{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T01:19:02Z","timestamp":1774315142519,"version":"3.50.1"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alzheimer\u2019s disease tau pathology spreads through neuronal pathways and synaptic connections. Alteration in synaptic activity facilitates tau spreading. Multiple neurotransmitter systems are shown to be implicated in Alzheimer\u2019s disease, but their influence on the trans-synaptic spread of tau is not well understood. I aimed to combine resting-state functional magnetic resonance imaging connectomics, neurotransmitter receptor profiles, and tau-PET data to explain the regional susceptibility to tau accumulation. The tau-PET imaging data of 161 amyloid-beta-negative cognitively unimpaired participants as control and 259 amyloid-beta-positive subjects were recruited from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI). Linear regression analysis revealed that a higher tau-PET z-score is associated with a lower density of nine receptors in the serotonin, dopamine, gamma-aminobutyric acid (GABA), acetylcholine, and glutamate systems. Furthermore, adding four neurotransmitter receptor density z-scores significantly increased the proportion of explained variance by 3% to 7% compared to the epicenter-connectivity distance model in the group-level analysis. Also, adding nine neurotransmitter receptor density z-scores to the epicenter-connectivity distance model increased the explanatory power of variability in individual levels of tau-PET z-score by 3% to 8%. The current study demonstrated the additive value of atlas-based neurotransmitter receptor mapping and individual-level amyloid-beta-PET scans to enhance the connectivity-based explanation of tau accumulation.<\/jats:p>","DOI":"10.1093\/cercor\/bhaf053","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T05:14:49Z","timestamp":1741929289000},"source":"Crossref","is-referenced-by-count":3,"title":["Connectomics and neurotransmitter receptor profile explain regional tau pathology in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4633-3340","authenticated-orcid":false,"given":"Fardin","family":"Nabizadeh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"key":"2025061306114194900_ref1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231810726","article-title":"Role of the cysteine in R3 tau peptide in copper binding and reactivity","volume":"23","author":"Bacchella","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2025061306114194900_ref2","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/bf00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol"},{"key":"2025061306114194900_ref3","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1007\/s00018-019-03349-1","article-title":"Mechanisms of secretion and spreading of pathological tau protein","volume":"77","author":"Brunello","year":"2020","journal-title":"Cell Mol Life Sci"},{"key":"2025061306114194900_ref4","doi-asserted-by":"publisher","first-page":"20150429","DOI":"10.1098\/rstb.2015.0429","article-title":"Impairments of neural circuit function in Alzheimer's disease","volume":"371","author":"Busche","year":"2016","journal-title":"Philos Trans R Soc Lond Ser B Biol Sci"},{"key":"2025061306114194900_ref5","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1126\/science.1162844","article-title":"Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease","volume":"321","author":"Busche","year":"2008","journal-title":"Science"},{"key":"2025061306114194900_ref6","doi-asserted-by":"publisher","first-page":"8740","DOI":"10.1073\/pnas.1206171109","article-title":"Critical role of soluble amyloid-\u03b2 for early hippocampal hyperactivity in a mouse model of Alzheimer's disease","volume":"109","author":"Busche","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025061306114194900_ref7","doi-asserted-by":"publisher","first-page":"641","DOI":"10.2165\/00023210-200317090-00004","article-title":"The glutamatergic system and Alzheimer's disease: therapeutic implications","volume":"17","author":"Butterfield","year":"2003","journal-title":"CNS Drugs"},{"key":"2025061306114194900_ref8","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.neuroimage.2005.10.029","article-title":"Brain hemodynamic changes mediated by dopamine receptors: role of the cerebral microvasculature in dopamine-mediated neurovascular