{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T23:04:24Z","timestamp":1781132664408,"version":"3.54.1"},"posted":{"date-parts":[[2025,5,28]]},"group-title":"Neuroscience","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Synaptic dysfunction is a hallmark of Alzheimer\u2019s disease (AD). Yet due to their plasticity, synapses may also adapt to early AD pathology. Here, we demonstrate that cholinergic neurons mount a presynaptic response to tau pathology in the living human brain. Using multi-tracer positron emission tomography in cognitively normal older adults at risk for AD, we observe that cholinergic neurons increase presynaptic vesicular acetylcholine transporter (VAChT) protein levels when colocalized to tau, but not amyloid. Notably, stronger VAChT responses were associated with cognitive resilience over a decade. Whole-brain single-nucleus RNA sequencing in human and mouse tissue reveal that cholinergic neurons are enriched for a plasticity gene-network anchored to the microtubule-associated protein tau (\n                  <jats:italic>MAPT<\/jats:italic>\n                  ) gene. In mice, forebrain-specific deletion of VAChT impairs cortical plasticity and hippocampal structural integrity. Overall, our findings identify cholinergic synaptic plasticity, and its failure, as a fundamental mechanism of resilience and vulnerability to tau in presymptomatic AD.\n                <\/jats:p>","DOI":"10.1101\/2025.05.27.656174","type":"posted-content","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T07:45:16Z","timestamp":1748418316000},"source":"Crossref","is-referenced-by-count":2,"title":["Cholinergic synaptic plasticity shapes resilience and vulnerability to tau"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6150-4403","authenticated-orcid":false,"given":"Kate M.","family":"Onuska","sequence":"first","affiliation":[{"name":"Schulich Medicine and Dentistry, Western University, London, ON, Canada"},{"name":"Robarts Research Institute, Western University, London, ON, Canada"},{"name":"Lawson Imaging Research Program, Lawson Health Research Institute, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4502-7170","authenticated-orcid":false,"given":"Hayley R.C.","family":"Shanks","sequence":"additional","affiliation":[{"name":"Schulich Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren A.","family":"Devito","sequence":"additional","affiliation":[{"name":"Schulich Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5187-8767","authenticated-orcid":false,"given":"Qi","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9702-3780","authenticated-orcid":false,"given":"Alycia M.","family":"Crooks","sequence":"additional","affiliation":[{"name":"Schulich Medicine and Dentistry, Western University, London, ON, Canada"},{"name":"Robarts Research Institute, Western University, London, ON, Canada"},{"name":"Lawson Imaging Research Program, Lawson Health Research Institute, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Germ\u00e1n-Castel\u00e1n","sequence":"additional","affiliation":[{"name":"Schulich Medicine and Dentistry, Western University, London, ON, Canada"},{"name":"Robarts Research Institute, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey N.","family":"Ngo","sequence":"additional","affiliation":[{"name":"Schulich Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8543-2467","authenticated-orcid":false,"given":"Roy A.M.","family":"Haast","sequence":"additional","affiliation":[{"name":"Robarts Research Institute, Western University, London, ON, Canada"},{"name":"Aix Marseille Universit\u00e9, CNRS, CRMBM, Marseille, France"},{"name":"APHM, H\u00f4pital Universitaire Timone, CEMEREM, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1120-2196","authenticated-orcid":false,"given":"Tallulah S.","family":"Andrews","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Western University, London, ON, Canada"},{"name":"Department of Computer Science, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1359-7411","authenticated-orcid":false,"given":"Kayla M.","family":"Williams","sequence":"additional","affiliation":[{"name":"McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7638-2007","authenticated-orcid":false,"given":"Fl\u00e1vio H.","family":"Beraldo","sequence":"additional","affiliation":[{"name":"Robarts Research Institute, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Qiu","sequence":"additional","affiliation":[{"name":"Douglas Mental Health University Institute, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Fajardo-Valdez","sequence":"additional","affiliation":[{"name":"Douglas Mental Health University Institute, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordana","family":"Remz","sequence":"additional","affiliation":[{"name":"StoP-Alzheimer Centre, Douglas Mental Health University Institute Research Centre, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7699-648X","authenticated-orcid":false,"given":"Alfie","family":"Wearn","sequence":"additional","affiliation":[{"name":"McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7232-8994","authenticated-orcid":false,"given":"Gary R.","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Psychology, York University, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8997-7090","authenticated-orcid":false,"given":"Etienne","family":"Aumont","sequence":"additional","affiliation":[{"name":"McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montr\u00e9al, QC, Canada"},{"name":"NeuroQAM Research Centre, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al (UQAM), Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6132-3020","authenticated-orcid":false,"given":"Jonathan