Blood-based biomarkers for Alzheimer's disease: Current state and future use in a transformed global healthcare landscape

Harald Hampel¹, Yan Hu², Jeffrey Cummings³, Soeren Mattke⁴, Takeshi Iwatsubo⁵, Akinori Nakamura⁶, Bruno Vellas⁷, Sid O'Bryant⁸, Leslie M Shaw⁹, Min Cho¹⁰, Richard Batrla¹⁰, Andrea Vergallo¹⁰, Kaj Blennow¹¹, Jeffrey Dage¹², Suzanne E Schindler¹³

Affiliations

¹ Alzheimer's Disease and Brain Health, Eisai Inc., Nutley, NJ, USA. Electronic address: harald_hampel@eisai.com.
² Alzheimer's Disease and Brain Health, Eisai Inc., Nutley, NJ, USA. Electronic address: helen_hu@eisai.com.
³ Chambers-Grundy Center for Transformative Neuroscience, Pam Quirk Brain Health and Biomarker Laboratory, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, NV, USA.
⁴ Center for Improving Chronic Illness Care, University of Southern California, Los Angeles, CA, USA.
⁵ Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Department of Biomarker Research, National Center for Geriatrics and Gerontology, Obu, Japan; Department of Cognition and Behavior Science, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷ University Paul Sabatier, Gérontopôle, Toulouse University Hospital, UMR INSERM 1285, Toulouse, France.
⁸ Institute for Translational Research, Texas College of Osteopathic Medicine, Department of Family Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA.
⁹ Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Alzheimer's Disease and Brain Health, Eisai Inc., Nutley, NJ, USA.
¹¹ Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
¹² Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.

PMID: 37295421
PMCID: PMC10720399
DOI: 10.1016/j.neuron.2023.05.017

Review

Blood-based biomarkers for Alzheimer's disease: Current state and future use in a transformed global healthcare landscape

Harald Hampel et al. Neuron. 2023.

. 2023 Sep 20;111(18):2781-2799.

doi: 10.1016/j.neuron.2023.05.017. Epub 2023 Jun 8.

Authors

Affiliations

¹ Alzheimer's Disease and Brain Health, Eisai Inc., Nutley, NJ, USA. Electronic address: harald_hampel@eisai.com.
² Alzheimer's Disease and Brain Health, Eisai Inc., Nutley, NJ, USA. Electronic address: helen_hu@eisai.com.
³ Chambers-Grundy Center for Transformative Neuroscience, Pam Quirk Brain Health and Biomarker Laboratory, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, NV, USA.
⁴ Center for Improving Chronic Illness Care, University of Southern California, Los Angeles, CA, USA.
⁵ Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Department of Biomarker Research, National Center for Geriatrics and Gerontology, Obu, Japan; Department of Cognition and Behavior Science, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷ University Paul Sabatier, Gérontopôle, Toulouse University Hospital, UMR INSERM 1285, Toulouse, France.
⁸ Institute for Translational Research, Texas College of Osteopathic Medicine, Department of Family Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA.
⁹ Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Alzheimer's Disease and Brain Health, Eisai Inc., Nutley, NJ, USA.
¹¹ Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
¹² Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.

PMID: 37295421
PMCID: PMC10720399
DOI: 10.1016/j.neuron.2023.05.017

Abstract

Timely detection of the pathophysiological changes and cognitive impairment caused by Alzheimer's disease (AD) is increasingly pressing because of the advent of biomarker-guided targeted therapies that may be most effective when provided early in the disease. Currently, diagnosis and management of early AD are largely guided by clinical symptoms. FDA-approved neuroimaging and cerebrospinal fluid biomarkers can aid detection and diagnosis, but the clinical implementation of these testing modalities is limited because of availability, cost, and perceived invasiveness. Blood-based biomarkers (BBBMs) may enable earlier and faster diagnoses as well as aid in risk assessment, early detection, prognosis, and management. Herein, we review data on BBBMs that are closest to clinical implementation, particularly those based on measures of amyloid-β peptides and phosphorylated tau species. We discuss key parameters and considerations for the development and potential deployment of these BBBMs under different contexts of use and highlight challenges at the methodological, clinical, and regulatory levels.

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Conflict of interest statement

Declaration of interests H.H. is an employee of Eisai and serves as reviewing editor for the journal Alzheimer’s & Dementia. H.H. is the inventor of 11 patents and has received no royalties for: In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders patent no. 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases patent no. 8298784; Neurodegenerative Markers for Psychiatric Conditions publication no. 20120196300; In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders publication no. 20100062463; In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders publication no. 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases publication no. 20090263822; In Vitro Method for The Diagnosis of Neurodegenerative Diseases patent no. 7547553; CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases publication no. 20080206797; In Vitro Method for The Diagnosis of Neurodegenerative Diseases publication no. 20080199966; Neurodegenerative Markers for Psychiatric Conditions publication no. 20080131921; and Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid: US patent no. 10921330. J.C. has provided consultation to Acadia, Actinogen, Alkahest, Alpha Cognition, AriBio, Biogen, BioVie, Cassava, Cerecin, Corium, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, GAP Innovations, Grifols, Janssen, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, OptoCeutics, Ono, Otsuka, PRODEO, Prothena, reMYND, Resverlogix, Roche, Sage Therapeutics, Signant Health, Simcere, Sunbird Bio, Suven, TrueBinding, and Vaxxinity pharmaceutical, assessment, and investment companies. A.N. ha no personal conflicts to declare, but his employer NCGG shares some patents with Shimadzu and receives royalty. S.M. serves on the board of directors of Senscio Systems and the scientific advisory board of AiCure Technologies, ALZpath, and Boston Millennia Partners and has received consulting fees from Biogen, C(2)N, Eisai, Novartis, and Roche/Genentech. S.O. has multiple patents on precision medicine for neurodegenerative diseases and is the founding scientist of Cx Precision Medicine, Inc. L.M.S. has received compensation for teaching activities from Biogen. Y.H., M.C., and R.B. are employees of Eisai. A.V. declares no competing interests related to the present paper. A.V.’s contribution to this paper reflects entirely and exclusively his own academic expertise on the matter. A.V. was an employee of Eisai (November 2019–June 2021). A.V. has not received any fees or honoraria since November 2019. Before November 2019, A.V. received lecture honoraria from Roche, MagQu, and Servier. K.B. has served as a consultant and on advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, 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 Gothenburg University Ventures Incubator Program. S.E.S. has analyzed data provided by C(2)N Diagnostics to Washington University and served on an advisory board for Eisai.

Figures

**Figure 1.. An overarching illustration of integration of BBBMs into patient journey**
Depicted in the figure is the patient journey (also referred to as clinical care pathway) that starts with a visit to a primary care physician (light green line) and to a dementia specialist (brown line). At present, a validated BBBM can be used as an aid during the diagnostic workup, in conjunction with clinical assessment, as a pathology confirmation tool for the initiation of treatment with existing and approved therapeutics (red drop). As more evidence accrues, BBBMs may be used for screening healthy adults at risk for AD (as determined based on age, family history, comorbidities, etc.), as well as for the monitoring of treatment response and disease progression (purple drop). Aβ, amyloid beta; AD, Alzheimer’s disease; BBBM, blood-based biomarker; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PET, positron emission tomography; pTau, phosphorylated tau; tTau, total tau.

See this image and copyright information in PMC

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Blood-based biomarkers for Alzheimer's disease: Current state and future use in a transformed global healthcare landscape

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Blood-based biomarkers for Alzheimer's disease: Current state and future use in a transformed global healthcare landscape

Authors

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Conflict of interest statement

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