The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease

Martí Colom-Cadena¹, Tara Spires-Jones¹, Henrik Zetterberg^{2

3

4

5}, Kaj Blennow^{2

3}, Anthony Caggiano⁶, Steven T DeKosky⁷, Howard Fillit⁸, John E Harrison^{9

10

11}, Lon S Schneider¹², Phillip Scheltens¹³, Willem de Haan^{13

14}, Michael Grundman¹⁵, Christopher H van Dyck¹⁶, Nicholas J Izzo⁶, Susan M Catalano¹⁷; Synaptic Health Endpoints Working Group

Affiliations

¹ Centre for Discovery Brain Sciences, UK Dementia Research Institute at The University of Edinburgh, Edinburgh, UK.
² Department of Psychiatry and Neurochemistry, University of Gothenburg, Mölndal, Sweden.
³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁴ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁵ UK Dementia Research Institute at UCL, London, UK.
⁶ Cognition Therapeutics. Inc., Pittsburgh, PA, USA.
⁷ McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
⁸ Alzheimer's Drug Discovery Foundation, New York, NY, USA.
⁹ Metis Cognition Ltd, Kilmington, UK.
¹⁰ Alzheimer Center, AUmc, Amsterdam, The Netherlands.
¹¹ Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹² Keck School of Medicine of USC, Los Angeles, CA, USA.
¹³ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
¹⁴ Department of Clinical Neurophysiology and MEG, VU University Medical Center, Amsterdam, Netherlands.
¹⁵ Global R&D Partners, San Diego, CA, USA.
¹⁶ Alzheimer's Disease Research Unit and Departments of Psychiatry, Neurology, and Neuroscience, Yale School of Medicine, New Haven, CT, USA.
¹⁷ Cognition Therapeutics. Inc., Pittsburgh, PA, USA. scatalano@cogrx.com.

PMID: 32122400
PMCID: PMC7053087
DOI: 10.1186/s13195-020-00588-4

Review

The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease

Martí Colom-Cadena et al. Alzheimers Res Ther. 2020.

. 2020 Mar 2;12(1):21.

doi: 10.1186/s13195-020-00588-4.

Authors

Affiliations

¹ Centre for Discovery Brain Sciences, UK Dementia Research Institute at The University of Edinburgh, Edinburgh, UK.
² Department of Psychiatry and Neurochemistry, University of Gothenburg, Mölndal, Sweden.
³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁴ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁵ UK Dementia Research Institute at UCL, London, UK.
⁶ Cognition Therapeutics. Inc., Pittsburgh, PA, USA.
⁷ McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
⁸ Alzheimer's Drug Discovery Foundation, New York, NY, USA.
⁹ Metis Cognition Ltd, Kilmington, UK.
¹⁰ Alzheimer Center, AUmc, Amsterdam, The Netherlands.
¹¹ Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹² Keck School of Medicine of USC, Los Angeles, CA, USA.
¹³ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
¹⁴ Department of Clinical Neurophysiology and MEG, VU University Medical Center, Amsterdam, Netherlands.
¹⁵ Global R&D Partners, San Diego, CA, USA.
¹⁶ Alzheimer's Disease Research Unit and Departments of Psychiatry, Neurology, and Neuroscience, Yale School of Medicine, New Haven, CT, USA.
¹⁷ Cognition Therapeutics. Inc., Pittsburgh, PA, USA. scatalano@cogrx.com.

PMID: 32122400
PMCID: PMC7053087
DOI: 10.1186/s13195-020-00588-4

Abstract

Background: Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD.Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance.Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD.Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs.The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD.

Conclusion: A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes.

Keywords: Alzheimer’s disease; Biomarker; Cerebrospinal fluid; Electroencephalography; Positron emission tomography; Synapse.

