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Novel synaptic markers predict early tau pathology and cognitive deficit in an asymptomatic population at risk of Alzheimer’s disease

Molecular Psychiatry volume 30, pages 2810–2820 (2025)Cite this article

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Abstract

Cognitive dysfunction in Alzheimer’s disease (AD) correlates closely with pathology in the neuronal microtubule-associated protein tau. Tau pathology may spread via neural synapses. In a population of cognitively unimpaired elderly at elevated risk of AD, we investigated four cerebrospinal (CSF) markers of synaptic dysfunction and degeneration. Three of these (SYT1, SNAP25, and ADAM23) are derived from pre-synaptic structures, while ADAM22 reflects post-synaptic changes. All four markers correlated strongly with tau protein measures. In statistical models, SYT1 accounted for more than half the total variance in both total- and P(181)-tau levels. Observed correlations with CSF levels of Alzheimer amyloid-β (Aβ42) were somewhat weaker. In longitudinal data, baseline levels of ADAM22 and ADAM23 robustly predicted increase over time in both total- and P-tau. CSF SYT1 levels also correlated with PET image uptake of tau and (at a trend level) Aβ in areas of interest for early AD pathology. CSF SYT1 and SNAP25 levels correlated inversely with a global psychometric score and several of its domain subscales. In quantitative trait loci analyses, all four synaptic markers were associated with at least one AD genetic risk locus. Upon “staging” participants by their evidence of amyloid and tau pathology (A/T/N framework), the CSF synaptic markers were unexpectedly reduced in participants with CSF evidence of amyloid but not tau pathology. They were clearly elevated, however, in the CSF of persons with indications of both tau and amyloid pathology. These observations provide evidence for clear pre-synaptic degeneration in cognitively unimpaired persons with biomarker evidence of early AD pathology.

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Fig. 1: Association between CSF ADAM22, ADAM23, SYT1, SNAP25, and AD biomarkers in the PREVENT-AD cohort.
Fig. 2: Association between baseline CSF ADAM22, ADAM23, SYT1, SNAP25, GAP43 and baseline PET tau and PET A_42 in the PREVENT-AD cohort.
Fig. 3: Cognitive performance as a function of levels of CSF ADAM22, ADAM23, and SYT1 in the PREVENT-AD cohort.
Fig. 4: Pathological staging of CSF synaptic markers at baseline.
Fig. 5: Baseline cognition as a function of the polygenic risk scores of CSF ADAM22.

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Data availability

Figures data has been archived at https://doi.org/10.5281/zenodo.14003860. The multimodal data, including subject characteristics, CSF biomarkers levels, tau and amyloid-PET SUVR, APOE genotypes, and RBANS scores, have been summarized in the supporting data files from the PREVENT-AD data release 7. Other datasets are available from the corresponding authors upon reasonable request.

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Acknowledgements

The authors would like to thank Mrs. Jennifer Tremblay-Mercier, Doris Dea, and Louise Théroux for their individual contributions at different stages of the project. The authors would also like to thank Drs. Lisa Munter and Patricia Silveira for their technical expertise. The funding agency played no role in the conduct of the study. JP is supported by the Fonds de recherche en santé du Québec (FRSQ), the CIHR (# PJT 153287, 178210), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the J.L. Levesque Foundation. SV is supported by the FRQS, the CIHR (PJT: 178385, 438655), and Brain Canada whereas JCB is supported by CIHR. HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #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, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the Bluefield Project, Cure Alzheimer’s Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, 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). KB is supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270, and #AF-994551), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), the Alzheimer’s Association 2022-2025 Grant (SG-23-1038904 QC), La Fondation Recherche Alzheimer (FRA), Paris, France, the Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark, and Familjen Rönströms Stiftelse, Stockholm, Sweden. Data used in preparation of this article were obtained from the program of PRe-symptomatic EValuation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD) at the Centre for Studies on Prevention of Alzheimer’s Disease (StoP-AD), Douglas Mental Health University Institute Research Center (http://douglas.research.mcgill.ca/stop-ad-centre). A complete listing of the PREVENT-AD Research Group can be found at: https://preventad.loris.ca/acknowledgements/acknowledgements.php?date=2024-12-30.

