Biomarkers for Alzheimer’s disease across diverse biological domains: an umbrella review and evidence map

This study aimed to systematically assess the quality, biases, and credibility of associations between potential Alzheimer's disease (AD) biomarkers through an umbrella review of existing meta-analyses. We systematically searched PubMed/MEDLINE, Embase, CINAHL, and Google Scholar up to December 18, 2024, for meta-analyses of observational studies examining biomarkers for AD. Two reviewers independently screened studies and extracted data. We recalculated effect sizes using random-effects models and converted all estimates to equivalent standardized mean differences or ratio of means. The quality of included reviews was assessed using AMSTAR2, and the credibility of each association was graded using predefined criteria (Class I-IV). A total of 35 articles provided 106 unique meta-analyses covering 1,277 original studies and 156,161 participants across 40 countries. Of these, 52 biomarkers showed statistically significant associations with AD upon re-analysis. Among them, 30 associations included more than 1,000 participants, 49 showed substantial heterogeneity (I2 > 50 %), and 17 had prediction intervals that excluded the null. Only one biomarker (blood YKL-40) reached Class I (convincing) evidence. Eleven associations were classified as highly suggestive (Class II), 14 as suggestive (Class III), and 26 as weak (Class IV) evidence levels. Biomarkers with high credibility (Class I-III) included urine formaldehyde, macular RNFL (optical coherence tomography), olfactory scores, plasma Aβ42/Aβ40 ratio, blood and CSF YKL-40, sTREM2, GFAP, ApoA-I, peripheral BDNF, and F2-isoprostane levels. This umbrella review provides a comprehensive evidence map of AD-related biomarkers. While 52 biomarkers were identified as statistically significant, only a subset met high credibility thresholds, emphasizing the need for large-scale, prospective studies to validate their clinical utility. PROSPERO CRD42024567136.