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

Jiseung Kang¹, Yejun Son², Yesol Yim², Hanseul Cho³, Jaewon Kim⁴, Arianna R S Lark⁵, Fayaz A Mir⁵, Hyeon Jin Kim², Jaeyu Park², Hayeon Lee⁶, Tae Kim⁷, Guillaume Fond⁸, Laurent Boyer⁸, Masoud Rahmati⁹, Lee Smith¹⁰, Dong Keon Yon¹¹, Christa J Nehs¹²

Affiliations

¹ School of Health and Environmental Science, Korea University College of Health Science, Seoul, South Korea; Department of Health and Safety Convergence Science, Korea University Graduate School, Seoul, South Korea.
² Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea; Department of Precision Medicine, Kyung Hee University College of Medicine, Seoul, South Korea.
³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea.
⁵ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA; Mass General Brigham Department of Anesthesiology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea; Department of Electronics and Information Convergence Engineering, Kyung Hee University, Yongin, South Korea.
⁷ Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, South Korea.
⁸ CEReSS-Health Service Research and Quality of Life Center, Assistance Publique-Hopitaux de Marseille, Aix Marseille University, Marseille, France.
⁹ CEReSS-Health Service Research and Quality of Life Center, Assistance Publique-Hopitaux de Marseille, Aix Marseille University, Marseille, France; Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khoramabad, Iran; Department of Physical Education and Sport Sciences, Faculty of Literature and Humanities, Vali-E-Asr University of Rafsanjan, Rafsanjan, Iran.
¹⁰ Centre for Health, Performance, and Wellbeing, Anglia Ruskin University, Cambridge, UK; Department of Public Health, Faculty of Medicine, Biruni University, Istanbul, Turkey.
¹¹ Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea; Department of Precision Medicine, Kyung Hee University College of Medicine, Seoul, South Korea; Department of Pediatrics, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, South Korea. Electronic address: yonkkang@gmail.com.
¹² Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA; Mass General Brigham Department of Anesthesiology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: CNEHS@mgh.harvard.edu.

PMID: 40680830
DOI: 10.1016/j.jare.2025.07.022

Free article

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

Jiseung Kang et al. J Adv Res. 2025.

Free article

. 2025 Jul 17:S2090-1232(25)00547-8.

doi: 10.1016/j.jare.2025.07.022. Online ahead of print.

Authors

Affiliations

¹ School of Health and Environmental Science, Korea University College of Health Science, Seoul, South Korea; Department of Health and Safety Convergence Science, Korea University Graduate School, Seoul, South Korea.
² Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea; Department of Precision Medicine, Kyung Hee University College of Medicine, Seoul, South Korea.
³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea.
⁵ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA; Mass General Brigham Department of Anesthesiology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea; Department of Electronics and Information Convergence Engineering, Kyung Hee University, Yongin, South Korea.
⁷ Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, South Korea.
⁸ CEReSS-Health Service Research and Quality of Life Center, Assistance Publique-Hopitaux de Marseille, Aix Marseille University, Marseille, France.
⁹ CEReSS-Health Service Research and Quality of Life Center, Assistance Publique-Hopitaux de Marseille, Aix Marseille University, Marseille, France; Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khoramabad, Iran; Department of Physical Education and Sport Sciences, Faculty of Literature and Humanities, Vali-E-Asr University of Rafsanjan, Rafsanjan, Iran.
¹⁰ Centre for Health, Performance, and Wellbeing, Anglia Ruskin University, Cambridge, UK; Department of Public Health, Faculty of Medicine, Biruni University, Istanbul, Turkey.
¹¹ Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, South Korea; Department of Precision Medicine, Kyung Hee University College of Medicine, Seoul, South Korea; Department of Pediatrics, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, South Korea. Electronic address: yonkkang@gmail.com.
¹² Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA; Mass General Brigham Department of Anesthesiology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: CNEHS@mgh.harvard.edu.

PMID: 40680830
DOI: 10.1016/j.jare.2025.07.022

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Study registration: PROSPERO CRD42024567136.

Keywords: Alzheimer’s disease; Biomarker; Umbrella review.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

LinkOut - more resources

Full Text Sources
- Elsevier Science
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Miscellaneous