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  • Review Article
  • Published:

Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives

Nature Reviews Drug Discovery volume 9, pages 560–574 (2010)Cite this article

Subjects

Key Points

  • Recent research progress into the molecular pathogenesis of Alzheimer's disease has been translated into several promising drug candidates that have the potential to produce disease-modifying effects.

  • Biomarkers that reflect the central pathogenic processes in Alzheimer's disease have been developed and validated in numerous studies. These include cerebrospinal fluid (CSF) assays for tau and amyloid-β isoforms; magnetic resonance imaging (MRI) measurements of brain atrophy; and positron emission tomography (PET) techniques for brain metabolism and amyloid-β deposition.

  • Academic institutions, the pharmaceutical industry and regulatory organizations all agree that biomarkers have an important role in the drug development process.

  • Biomarkers have several potential uses in clinical trials. These include their use as diagnostic aids to enrich the patient sample with cases of Alzheimer's disease; as tools to identify and monitor the biochemical effect of the drug candidate; and as safety markers to detect potential side effects of the drug.

  • Evidence obtained from biomarker studies showing that a drug candidate affects the central disease processes in Alzheimer's disease will, together with a beneficial effect on cognition, be essential for the drug to be labelled as disease-modifying.

  • A catch-22-like situation exists in validating Alzheimer's disease biomarkers for use in drug development. Biomarker validation depends on effective drugs that target Alzheimer's disease pathogenesis, which are not currently available. At the same time, evidence from biomarker studies is needed for a new drug to be labelled as disease-modifying.

  • There are numerous ongoing clinical trials investigating disease-modifying drug candidates, which include biomarkers as end points. These trials will provide information on whether biomarkers will be valuable tools as surrogate end points to predict the clinical outcome and as the basis for a disease-modifying claim of the drug.

  • If disease-modifying drugs are approved for the treatment of Alzheimer's disease, biomarkers will facilitate the diagnosis of Alzheimer's disease very early on in the course of the disease before neurodegeneration is too severe and widespread.

Abstract

Advances in therapeutic strategies for Alzheimer's disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease. To effectively test compounds for Alzheimer's disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates. Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments. Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies.

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Figure 1: Detection of disease-modifying treatment effects.
Figure 2: Detection of effects of cholinergic treatment on cortical activation in patients with Alzheimer's disease using functional magnetic resonance imaging.
Figure 3: The four categories of biomarker: target, mechanism, pathophysiological and diagnostic.
Figure 4: Translation of biomarkers.

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Acknowledgements

The authors would like to thank K. Duggan for technical assistance. H.H. acknowledges support by the Science Foundation Ireland Investigator Neuroimaging Grant Programme (08/IN.1/B1846).

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Authors and Affiliations

  1. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Johann Wolfgang Goethe-University, Heinrich-Hoffmann-Str. 10, 60528, Frankfurt/Main, Germany

    Harald Hampel

  2. Global Medical Affairs and Clinical Strategy, GE Healthcare, 101 Carnegie Center, Princeton, 08540, New Jersey, USA

    Richard Frank

  3. Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, D-53175, Bonn, Germany

    Karl Broich

  4. Department of Psychiatry, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany

    Stefan J. Teipel

  5. DZNE, German Center for Neurodegenerative Disorders, Gehlsheimer Str. 20, 18147, Rostock, Germany

    Stefan J. Teipel & Frank Jessen

  6. Division of Neurology Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, 20993, Maryland, USA

    Russell G. Katz

  7. Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College, Queen Square House, Queen Square, WC1 3BG, London, UK

    John Hardy

  8. Wolfson Molecular Imaging Centre, University of Manchester, 27 Palatine Road, M20 3LJ, Manchester, UK

    Karl Herholz

  9. School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Trinity Centre for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital, Tallaght, 24, Dublin, Ireland

    Arun L. W. Bokde

  10. Department of Psychiatry, Rheinische Friedrich-Wilhelm University Bonn, Sigmund-Freud-Strasse 25, 53105, Bonn, Germany

    Frank Jessen

  11. Department of Psychiatry, Alzheimer Memorial Center, Ludwig-Maximilian University, Nussbaumstr. 7, 80336, Munich, Germany

    Yvonne C. Hoessler

  12. Senior Scientific Advisor, Office of the Commissioner, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, 20993, Maryland, USA

    Wendy R. Sanhai

  13. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, S-431 80, Mölndal, Sweden

    Henrik Zetterberg & Kaj Blennow

  14. Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, 20993, Maryland, USA

    Janet Woodcock

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Correspondence to Harald Hampel.