coupling","volume":"30","author":"Choi","year":"2006","journal-title":"NeuroImage"},{"key":"2025061306114194900_ref9","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s40035-022-00282-5","article-title":"EEG\/ERP evidence of possible hyperexcitability in older adults with elevated beta-amyloid","volume":"11","author":"Devos","year":"2022","journal-title":"Transl Neurodegener"},{"key":"2025061306114194900_ref10","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/s1474-4422(21)00066-1","article-title":"Clinical diagnosis of Alzheimer's disease: recommendations of the international working group","volume":"20","author":"Dubois","year":"2021","journal-title":"Lancet Neurol"},{"key":"2025061306114194900_ref11","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.neuropharm.2010.02.010","article-title":"Neurochemical basis for symptomatic treatment of Alzheimer's disease","volume":"59","author":"Francis","year":"2010","journal-title":"Neuropharmacology"},{"key":"2025061306114194900_ref12","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd1327","article-title":"Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer's disease","volume":"6","author":"Franzmeier","year":"2020","journal-title":"Sci Adv"},{"key":"2025061306114194900_ref13","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41467-019-14159-1","article-title":"Functional brain architecture is associated with the rate of tau accumulation in Alzheimer\u2019s disease","volume":"11","author":"Franzmeier","year":"2020","journal-title":"Nat Commun"},{"key":"2025061306114194900_ref14","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/11866763_8","article-title":"Symmetric atlasing and model based segmentation: an application to the hippocampus in older adults","volume":"9","author":"Grabner","year":"2006","journal-title":"Med Image Comput Comput Assist Interv"},{"key":"2025061306114194900_ref15","doi-asserted-by":"publisher","first-page":"8092","DOI":"10.1523\/jneurosci.0438-17.2017","article-title":"Structural basis of large-scale functional connectivity in the mouse","volume":"37","author":"Grandjean","year":"2017","journal-title":"J Neurosci"},{"key":"2025061306114194900_ref16","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1038\/s41593-022-01186-3","article-title":"Mapping neurotransmitter systems to the structural and functional organization of the human neocortex","volume":"25","author":"Hansen","year":"2022","journal-title":"Nat Neurosci"},{"key":"2025061306114194900_ref17","doi-asserted-by":"publisher","first-page":"4682","DOI":"10.1038\/s41467-022-32420-y","article-title":"Local molecular and global connectomic contributions to cross-disorder cortical abnormalities","volume":"13","author":"Hansen","year":"2022","journal-title":"Nat Commun"},{"key":"2025061306114194900_ref18","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1016\/j.neuron.2012.08.019","article-title":"Synaptic energy use and supply","volume":"75","author":"Harris","year":"2012","journal-title":"Neuron"},{"key":"2025061306114194900_ref19","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1016\/j.clinph.2021.03.050","article-title":"Subclinical epileptiform activity accelerates the progression of Alzheimer's disease: A long-term EEG study","volume":"132","author":"Horvath","year":"2021","journal-title":"Clin Neurophysiol"},{"key":"2025061306114194900_ref20","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.neuint.2004.03.007","article-title":"Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease","volume":"45","author":"Hynd","year":"2004","journal-title":"Neurochem Int"},{"key":"2025061306114194900_ref21","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/nrn1387","article-title":"Neurovascular regulation in the normal brain and in Alzheimer's disease","volume":"5","author":"Iadecola","year":"2004","journal-title":"Nat Rev Neurosci"},{"key":"2025061306114194900_ref22","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/s1474-4422(12)70291-0","article-title":"Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers","volume":"12","author":"Jack","year":"2013","journal-title":"Lancet Neurol"},{"key":"2025061306114194900_ref23","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1038\/s41593-018-0238-6","article-title":"Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases","volume":"21","author":"Jucker","year":"2018","journal-title":"Nat Neurosci"},{"key":"2025061306114194900_ref25","doi-asserted-by":"publisher","first-page":"1-15.e11-14","DOI":"10.1016\/j.jalz.2014.07.003","article-title":"The