CXCL5, showed high discriminatory performance in distinguishing AD patients from controls. The biological processes regulated by these proteins involve astrocyte and microglia activation, modulation of amyloid and tau misfolding, and dysfunction of the blood-brain barrier. Additional studies are needed to confirm these results and validate proximity extension assay as a technique for biomarker discovery in neurological diseases.