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Competing interests

Harald Hampel has participated on the Advisory Board of BRAHMS, Henningsdorf, Germany, and has received research support for his institutions from the same company.

Richard Frank is an employee of GE Healthcare.

John Hardy is a consultant for Eisai and MerckSerono.

Kaj Blennow has participated on the Advisory Board for Innogenetics NV, Ghent, Belgium, and has received research support to his institution from the same company.

Karl Broich, Stefan J. Teipel, Russel G. Katz, Karl Herholz, Arun L.W. Bokde, Frank Jessen, Yvonne C. Hoessler, Wendy R. Sanhai, Henrik Zetterberg and Janet Woodcock declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Imaging biomarkers for Alzheimer's disease (PDF 565 kb)

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

FURTHER INFORMATION

ADNI

ADNI clinical trial

Alzheimer's Association Research Roundtable

Guidance for Industry Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act

Improved Predictivity of Efficacy Evaluation — Brain Disorders

Improved Predictivity of Efficacy Evaluation — Brain Disorders

The Biomarkers Consortium

The Critical Path Initiative

Glossary

Amyloid-β

(Aβ). An aggregation-prone peptide derived from the amyloid precursor protein. The 42 amino acid isoform of the peptide is the main component of plaques in Alzeimer's disease.

Tau protein

A microtubule-associated protein located in the neuronal axons. Hyperphosphorylated tau is the main component of neurofibrillary tangles in Alzheimer's disease.

DSM-IV

(Diagnostic and Statistical Manual of Mental Disorders, Fourth edition). This manual outlines diagnostic criteria for psychiatric disorders and is published by the American Psychiatric Association.

ICD-10

(International Statistical Classification of Diseases, Tenth edition). This book outlines diagnostic criteria for human diseases and is published by the World Health Organization.

NINCDS-ADRDA

(The National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association). This outlines criteria for diagnosing Alzheimer's disease.

Primary end point

A primary end point is defined as the single main question to be answered in a given clinical trial.

Biomarker

An objective measure of a biological or pathogenic process that can be used to evaluate disease risk or prognosis. It can be used to guide clinical diagnosis or to monitor therapeutic interventions.

Surrogate end point

A substitute for a clinical end point in a clinical trial.

Secondary end point

An end point in a trial that provides additional characterization of treatment effect, but is not sufficient by itself to fully characterize the benefit or to support a claim for a treatment effect.

Longitudinal study

A research study with repeated observations of the same patients over long periods of time.

Phantom test

A plastic cylinder with standardized measures and density used for calibration of magnetic resonance imaging devices.

Transformation map

A spatially extended vector field that describes the spatial warps that are needed to align a three-dimensional image of the brain into a common standard space.

Classical plaque

A dense aggregation of amyloid-β protein with classical amyloid characteristics, which is surrounded by swollen neuritis and reactive glial cells.

Diffuse plaque

An aggregation of amyloid-β protein that can only be detected using immunohistochemistry.

AN1792 vaccination trial

The first clinical trial on active amyloid-β immunotherapy in Alzheimer's disease.

Huntington's protocol

Individuals who have family members with Huntington's disease are offered genetic counselling, which includes the possibility of presymptomatic DNA testing. However, this is only offered after a series of careful counselling sessions to ensure that the individual understands the issues involved in knowing their genetic status.

TOMM40

A gene encoding a mitochondrial protein that is located on chromosome 19 adjacent to the apolipoprotein E gene.

Risk chart

A graph illustrating the risk of developing Alzheimer's disease by age. This risk is modified by genetic status, especially by apolipoprotein E genotype status. Other genes will have a smaller effect on this chart (except in families with amyloid precursor protein and presenilin mutations).

Phase 0 trial

An exploratory first-in-human trial with single subtherapeutic drug doses and small numbers of subjects to provide first data on drug pharmacokinetics and pharmacodynamics.

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Hampel, H., Frank, R., Broich, K. et al. Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nat Rev Drug Discov 9, 560–574 (2010). https://doi.org/10.1038/nrd3115

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