Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease

Michelle M Mielke¹, Matthew Anderson², J Wesson Ashford^{3

4}, Andreas Jeromin⁵, Pei-Jung Lin⁶, Allyson Rosen^{7

8}, Jamie Tyrone⁹, Lawren Vandevrede¹⁰, Deanna R Willis¹¹, Oskar Hansson^{12

13}, Ara S Khachaturian¹⁴, Suzanne E Schindler¹⁵, Joan Weiss¹⁶, Richard Batrla¹⁷, Sasha Bozeat¹⁸, John R Dwyer¹⁹, Drew Holzapfel^{20

21}, Daryl Rhys Jones¹⁷, James F Murray²¹, Katherine A Partrick²⁰, Emily Scholler^{20

21}, George Vradenburg^{20

21}, Dylan Young²², Joel B Braunstein²³, Samantha C Burnham²⁴, Fabricio Ferreira de Oliveira²⁵, Yan Helen Hu¹⁷, Soeren Mattke²⁶, Zul Merali²⁷, Mark Monane²³, Marwan Noel Sabbagh²⁸, Eli Shobin²⁹, Michael Weiner³⁰, Chinedu T Udeh-Momoh^{1

27}

Affiliations

¹ Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, USA.
² Atrium Health, Charlotte, North Carolina, USA.
³ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA.
⁴ War Related Illness and Injury Study Center, VA Palo Alto Health Care System, Palo Alto, California, USA.
⁵ ALZpath, Carlsbad, California, USA.
⁶ Center for the Evaluation of Value and Risk in Health Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA.
⁷ Palo Alto Veterans Affairs Medical Center, Palo Alto, California, USA.
⁸ Stanford University School of Medicine, Stanford, California, USA.
⁹ Patient Advocate, Sacramento, California, USA.
¹⁰ Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.
¹¹ Department of Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹² Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
¹³ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
¹⁴ The Campaign to Prevent Alzheimer's Disease, Rockville, Maryland, USA.
¹⁵ Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ US Department of Health and Human Services, Health Resources and Services Administration, Bureau of Health Workforce, Rockville, Maryland, USA.
¹⁷ Eisai Inc, Nutley, New Jersey, USA.
¹⁸ F. Hoffman-La Roche AG, Basel, Switzerland.
¹⁹ Global Alzheimer's Platform Foundation, Washington, District of Columbia, USA.
²⁰ The Global CEO Initiative on Alzheimer's Disease, Philadelphia, Pennsylvania, USA.
²¹ Davos Alzheimer's Collaborative, Philadelphia, Pennsylvania, USA.
²² Guidehouse, McLean, Virginia, USA.
²³ C2N Diagnostics, St. Louis, Missouri, USA.
²⁴ Eli Lilly & Co., Indianapolis, Indiana, USA.
²⁵ Federal University of São Paulo, São Paulo, Brazil.
²⁶ The USC Brain Health Observatory, University of Southern California, Los Angeles, California, USA.
²⁷ Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
²⁸ Barrow Neurological Institute, Phoenix, Arizona, USA.
²⁹ Biogen, Cambridge, Massachusetts, USA.
³⁰ Departments of Radiology and Biomedical Imaging, Medicine, Psychiatry, and Neurology, University of California, San Francisco, California, USA.

PMID: 39351838
PMCID: PMC11567872
DOI: 10.1002/alz.14184

Review

Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease

Michelle M Mielke et al. Alzheimers Dement. 2024 Nov.

. 2024 Nov;20(11):8216-8224.

doi: 10.1002/alz.14184. Epub 2024 Oct 1.

