Advances in the Discovery of Biomarkers for Alzheimer’s Disease

This report describes current thinking regarding the temporal relationship of asymptomatic disease, MCI, and fully established Alzheimer's disease. Biomarkers that can identify individuals at risk will allow therapeutic intervention at the earliest stages. Next-generation "omics" technologies have identified potential multiplex markers as diagnostic aids and prognostic markers in blood and CSF.

Features and benefits

• Gain insight into the current thinking in AD research with regard to the temporal association of biomarkers with disease progression.
• Compare the opportunities provided by different biological fluids, including CSF, blood, saliva, and urine as sources of biomarkers in AD.
• Assess advances in the use of imaging technologies, including MRI and PET as diagnostic and prognostic tools.
• Evaluate the role played by cognitive testing, especially in computer-based formats and in combination with "omic" and imaging technologies.
• Understand the critical importance of developing tests amenable to mass employment, and the importance of biomarkers

Highlights

Aβ42 and tau protein are accepted biomarkers in CSF and can be used to confirm the diagnosis of AD and to differentiate from other dementias. They have also achieved regulatory acceptance for clinical trial enrichment. Aβ42 and/or tau in blood are not suitable as biomarkers.

Multiple individual proteins and genes associated with sporadic AD have been identified but these are not necessarily adequate as biomarkers. Both gene and protein multiplex assays based on next-generation technologies have provided potential multiplex panels that are in development as diagnostic and prognostic tools.

Progress with multiplex panels using blood-based tests on relevant omics platforms has been outstanding. Together with computer-based cognitive testing, these may provide a testing regime applicable to large populations, enabling therapeutic intervention at the earliest time in the AD progression and the best chance of therapeutic effect.

Your key questions answered

• Which biomarkers look most promising for diagnosis of the very earliest signs of disease and for following progression from healthy to MCI to AD?
• What contribution can imaging make to the diagnosis of AD and to predicting progression from MCI to AD?
• What is the relative potential of CSF, blood, saliva, and urine in providing a suitable biomarker for AD?
• What are the prospects for identifying at-risk subjects early enough to initiate disease prevention/modification therapy?
• Is the beta-amyloid hypothesis as important in biomarker research as it has been in efforts to develop therapies for AD?

Table Of Contents

About the author
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EXECUTIVE SUMMARY
Introduction
Biomarkers in Alzheimer’s disease
Aβ and tau as biomarkers
Genomics and non-genomic factors
Transcriptomics
Proteomics
Biomarkers in saliva and urine
Metabonomics
Imaging
Use of cognitive testing to detect preclinical Alzheimer’s disease

Introduction
Summary
Introduction
Phases of AD: model of preclinical, MCI, and dementia

Biomarkers in Alzheimer’s disease
Summary
Introduction
Biomarker definitions

Aβ and tau as biomarkers
Summary
Introduction
Amyloid
Background
Developments in understanding of the toxic species of Aβ
Tau
Aβ/tau as biomarkers in CSF and plasma
CSF amyloid and tau
Aβ and tau aids differentiation of AD from other dementias
Plasma Aβ as a biomarker in AD
Plasma tau as a biomarker in AD
Other CSF biomarkers
Aβ oligomers
ALZAS protein
BACE1
Clusterin
Isoprostanes
Proteomic 15/17 panel
Ubiquitin

Genomics and non-genomic factors
Summary
Introduction
Genetic factors in FAD
Genetic risk factors in sporadic AD
Apolipoprotein E
Other AD genes
Non-genetic risk factors
Transcriptomics
Summary
Introduction
Non-coding RNA
miRNA
Long ncRNA
Epigenetic control of RNA in AD
Summary

Proteomics
Summary
Introduction
Plasma proteomic screen in AD

Biomarkers in saliva and urine
Summary
Introduction
Saliva
Urine

Metabonomics
Summary
Introduction
Key developments

Imaging
Summary
Introduction
Volumetric MRI as a neurodegeneration marker
FDG-PET detects functional changes in AD
[11C]-PiB amyloid imaging

Use of cognitive testing to detect preclinical Alzheimer’s disease
Summary
Introduction
Cognitive testing in AD

Conclusion
Conclusion

Appendix
Methodology
Primary research
Secondary research
Scope
Abbreviations
References

List Of Tables

Table: Tau and Aβ in the differentiation of AD from other dementias
Table: Potential CSF protein biomarkers (part 1)
Table: Potential CSF protein biomarkers (part 2)
Table: Potential CSF protein biomarkers (part 3)
Table: Genetic associations in FAD
Table: Genetic associations in sporadic AD (part 1)
Table: Genetic associations in sporadic AD (part 2)
Table: NextGen Sciences human CSF AD 37-plex screen (part 1)
Table: NextGen Sciences human CSF AD 37-plex screen (part 2)
Table: NextGen Sciences 15-plex plasma screen
Table: Summary of AD biomarker technologies by company

List Of Figures

Figure: Hypothetical model of the phases of AD
Figure: Detailed description of the preclinical phase of AD
Figure: Aβ production from APP
Figure: Stages of neurotoxicity
Figure: Regulation of BACE1 by miRNA
Figure: Regulation of homocysteine metabolism
Figure: Chemical structures of Thioflavin-T, PiB, and GE-067