Centiloid project: standardizing quantitative amyloid plaque estimation by PET","volume":"11","author":"Klunk","year":"2015","journal-title":"Alzheimers Dement"},{"key":"2025061306114194900_ref26","doi-asserted-by":"publisher","first-page":"e2259","DOI":"10.1212\/wnl.0000000000010612","article-title":"Association of epileptiform abnormalities and seizures in Alzheimer disease","volume":"95","author":"Lam","year":"2020","journal-title":"Neurology"},{"key":"2025061306114194900_ref27","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1007\/s00259-014-2753-3","article-title":"Amyloid PET imaging in Alzheimer's disease: a comparison of three radiotracers","volume":"41","author":"Landau","year":"2014","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"2025061306114194900_ref28","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nrn2153","article-title":"NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders","volume":"8","author":"Lau","year":"2007","journal-title":"Nat Rev Neurosci"},{"key":"2025061306114194900_ref29","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1002\/syn.20818","article-title":"Molecular and cellular events of dopamine D1 receptor-mediated tau phosphorylation in SK-N-MC cells","volume":"65","author":"Lebel","year":"2011","journal-title":"Synapse"},{"key":"2025061306114194900_ref30","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/2051-5960-1-34","article-title":"Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments","volume":"1","author":"Levenga","year":"2013","journal-title":"Acta Neuropathol Commun"},{"key":"2025061306114194900_ref31","doi-asserted-by":"publisher","first-page":"31","DOI":"10.3389\/fnagi.2016.00031","article-title":"Implications of GABAergic neurotransmission in Alzheimer's Disease","volume":"8","author":"Li","year":"2016","journal-title":"Front Aging Neurosci"},{"key":"2025061306114194900_ref32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031302","article-title":"Trans-synaptic spread of tau pathology in vivo","volume":"7","author":"Liu","year":"2012","journal-title":"PLoS One"},{"key":"2025061306114194900_ref33","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1124\/jpet.122.001307","article-title":"Metabotropic glutamate receptors modulate Exocytotic tau release and propagation","volume":"383","author":"Mazzo","year":"2022","journal-title":"J Pharmacol Exp Ther"},{"key":"2025061306114194900_ref34","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1038\/nn.2145","article-title":"Rapid and modifiable neurotransmitter receptor dynamics at a neuronal synapse in vivo","volume":"11","author":"McCann","year":"2008","journal-title":"Nat Neurosci"},{"key":"2025061306114194900_ref35","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/j.biopsych.2012.08.027","article-title":"Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity","volume":"73","author":"McCormick","year":"2013","journal-title":"Biol Psychiatry"},{"key":"2025061306114194900_ref36","doi-asserted-by":"publisher","first-page":"403","DOI":"10.3389\/fncel.2019.00403","article-title":"Normal and pathological tau uptake mediated by M1\/M3 muscarinic receptors promotes opposite neuronal changes","volume":"13","author":"Morozova","year":"2019","journal-title":"Front Cell Neurosci"},{"key":"2025061306114194900_ref37","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcad286","article-title":"sTREM2 is associated with attenuated tau aggregate accumulation in the presence of amyloid-\u03b2 pathology","volume":"5","author":"Nabizadeh","year":"2023","journal-title":"Brain Communications"},{"key":"2025061306114194900_ref38","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcae198","article-title":"Disruption in functional networks mediated tau spreading in Alzheimer\u2019s disease","volume":"6","author":"Nabizadeh","year":"2024","journal-title":"Brain Communications"},{"key":"2025061306114194900_ref39","doi-asserted-by":"publisher","first-page":"17702","DOI":"10.1038\/s41598-017-17377-z","article-title":"Growth associated protein 43 (GAP-43) as a novel target for the diagnosis, treatment and prevention of Epileptogenesis","volume":"7","author":"Nemes","year":"2017","journal-title":"Sci