PubMed Disclaimer

Conflict of interest statement

Anthony Caggiano, Nicholas Izzo, and Susan Catalano are employees or have financial interest in Cognition Therapeutics, Inc. Henrik Zetterberg has served at scientific advisory boards for Cognition Therapeutics, Roche Diagnostics, Wave and Samumed; has given lectures in symposia sponsored by Biogen and Alzecure; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. Tara Spires-Jones is a scientific advisory board member of Cognition Therapeutics and receives collaborative grant funding from two pharmaceutical companies. John Harrison has received consultancy payments and honoraria from the following organizations in the past 2 years: 23andMe, Alzecure, Aptinyx, Athira Pharma, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, CRF Bracket, Cognition Therapeutics, Compass Therapeutics, Curasen, DeNDRoN, EIP Pharma, Eisai, Eli Lilly, GfHEu, Heptares, Johnson & Johnson, Lundbeck, Lysosome Therapeutics, Merck, Neurodyn, Neurotrack, Novartis, Nutricia, Probiodrug, Regeneron, Rodin Therapeutics, Roivant, Sanofi, Takeda, vTv Therapeutics, and Winterlight Labs. Kaj Blennow has served as a consultant or at advisory boards for Alector, Biogen, Cognition Therapeutics, Lilly, MagQu, Novartis, and Roche Diagnostics and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. Christopher van Dyck has served as a consultant or scientific advisor in the past 2 years for Roche, Eisai, and Kyowa Kirin and received grant support for clinical trials from Roche, Genentech, Eisai, Biogen, Eli Lilly, Novartis, Merck, Biohaven, and Janssen. Lon Schneider reports grants and personal fees from Eli Lilly, personal fees from Avraham, Ltd., personal fees from Boehringer Ingelheim, grants and personal fees from Merck, personal fees from Neurim, Ltd., personal fees from Neuronix, Ltd., personal fees from Cognition Therapeutics, personal fees from Eisai, personal fees from Takeda, personal fees from vTv, grants and personal fees from Roche/Genentech, grants from Biogen, grants from Novartis, personal fees from Abbott, and grants from Biohaven, outside the submitted work. Philip Scheltens reports consultancies with Axon Neuroscience, Cognition Therapeutics, Vivoryon, and Novartis, as well as a DSMB membership with Genentech. Michael Grundman is a paid consultant to Cognition Therapeutics. Howard Fillit has been a consultant to Axovant, vTv, Lundbeck, Otsuka, Lilly, Biogen (RTI), Roche, Genentech, Merck, Samus, Pfizer, and Alector in the past 5 years and has no conflicts that are related to this manuscript. Steven T. DeKosky is a member of the Neuroscience Advisory Board for Amgen, Chair of the Medical Scientific Advisory Board for Acumen, Chair of the Drug Monitoring Committee for Biogen, Chair of the Medical Advisory Board for Cognition Therapeutics, and Editor for Dementia for UpToDate. Martí Colom Cadena and Willem de haan declare that they have no competing interests.

Figures

**Fig. 1**
High-resolution array tomography imaging reveals plaque-associated synapse loss in human temporal cortex. Scale bar 10 μm

**Fig. 2**
Amyloid and tau biomarkers can be used to confirm AD pathology, and biomarkers of synaptic damage and loss will be useful for predicting cognitive decline

See this image and copyright information in PMC

References

1. Nichols E, Szoeke CEI, Vollset SE, Abbasi N, Abd-Allah F, Abdela J, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):88–106. doi: 10.1016/S1474-4422(18)30403-4. - DOI - PMC - PubMed
1. Association A. 2018 Alzheimer’s disease facts and figures. Alzheimer’s Dement. Elsevier; 2018; 14(3):367–429 [cited 2018 Jun 18]. Available from: https://www.sciencedirect.com/science/article/pii/S1552526018300414.
1. Persson CM, Wallin AK, Levander S, Minthon L. Changes in cognitive domains during three years in patients with Alzheimer’s disease treated with donepezil. BMC Neurol. 2009;9:7. doi: 10.1186/1471-2377-9-7. - DOI - PMC - PubMed
1. Ito K, Ahadieh S, Corrigan B, French J, Fullerton T, Tensfeldt T, et al. Disease progression meta-analysis model in Alzheimer’s disease. Alzheimers Dement. 2010;6(1):39–53. doi: 10.1016/j.jalz.2009.05.665. - DOI - PubMed
1. Kandimalla R, Reddy PH. Therapeutics of neurotransmitters in Alzheimer’s disease. J Alzheimers Dis. 2017;57(4):1049–1069. doi: 10.3233/JAD-161118. - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease

Affiliations

The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical