Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr;21(4):e14587.
doi: 10.1002/alz.14587.

The CentiMarker project: Standardizing quantitative Alzheimer's disease fluid biomarkers for biologic interpretation

Guoqiao Wang  1   2 , Yan Li  1 , Chengjie Xiong  2 , Yuchen Cao  1 , Suzanne E Schindler  1 , Eric McDade  1 , Kaj Blennow  3   4   5 , Oskar Hansson  6   7 , Jeffrey L Dage  8 , Clifford R Jack Jr  9 , Charlotte E Teunissen  10 , Leslie M Shaw  11 , Henrik Zetterberg  3   4   12   13   14 , Laura Ibanez  1 , Jigyasha Timsina  15   16 , Cruchaga Carlos  1   15   16 ; Alzheimer's Disease Neuroimaging Initiative; Randall J Bateman  1
Affiliations

The CentiMarker project: Standardizing quantitative Alzheimer's disease fluid biomarkers for biologic interpretation

Guoqiao Wang et al. Alzheimers Dement. 2025 Apr.

Abstract

Introduction: Biomarkers play a crucial role in understanding Alzheimer's disease (AD) pathogenesis and treatment effects. However, comparing biomarker measures without standardization and appreciating their magnitude relative to the disease can be challenging.

Methods: To address this issue, we propose the CentiMarker approach, similar to Centiloid, which provides a standardized scale between normal (0) and nearly maximum abnormal AD (100) ranges. We applied this scale to cerebrospinal fluid (CSF) biomarkers in dominantly inherited AD and sporadic AD cohorts.

Results: CentiMarkers facilitated the interpretation of disease abnormality, demonstrating comparable changes and distributions of AD biomarkers across disease stages. CentiMarkers make the treatment effect more comparable than their original scales across various biomarkers.

Discussion: The versatility of CentiMarkers makes it a valuable tool for standardized biomarker comparison in AD research, enabling informed cross-study comparisons and contributing to accelerated therapeutic development. Adoption of the CentiMarker scale could enhance biomarker reporting and advance our understanding of AD.

Highlights: Comparing fluid biomarkers without appreciating their magnitude relative to the disease can be challenging. We propose a CentiMarker metric to standardize biomarker measures from normal (0) and nearly maximum abnormal AD (100) ranges. CentiMarkers make the treatment effect more comparable across various biomarkers than when using the original scales.

Keywords: Alzheimer's disease; CentiMarker; biomarker standardization; fluid biomarker.