D.","family":"Thiessen","sequence":"additional","affiliation":[{"name":"Lawson Imaging Research Program, Lawson Health Research Institute, London, ON, Canada"},{"name":"Division of Medical Physics, CancerCare Manitoba, Winnipeg, MB, Canada"},{"name":"Department of Radiology, University of Manitoba, Winnipeg, MB, Canada"},{"name":"Department of Medical Biophysics, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Fox","sequence":"additional","affiliation":[{"name":"Lawson Imaging Research Program, Lawson Health Research Institute, London, ON, Canada"},{"name":"Department of Medical Biophysics, Western University, London, ON, Canada"},{"name":"Department of Physics and Astronomy, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0269-9364","authenticated-orcid":false,"given":"Justin W.","family":"Hicks","sequence":"additional","affiliation":[{"name":"Lawson Imaging Research Program, Lawson Health Research Institute, London, ON, Canada"},{"name":"Department of Medical Biophysics, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3180-3709","authenticated-orcid":false,"given":"Timothy J.","family":"Bussey","sequence":"additional","affiliation":[{"name":"Robarts Research Institute, Western University, London, ON, Canada"},{"name":"Department of Physiology and Pharmacology, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8416-8171","authenticated-orcid":false,"given":"Lisa M.","family":"Saksida","sequence":"additional","affiliation":[{"name":"Robarts Research Institute, Western University, London, ON, Canada"},{"name":"Department of Physiology and Pharmacology, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5824-3740","authenticated-orcid":false,"given":"Jennifer","family":"Tremblay-Mercier","sequence":"additional","affiliation":[{"name":"StoP-Alzheimer Centre, Douglas Mental Health University Institute Research Centre, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4229-4687","authenticated-orcid":false,"given":"John C.S.","family":"Breitner","sequence":"additional","affiliation":[{"name":"Douglas Mental Health University Institute, Montr\u00e9al, QC, Canada"},{"name":"StoP-Alzheimer Centre, Douglas Mental Health University Institute Research Centre, Montr\u00e9al, QC, Canada"},{"name":"Department of Psychiatry, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6979-1259","authenticated-orcid":false,"given":"Jean-Paul","family":"Soucy","sequence":"additional","affiliation":[{"name":"McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8018-4545","authenticated-orcid":false,"given":"Judes","family":"Poirier","sequence":"additional","affiliation":[{"name":"Douglas Mental Health University Institute, Montr\u00e9al, QC, Canada"},{"name":"StoP-Alzheimer Centre, Douglas Mental Health University Institute Research Centre, Montr\u00e9al, QC, Canada"},{"name":"Department of Psychiatry, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Andr\u00e9","family":"Bedard","sequence":"additional","affiliation":[{"name":"McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montr\u00e9al, QC, Canada"},{"name":"NeuroQAM Research Centre, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al (UQAM), Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2338-0467","authenticated-orcid":false,"given":"Sylvia","family":"Villeneuve","sequence":"additional","affiliation":[{"name":"McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Douglas Mental Health University Institute, Montr\u00e9al, QC, Canada"},{"name":"StoP-Alzheimer Centre, Douglas Mental Health University Institute Research Centre, Montr\u00e9al, QC, Canada"},{"name":"Department of Psychiatry, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vania F.","family":"Prado","sequence":"additional","affiliation":[{"name":"Robarts Research Institute, Western University, London, ON, Canada"},{"name":"Department of Physiology and Pharmacology, Western University, London, ON, Canada"},{"name":"Department of Anatomy and Cell Biology, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3028-5778","authenticated-orcid":false,"given":"Marco A.M.","family":"Prado","sequence":"additional","affiliation":[{"name":"Robarts Research Institute, Western University, London, ON, Canada"},{"name":"Department of Physiology and Pharmacology, Western University, London, ON, Canada"},{"name":"Department of Anatomy and Cell Biology, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1530-8916","authenticated-orcid":false,"given":"R. Nathan","family":"Spreng","sequence":"additional","affiliation":[{"name":"McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"},{"name":"StoP-Alzheimer Centre, Douglas Mental Health University Institute Research Centre, Montr\u00e9al, QC, Canada"},{"name":"Department of Psychiatry, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Psychology, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0585-7524","authenticated-orcid":false,"given":"Taylor W.","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Robarts Research Institute, Western University, London, ON, Canada"},{"name":"Lawson Imaging Research Program, Lawson Health Research Institute, London, ON, Canada"},{"name":"Department of Physiology and Pharmacology, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the PREVENT-AD Research Group.","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.27.656174","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T11:15:20Z","timestamp":1775474120000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.05.27.656174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,28]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1101\/2025.05.27.656174","relation":{},"subject":[],"published":{"date-parts":[[2025,5,28]]},"subtype":"preprint"}}