Pathophysiological subtypes of mild cognitive impairment due to Alzheimer’s disease identified by CSF proteomics

Abstract

S1) represents original features in relation to previous studies, since we (1) focused on the initial phases of AD, that is, patients with MCI within the Cognitive Complaints Cohort (CCC) [4]; (2) recruited patients with MCI who exhibited amyloid and neuronal injury biomarkers indicative of a high likelihood of AD (MCIAD; n = 45; adapted from the National Institute on Aging—Alzheimer’s Association workgroups [5]); (3) selected a control group of MCI patients without any biomarkers of Aβ deposition or neuronal injury (MCIOther; n = 23), in order to control for nonspecific changes that might influence the CSF proteome in patients with MCI; and (4) applied the same methodology to MCI patients with (n = 92) and without (n = 102) AD pathology from the European Medical Information Framework for Alzheimer’s Disease (EMIF-AD) cohort for further validation (Fig. 1a and Additional file 2: SEE PDF] CSF proteomics [6], generic functional analysis and gene ontology analysis (GO) of the quantified proteins showed similar biological pathways altered in patients from both cohorts (Additional file 1: Table S6). [...]in the CCC cohort, NRP2 (neuropilin 2), APOA1 (apolipoporotein A I), AHSG/FETUA (alpha 2-HS glycoprotein), ORM1/A1AG1 (alpha-1-acid glycoprotein 1) and NBL1 (neuroblastoma suppressor of tumorigenicity 1) were identified as the most important CSF proteins to distinguish MCIAD from MCIOther patients, corresponding to the five highest VIP scores (Fig. 1c). S3 and S4), the two clusters could best describe the CSF proteomic data. [...]when performing an exploratory random forest classification of patients on the resulting two clusters, a small error was observed (< 9.5%) with both Cluster 1 and 2 being classified with high accuracy (> 85%) in the two cohorts.