Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease

TLDR

Plasma biomarkers have been proposed to aid Alzheimer disease diagnosis, but few have been validated in independent cohorts. The study aimed to identify plasma biomarkers associated with AD in two independent cohorts and validate them in the multicenter ADNI cohort. Using targeted proteomics, the authors measured 190 plasma proteins in 600 participants from two centers, identified 17 analytes linked to very mild dementia/MCI or AD, and found that four of these (apoE, B‑type natriuretic peptide, C‑reactive protein, pancreatic polypeptide) were also altered in the ADNI cohort, with regression linking CSF Aβ42, t‑tau/Aβ42 ratios, APOE4 allele count, and plasma BNP and pancreatic polypeptide levels. Four plasma analytes were consistently associated with very mild dementia/MCI/AD across three independent cohorts and may predict underlying AD via their association with CSF biomarkers, though prospective confirmation of plasma–CSF amyloid correlation is needed.

Abstract

<h3>Objectives:</h3> 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 Alzheimer9s Disease Neuroimaging Initiative (ADNI). <h3>Methods:</h3> 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 <i>APOE</i>4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. <h3>Conclusion:</h3> 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.