Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease

Abstract

Objectives: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI).

Methods: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide.

Conclusion: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.

Figure. Flow diagram of subjects included in the plasma multianalyte profiling study and general analytical strategy

Subjects from University of Pennsylvania (Penn) and Alzheimer's Disease Neuroimaging Initiative (ADNI) were stratified into normal cognition, mild cognitive impairment (MCI), and clinically probable Alzheimer disease (AD) according to published criteria, along with additional patients from Penn with non-AD dementia. Subjects from Washington University were stratified according to Clinical Dementia Rating scale (CDR) according to published criteria (see Methods). In each cohort, mild impairment likely due to AD (mild cognitive and AD, or CDR of 0.5 and 1) were grouped and compared with subjects with normal cognition or CDR of 0.