PubMed Disclaimer

Conflict of interest statement

G.W.is the biostatistics core co‐leader for the Dominantly Inherited Alzheimer Network‐Trial Unit (DIAN‐TU). He discloses serving on the Data Safety Monitoring Board (DSMB) for Eli Lilly and Company, Amydis Corporate, and Abata Therapeutics, as well as working as a statistical consultant for Alector, Inc. and Pharmapace, Inc. He also serves as DSMB member for another five studies funded by the National Institutes of Health (NIH). R.J.B.is the Director of the DIAN‐TU and Principal Investigator of the DIAN‐TU‐001. He co‐founded C2N Diagnostics. Washington University and R.J.B. have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics, blood plasma assay, and methods of diagnosing Alzheimer's disease [AD] with phosphorylation changes) that is licensed by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. R.J.B. has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb, and Novartis. He receives research support from the National Institute on Aging (NIA) of the NIH, DIAN‐TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman‐La Roche, Ltd., and Avid Radiopharmaceuticals), Alzheimer's Association, GHR Foundation, Anonymous Organization, DIAN‐TU Pharma Consortium (Active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann‐La Roche, Ltd./Genentech. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience). He has been an invited speaker for Novartis and serves on the Advisory Board for F. Hoffman La Roche, Ltd. E.M.is the Associate Director of the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and Alector; scientific consultant for Eisai and Eli Lilly and Company; institutional grant support from Eli Lilly and Company, F. Hoffmann‐La Roche, Ltd., and Janssen. J.L.D. is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents and/or compositions of matter for p‐tau assays and Aβ‐targeting therapeutics. J.L.D. has served as a consultant on advisory boards for Eisai, Abbvie, Genotix Biotechnologies Inc, Gates Ventures, Karuna Therapeutics, AlzPath Inc., Cognito Therapeutics, Inc., and Prevail Therapeutics, and received research support from ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics, and Eli Lilly and Company in the past 2 years. J.L.D. has received speaker fees from Eli Lilly and Company. J.L.D. is a founder and advisor for Monument Biosciences. J.L.D. has stock or stock options in Eli Lilly and Company, Genotix Biotechnologies, AlzPath Inc., and Monument Biosciences. S.E.S. has served as a consultant or an advisory board or received speaker's fees from Eisai, Eli Lilly, and Novo Nordisk. K.B. has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this article. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside the submitted work). C.C. has received research support from GSK and Eisai. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. C.C. is a member of the advisory board of Circular Genomics and owns stocks in this company. All the other authors reported no conflicts of interest. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Illustration of CentiMarkers approach. The rectangles indicate the CentiMarker 0 and CentiMarker 100 for each biomarker. Aβ42/40, CSF Aβ42‐to‐40 ratio; pT217/217, CSF pT217‐to‐T217 ratio; NfL, CSF Neurofilament Light Chain; MTBR‐243, Microtubule Binding Region‐243.
FIGURE 2
FIGURE 2
Comparison of different CentiMarkers in the same study by stage of disease between normal controls (green circles) and MCs (color triangles) as presented by the Loess curves and scatter data points. The MCs included only the baseline data from the treatment groups and all the data from the placebo group in the DIAN‐TU‐001 trial. The x‐axis represents the EYO based on mutation information, with zero indicating the expected onset of symptoms, covering a range of 25 years to represent disease progression. EYO, estimated years to symptom onset; MCs, mutation carriers.
FIGURE 3
FIGURE 3
Comparison of different CentiMarkers as presented by the Loess curves and scatter data points within a cohort by stage of disease comparing normal controls (green circles) to MCs (color triangles) using the DIAN observational cohort. The x‐axis represents the EYO based on mutation information, with zero indicating the expected onset of symptoms, covering a range of 25 years to represent disease progression. EYO, estimated years to symptom onset; MCs, mutation carriers.
FIGURE 4
FIGURE 4
Comparison of CentiMarkers across clinical cohorts utilizing disease progression trajectories between DIAN‐TU‐001 (non‐treated, blue solid line) and DIAN‐OBS (observational cohort in red dashed line) as presented by the Loess curves with 95% CI. These curve fits show similar biomarker changes by EYO across studies demonstrating comparability of CentiMarkers across studies. EYO, estimated years to symptom onset.
FIGURE 5
FIGURE 5
Utilizing CentiMarkers facilitates the interpretation and comparison across biomarkers by converting them to a similar scale, whereas using raw values is more difficult to compare as units are different and not scaled to disease ranges. Estimated mean change from baseline in CentiMarkers with 95% confidence intervals for the gantenerumab and placebo groups using MMRM analyses in the DIAN‐TU‐001 trial. These results demonstrate the magnitude of disease normalization compared to normal (CM 0) versus fully abnormal (CM 100) states. Raw values are in the unit of ng/mL.
FIGURE 6
FIGURE 6
Illustration of treatment effects over EYO relative to mutation non‐carriers (green line). Participants treated with gantenerumab (blue line) showed slower progression than those non‐gantenerumab treated (purple line) across multiple biomarkers as presented by the Loess curves with 95% CI. The relative differences of treatment effect indicate that although there were improvements in multiple biomarkers, the measures did not reach normal CentiMarker levels for some measures. EYO, estimated years to symptom onset.
FIGURE 7
FIGURE 7
Illustration of CentiMarkers in ADNI as presented by the Loess curves and scatter data points. EYO is calculated by using the individual's own age at symptom onset as EYO of 0. ADNI, Alzheimer's Disease Neuroimaging Initiative; CSF, cerebrospinal fluid. EYO, estimated years to symptom onset.
See this image and copyright information in PMC

Update of

References

    1. Salloway S, Farlow M, McDade E, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Nat Med. 2021;27(7):1187‐1196. - PMC - PubMed
    1. Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9‐21. - PubMed
    1. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER‐ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512‐527. - PMC - PubMed
    1. Wang G, Li Y, Xiong C, et al. Evaluation of dose‐dependent treatment effects after mid‐trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Alzheimers Dement. 2022;14(1):e12367. - PMC - PubMed
    1. Kuhlmann J, Andreasson U, Pannee J, et al. CSF Aβ1–42–an excellent but complicated Alzheimer's biomarker–a route to standardisation. Clin Chim Acta. 2017;467:27‐33. - PubMed

Grants and funding