Authors

Affiliations

¹ Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, USA.
² Atrium Health, Charlotte, North Carolina, USA.
³ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA.
⁴ War Related Illness and Injury Study Center, VA Palo Alto Health Care System, Palo Alto, California, USA.
⁵ ALZpath, Carlsbad, California, USA.
⁶ Center for the Evaluation of Value and Risk in Health Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA.
⁷ Palo Alto Veterans Affairs Medical Center, Palo Alto, California, USA.
⁸ Stanford University School of Medicine, Stanford, California, USA.
⁹ Patient Advocate, Sacramento, California, USA.
¹⁰ Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.
¹¹ Department of Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹² Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
¹³ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
¹⁴ The Campaign to Prevent Alzheimer's Disease, Rockville, Maryland, USA.
¹⁵ Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ US Department of Health and Human Services, Health Resources and Services Administration, Bureau of Health Workforce, Rockville, Maryland, USA.
¹⁷ Eisai Inc, Nutley, New Jersey, USA.
¹⁸ F. Hoffman-La Roche AG, Basel, Switzerland.
¹⁹ Global Alzheimer's Platform Foundation, Washington, District of Columbia, USA.
²⁰ The Global CEO Initiative on Alzheimer's Disease, Philadelphia, Pennsylvania, USA.
²¹ Davos Alzheimer's Collaborative, Philadelphia, Pennsylvania, USA.
²² Guidehouse, McLean, Virginia, USA.
²³ C2N Diagnostics, St. Louis, Missouri, USA.
²⁴ Eli Lilly & Co., Indianapolis, Indiana, USA.
²⁵ Federal University of São Paulo, São Paulo, Brazil.
²⁶ The USC Brain Health Observatory, University of Southern California, Los Angeles, California, USA.
²⁷ Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
²⁸ Barrow Neurological Institute, Phoenix, Arizona, USA.
²⁹ Biogen, Cambridge, Massachusetts, USA.
³⁰ Departments of Radiology and Biomedical Imaging, Medicine, Psychiatry, and Neurology, University of California, San Francisco, California, USA.

PMID: 39351838
PMCID: PMC11567872
DOI: 10.1002/alz.14184

Abstract

Blood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational pathways for BBMs: one for current use for triaging and another for future use to confirm amyloid pathology. These pathways provide a standardized diagnostic approach with guidance on interpreting BBM test results. Integrating BBMs into clinical practice will simplify the diagnostic process and facilitate timely access to DMTs for eligible patients.

Keywords: Alzheimer's disease; amyloid; biomarker; blood‐based biomarkers; clinical implementation; clinical practice; cognitive impairment; disease‐modifying treatment; patient journey; primary care; secondary care.

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Conflict of interest statement

M.M.M. has consulted, or served on advisory boards, for Biogen, Eisai, LabCorp, Eli Lilly, Merck, Roche, Siemens Healthineers, and Sunbird Bio and receives grant support from the National Institute of Health, Department of Defense, and Alzheimer's Association. A.J. is an employee to ALZpath, Inc, and equity holder. P‐J. L. has consulted for Eli Lilly and reports research support from Biogen, Eisai, Eli Lilly, Genentech, and Incyte (to the institution). L.V. is a principal investigator for clinical trials sponsored by Biogen. O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, O.H. has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. A.S.K. received payments through organizational affiliations for grants, contracts, and consulting fees, honoraria, meeting support, travel support, in‐kind research/professional support over the last 36 months from the Alzheimer's Association, Acadia Pharmaceuticals, Alzheon, Biogen, Clinical Trials Alzheimer's Disease Conference, Davos Alzheimer's Consortium, Digicare Realized, Eisai, Eli Lilly, Embic, Relz Plc, High Lantern Group, International Neurodegenerative Disorders Research Center, and Serdi Publishing. S.E.S. has analyzed plasma biomarker data provided by C2N Diagnostics to Washington University; no personal or research funding was provided by C2N Diagnostics to S.E.S. S.E.S. has served on scientific advisory boards for Eisai. S.E.S. has an unpaid position on the Board of the Greater Missouri Alzheimer's Association. J.F.M. is a stockholder of Eli Lilly and Company. S.B. is an employee and stock owner at Hoffman–La Roche. E.S. is an employee and shareholder of Biogen. J.B.B. and M.M. are employees and shareholders of C2N Diagnostics. F.F.O. receives research support from FAPESP—The State of São Paulo Research Foundation. S.M. serves on the board of directors of Senscio Systems, Inc. and the scientific advisory board of AiCure Technologies, ALZPath and Boston Millennia Partners., and has received consulting and/or speaker fees from Biogen, C2N, Eisai, Novartis, Novo Nordisk, and Roche/Genentech. M.W.W. has served on Advisory Boards for Acumen Pharmaceutical, Alzheon, Inc., Cerecin, Merck Sharp & Dohme Corp., and NC Registry for Brain Health. M.W.W. also serves on the USC ACTC grant which receives funding from Eisai. M.W.W. has provided consulting to Boxer Captial, LLC, Cerecin, Inc., Clario, Dementia Society of Japan, Dolby Family Ventures, Eisai, Guidepoint, Health and Wellness Partners, Indiana University, LCN Consulting, MEDA Corp., Merck Sharp & Dohme Corp., NC Registry for Brain Health, Prova Education, T3D Therapeutics, University of Southern California (USC), and WebMD. M.W.W. holds stock options with Alzeca, Alzheon, Inc., ALZPath, Inc., and Anven. M.W.W. received support for research from the following funding sources: National Institutes of Health (NIH)/NINDS/National Institute on Aging (NIA), Department of Defense (DOD), California Department of Public Health (CDPH), University of Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer's Association, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI‐BHR), The Stroke Foundation, and the Veterans Administration. D.R.J., R.B., and Y.H.H. are employees of Eisai Inc. S. C. B. is an employee and minor shareholder of Eli Lilly and Company and has a patent for a method for the detection of neurological disease. M.A., J.W.A., A.R., J.T., D.W., J.W., J.R.D., D.H., K.A.P., E.S., G.V., D.Y., M.N.S., Z.M., and C.U‐M. declare no competing interests. Author disclosures are available in the Supporting Information.

