Proteomics as a reliable approach for discovery of blood-based Alzheimer's disease biomarkers: A systematic review and meta-analysis.

In order to gauge the impact of proteomics in discovery of Alzheimer's disease (AD) blood-based biomarkers, this study had systematically reviewed articles published between 1984-2019. Articles that fulfilled the inclusion criteria were assessed for risk of bias. A meta-analysis was performed for replicable candidate biomarkers (CB). Of the 1651 articles that were identified, 17 case-control and two cohort studies, as well as three combined case-control and longitudinal designs were shortlisted. A total of 207 AD and mild cognitive impairment (MCI) CB were discovered, with 48 reported in >2 studies. This review highlights six CB, namely alpha-2-macroglobulin (α2M), pancreatic polypeptide (PP), apolipoprotein A-1 (ApoA-1), afamin, insulin growth factor binding protein-2 (IGFBP-2) and fibrinogen-γ-chain, all of which exhibited consistent pattern of regulation in >three independent cohorts. They are involved in AD pathogenesis via amyloid-beta (Aβ), neurofibrillary tangles, diabetes and cardiovascular diseases (CVD). Meta-analysis indicated that ApoA-1 was significantly downregulated in AD (SMD = -1.52, 95% CI: -1.89, -1.16, p < 0.00001), with low inter-study heterogeneity (I = 0%, p = 0.59). α2M was significantly upregulated in AD (SMD = 0.83, 95% CI: 0.05, 1.62, p = 0.04), with moderate inter-study heterogeneity (I = 41%, p = 0.19). Both CB are involved in Aβ formation. These findings provide important insights into blood-based AD biomarkers discovery via proteomics.