Author information

Authors and Affiliations

  1. Douglas Mental Health University Institute, Montréal, QC, Canada

    Jiarui Ao, Cynthia Picard, Sylvia Villeneuve, John C. S. Breitner & Judes Poirier

  2. Centre for the Studies in the Prevention of Alzheimer’s Disease, Montréal, QC, Canada

    Jiarui Ao, Cynthia Picard, Sylvia Villeneuve, John C. S. Breitner & Judes Poirier

  3. Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, Montréal, QC, Canada

    Daniel Auld

  4. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Henrik Zetterberg, H. Zetterberg & K. Blennow

  5. Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden

    Henrik Zetterberg, Ann Brinkmalm & Kaj Blennow

  6. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    Henrik Zetterberg

  7. UK Dementia Research Institute at UCL, London, UK

    Henrik Zetterberg

  8. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China

    Henrik Zetterberg

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

    Henrik Zetterberg

  10. Inst. of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden

    Kaj Blennow

  11. Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France

    Kaj Blennow

  12. Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, PR China

    Kaj Blennow

  13. Centre for Studies on Prevention of Alzheimer’s Disease Centre, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada

    J. Breitner, J. Poirier, S. Villeneuve, A. A. Baril, S. Ducharme, M. Tedeshi-Dauar, C. Picard, A. Labonté, G. Aumont-Rodrigue, J. Ao, I. Sarty, J. Loncke & A. Poirier

  14. Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada

    M. Geddes & M. Montembeault

  15. Montreal Neurological Institute and Hospital, Montreal, QC, Canada

    N. Spreng

  16. Centre de recherche de l’Institut Universitaire de Gériatrie de Montreal, Montreal, QC, Canada

    A. Pichet-Bessette

  17. Université de Montréal, Montreal, QC, Canada

    A. Pichet-Bessette

  18. Department of Pharmacology, McGill University, Montreal, QC, Canada

    L. Munter

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  1. Jiarui Ao
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Consortia

for the PREVENT-AD research group

  • J. Breitner
  • , J. Poirier
  • , S. Villeneuve
  • , H. Zetterberg
  • , K. Blennow
  • , A. A. Baril
  • , M. Geddes
  • , S. Ducharme
  • , M. Montembeault
  • , N. Spreng
  • , A. Pichet-Bessette
  • , L. Munter
  • , M. Tedeshi-Dauar
  • , C. Picard
  • , A. Labonté
  • , G. Aumont-Rodrigue
  • , J. Ao
  • , I. Sarty
  • , J. Loncke
  •  & A. Poirier

Contributions

JA, JP, CP, SV, JB, KB, and HZ conceptualized the research. CP, JA, AB, HZ, and KB performed CSF biomarkers measurements, data quality control, and data compilation. DA, CP, and JA performed the pan-genomic analysis of DNA samples and risk assessments. JP, JA, CP, AB, SV, and JB contributed to the data analysis. JP, JA, CP, SV, and CP developed the algorithms for data analysis. JA, JP, JB, and SV wrote the original manuscript draft. All authors reviewed, edited, and approved the final manuscript.

Corresponding author

Correspondence to Judes Poirier.

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Competing interests

JP serves as a scientific advisor to the Alzheimer Society of France. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, 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 Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, 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).KB has served as a consultant and on advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, and Moleac Pte. Ltd, Neurimmune, 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 GU Ventures Incubator Program, outside the work presented in this paper. All other authors have nothing to disclose.

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Ao, J., Picard, C., Auld, D. et al. Novel synaptic markers predict early tau pathology and cognitive deficit in an asymptomatic population at risk of Alzheimer’s disease. Mol Psychiatry 30, 2810–2820 (2025). https://doi.org/10.1038/s41380-024-02884-z

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