Figures

**FIGURE 1**
The integration of AD BBM tests as a triaging tool to support the determination of eligibility for DMT. The pathway follows a symptomatic patient with cognitive concerns, starting in a primary care setting (purple boxes) and through secondary care (blue boxes) to determine eligibility for a DMT. Determining APOE ε4 status should occur after a confirmatory CSF/PET test (gray outline). Patients can exit the DMT pathway at various steps when AD is not deemed the likely cause of cognitive impairment (red line). * Medical history includes history of present illness, past medical history, family history, social history, medications, allergies, and review of systems. ^† Steps 1 and 2 can occur during the same visit. ^‡ Step 3 can occur in primary or secondary care depending on how comfortable the primary care HCP is interpreting and disclosing BBM and/or neuroimaging results, the availability of structural brain neuroimaging, and associated wait times. Aβ, amyloid beta; AD, Alzheimer's disease; APOE, apolipoprotein E; BBM, blood‐based biomarker; CSF, cerebrospinal fluid; DMT, disease‐modifying therapy; HCP, healthcare professional; PET, positron emission tomography; Rx, medical prescription.

**FIGURE 2**
This figure is a simplified version of the pathway presented in Figure 1 illustrating where AD BBM tests (red text) can be integrated as triaging tools to support the determination of eligibility for DMT. Determining APOE ε4 status should occur after a confirmatory CSF/PET test (dotted line). Aβ, amyloid beta; AD, Alzheimer's disease; APOE, apolipoprotein E; BBM, blood‐based biomarker; CSF, cerebrospinal fluid; DMT, disease‐modifying therapy; HCP, healthcare professional; PET, positron emission tomography; Rx, medical prescription.

**FIGURE 3**
The integration of AD BBM tests as a confirmatory tool to detect the presence or absence of amyloid pathology to support the determination of eligibility for DMT. The pathway follows a symptomatic patient with cognitive concerns, starting in a primary care setting (purple boxes) through secondary care (blue boxes) to determine eligibility for a DMT. Determining APOE ε4 status should occur after a confirmatory BBM test (gray outline). Patient can exit the DMT pathway at various steps when AD is not deemed the likely cause of cognitive impairment (red line). * Medical history includes history of present illness, past medical history, family history, social history, medications, allergies, and review of systems. ^† Steps 1 and 2 can occur during the same visit. ^‡ Step 3 can occur in primary or secondary care depending on how comfortable primary care HCP is interpreting and disclosing BBM and/or neuroimaging results, the availability of structural brain neuroimaging, and associated wait times. Aβ, amyloid beta; AD, Alzheimer's disease; APOE, apolipoprotein E; BBM, blood‐based biomarker; CSF, cerebrospinal fluid; DMT, disease‐modifying therapy; HCP, healthcare professional; PET, positron emission tomography; Rx, medical prescription.

**FIGURE 4**
This figure is a simplified version of the pathway presented in Figure 3 illustrating where AD BBMs tests (red text) can be integrated as confirmatory tools to support the determination of eligibility for DMT. Determining APOE ε4 status should occur after a confirmatory BBM test (dotted line). Aβ, amyloid beta; AD, Alzheimer's disease; APOE, apolipoprotein E; BBM, blood‐based biomarker; CSF, cerebrospinal fluid; DMT, disease‐modifying therapy; HCP, healthcare professional; PET, positron emission tomography; Rx, medical prescription.

See this image and copyright information in PMC

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Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease

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Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease

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