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In this proof-of-concept study, we assess new biophysical models of non-invasive human MEG imaging to test the pharmacological and disease modulation of NMDA-receptor inhibition. Magnetoencephalography was recorded during an auditory mismatch negativity paradigm from (1) neurologically-healthy people on memantine or placebo (n\u2009=\u200919, placebo-controlled crossover design); (2) people with Alzheimer\u2019s disease at baseline and 16-months (n\u2009=\u200942, amyloid-biomarker positive, longitudinal observational design). Optimised dynamic causal models inferred voltage-dependent NMDA-receptor blockade using Parametric Empirical Bayes to test group effects. The mismatch negativity amplitude was attenuated when Alzheimer\u2019s disease was more severe (lower baseline mini-mental state examination)\u00a0and after follow-up (\n                    <jats:italic>versus<\/jats:italic>\n                    baseline). Memantine increased NMDA-receptor inhibition, compared to placebo. Alzheimer\u2019s disease reduced NMDA-receptor inhibition in proportion to severity and over time. In line with preclinical studies, we confirm in humans that memantine and Alzheimer\u2019s disease have opposing effects on NMDA-receptor inhibition. The ability to infer such receptor dynamics and pharmacology from non-invasive physiological recordings has wide applications, including the assessment of other neurological disorders and novel drugs intended for symptomatic or disease-modifying treatments.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03288-3","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T06:39:02Z","timestamp":1760078342000},"page":"1587-1596","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Alzheimer\u2019s disease and memantine effects on NMDA-receptor blockade: non-invasive in vivo insights from magnetoencephalography"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6626-7686","authenticated-orcid":false,"given":"Juliette H.","family":"Lanskey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirhossein","family":"Jafarian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melek","family":"Karadag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ece","family":"Kocagoncu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Rouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie E.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Naessens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Raymont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8460-8854","authenticated-orcid":false,"given":"Mark","family":"Woolrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3094-2475","authenticated-orcid":false,"given":"Krish D.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0712-2639","authenticated-orcid":false,"given":"Richard N.","family":"Henson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7216-8679","authenticated-orcid":false,"given":"James B.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"3288_CR1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41582-022-00749-z","volume":"19","author":"M Tzioras","year":"2022","unstructured":"Tzioras M, McGeachan RI, Durrant CS, Spires-Jones TL. 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JBR receives consultancy fees from Astex, Asceneuron, Alector, Astraonautx, Booster Therapeutics, Ferrer, Eisai, ClinialInk, Prevail, SV Health, Rowe&Rowe consultancy, Curasen, CumulusNeuro, VesperBio which are unrelated to the current work. KDS receives consultancy fees from Draig Therapeutics, which are unrelated to the current work. MW receives FSL royalties and consultancy fees from Wellcome Trust grant funding interview panel, which are unrelated to the current work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. Approval The studies were approved by the local ethics committee, the East of England Cambridge Central Research Ethics Committee (REC reference 18\/EE\/0042). Written, informed consent was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}