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Monitoring synaptic pathology in Alzheimer’s disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives

Molecular Psychiatry (2024)Cite this article

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Abstract

Alzheimer’s disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aβ), a peptide comprised of 40–42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aβ instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aβ associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and β-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.

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Fig. 1: Comprehensive overview of pathological pathways and biomarkers indicative of synaptic damage in AD brain.
Fig. 2: Schematic representation of possible time course of synaptic biomarkers in relation to key AD biomarkers.

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Acknowledgements

Research by SL-O is funded by the Spanish Ministry of Science and Innovation (grant number FPU19/02117). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003).

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Author notes

  1. These authors contributed equally: Simone Lista, Robert Nisticò.

Authors and Affiliations

  1. i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012, Valladolid, Spain

    Simone Lista, Alejandro Santos-Lozano, Susana López-Ortiz & Juan Martín-Hernández

  2. Physical Activity and Health Research Group (PaHerg), Research Institute of the Hospital 12 de Octubre (‘imas12’), 28041, Madrid, Spain

    Alejandro Santos-Lozano

  3. 2E Science, 27038, Robbio, Italy

    Enzo Emanuele

  4. Experimental Neurology Laboratory, IRCCS Santa Lucia Foundation, 00143, Rome, Italy

    Nicola B. Mercuri

  5. Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy

    Nicola B. Mercuri

  6. CMRR, Memory Resources and Research Center, Montpellier University of Excellence i-site, 34295, Montpellier, France

    Audrey Gabelle

  7. Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, 00143, Rome, Italy

    Nunzia Maisto & Robert Nisticò

  8. Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, 00185, Rome, Italy

    Nunzia Maisto

  9. Department of Brain and Behavioral Sciences, University of Pavia, 27100, Pavia, Italy

    Camillo Imbimbo

  10. Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy

    Filippo Caraci

  11. Neuropharmacology and Translational Neurosciences Research Unit, Oasi Research Institute-IRCCS, 94018, Troina, Italy

    Filippo Caraci

  12. Department of Research and Development, Chiesi Farmaceutici, 43122, Parma, Italy

    Bruno P. Imbimbo

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

    Henrik Zetterberg

  14. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden

    Henrik Zetterberg

  15. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, WC1N, London, UK

    Henrik Zetterberg

  16. UK Dementia Research Institute at UCL, WC1E 6BT, London, UK

    Henrik Zetterberg

  17. Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China

    Henrik Zetterberg

  18. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53726, WI, USA

    Henrik Zetterberg

  19. School of Pharmacy, University of Rome “Tor Vergata”, 00133, Rome, Italy

    Robert Nisticò

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  1. Simone Lista
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Contributions

SL conceptualized the article, performed a critical review of the literature, wrote and revised the manuscript. AS-L and EE contributed to the writing and revision of the article and supervised artwork. NBM, AG, SL-O, JM-H, NM, CI, and FC supported the critical review of the literature, the writing, and/or the revision of the article. BPI and HZ contributed to the writing and revision of the article and supervised artwork. RN conceptualized the article, performed a critical review of the literature, wrote and revised the manuscript. All Authors read and approved the final manuscript.

Corresponding authors

Correspondence to Simone Lista or Robert Nisticò.

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Competing interests

EE is the unique owner of 2E Science, a for-profit private scientific company. Neither EE nor 2E Science have any commercial interest or financial tie in relation with this article. BPI is an employee at Chiesi Farmaceutici. He is listed among the inventors of a number of Chiesi Farmaceutici’s patents of anti-Alzheimer drugs. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). SL, AS-L, NBM, AG, SL-O, JM-H, NM, CI, FC, and RN declare that they have no conflicts of interest.

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Lista, S., Santos-Lozano, A., Emanuele, E. et al. Monitoring synaptic pathology in Alzheimer’s disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-023-02376-6

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