Comparison of Commonly Measured Plasma and Cerebrospinal Fluid Proteins and Their Significance for the Characterization of Cognitive Impairment Status

Background: Although cerebrospinal fluid (CSF) amyloid-β 42 peptide (Aβ 42) and phosphorylated tau (p-tau) and blood p-tau are valuable for differential diagnosis of Alzheimer’s disease (AD) from cognitively normal (CN) there is a lack of validated biomarkers for mild cognitive impairment (MCI). Objective: This study sought to determine how plasma and CSF protein markers compared in the characterization of MCI and AD status. Methods: This cohort study included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 75 proteins measured commonly in plasma and CSF (257 total, 46 CN, 143 MCI, and 68 AD). Logistic regression, least absolute shrinkage and selection operator (LASSO) and Random Forest (RF) methods were used to identify the protein candidates for the disease classification. Results: We observed that six plasma proteins panel (APOE, AMBP, C3, IL16, IGFBP2, APOD) outperformed the seven CSF proteins panel (VEGFA, HGF, PRL, FABP3, FGF4, CD40, RETN) as well as AD markers (CSF p-tau and Aβ 42) to distinguish the MCI from AD [area under the curve (AUC) = 0.75 (plasma proteins), AUC = 0.60 (CSF proteins) and AUC = 0.56 (CSF p-tau and Aβ 42)]. Also, these six plasma proteins performed better than the CSF proteins and were in line with CSF p-tau and Aβ 42 in differentiating CN versus MCI subjects [AUC = 0.89 (plasma proteins), AUC = 0.85 (CSF proteins) and AUC = 0.89 (CSF p-tau and Aβ 42)]. These results were adjusted for age, sex, education, and APOE ϵ4 genotype. Conclusions: This study suggests that the combination of 6 plasma proteins can serve as an effective marker for differentiating MCI from AD and CN.