Rep"},{"key":"2025061306114194900_ref40","doi-asserted-by":"publisher","first-page":"4531","DOI":"10.1073\/pnas.82.13.4531","article-title":"Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease","volume":"82","author":"Pearson","year":"1985","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025061306114194900_ref41","doi-asserted-by":"publisher","first-page":"6635","DOI":"10.1038\/s41467-022-34129-4","article-title":"Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease","volume":"13","author":"Pichet Binette","year":"2022","journal-title":"Nat Commun"},{"key":"2025061306114194900_ref42","doi-asserted-by":"publisher","first-page":"6635","DOI":"10.1038\/s41467-022-34129-4","article-title":"Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer\u2019s disease","volume":"13","author":"Pichet Binette","year":"2022","journal-title":"Nat Commun"},{"key":"2025061306114194900_ref43","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.neurobiolaging.2020.10.013","article-title":"Alterations of GABA B receptors in the APP\/PS1 mouse model of Alzheimer's disease","volume":"97","author":"Salazar","year":"2021","journal-title":"Neurobiol Aging"},{"key":"2025061306114194900_ref44","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/0306-4522(87)90063-7","article-title":"Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer's disease","volume":"23","author":"Saper","year":"1987","journal-title":"Neuroscience"},{"key":"2025061306114194900_ref45","doi-asserted-by":"publisher","first-page":"3095","DOI":"10.1093\/cercor\/bhx179","article-title":"Local-global Parcellation of the human cerebral cortex from intrinsic functional connectivity MRI","volume":"28","author":"Schaefer","year":"2018","journal-title":"Cereb Cortex"},{"key":"2025061306114194900_ref46","doi-asserted-by":"publisher","first-page":"4323","DOI":"10.1523\/jneurosci.3263-16.2017","article-title":"Phases of Hyperconnectivity and Hypoconnectivity in the default mode and salience networks track with amyloid and tau in clinically normal individuals","volume":"37","author":"Schultz","year":"2017","journal-title":"J Neurosci"},{"key":"2025061306114194900_ref47","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/j.tics.2019.04.002","article-title":"Neuromodulatory influences on integration and segregation in the brain","volume":"23","author":"Shine","year":"2019","journal-title":"Trends Cogn Sci"},{"key":"2025061306114194900_ref24","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41583-019-0240-3","article-title":"Amyloid-\u03b2-independent regulators of tau pathology in Alzheimer disease","volume":"21","author":"Kant","year":"2020","journal-title":"Nat Rev Neurosci"},{"key":"2025061306114194900_ref48","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.dadm.2016.12.010","article-title":"Tau-PET uptake: regional variation in average SUVR and impact of amyloid deposition","volume":"6","author":"Vemuri","year":"2017","journal-title":"Alzheimers Dement (Amst)"},{"key":"2025061306114194900_ref49","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/s41467-020-15701-2","article-title":"Spread of pathological tau proteins through communicating neurons in human Alzheimer\u2019s disease","volume":"11","author":"Vogel","year":"2020","journal-title":"Nat Commun"},{"key":"2025061306114194900_ref50","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1038\/s41591-021-01309-6","article-title":"Four distinct trajectories of tau deposition identified in Alzheimer's disease","volume":"27","author":"Vogel","year":"2021","journal-title":"Nat Med"},{"key":"2025061306114194900_ref51","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.3233\/jad-160763","article-title":"Role of glutamate and NMDA receptors in Alzheimer's Disease","volume":"57","author":"Wang","year":"2017","journal-title":"J Alzheimers Dis"},{"key":"2025061306114194900_ref52","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13024-016-0143-y","article-title":"The release and trans-synaptic transmission of tau via exosomes","volume":"12","author":"Wang","year":"2017","journal-title":"Mol Neurodegener"},{"key":"2025061306114194900_ref53","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.neurobiolaging.2018.10.027","article-title":"Administration of the benzodiazepine midazolam increases tau phosphorylation in the mouse brain","volume":"75","author":"Whittington","year":"2019","journal-title":"Neurobiol Aging"},{"key":"2025061306114194900_ref54","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1038\/nn.4328","article-title":"Neuronal activity enhances tau propagation and tau pathology in vivo","volume":"19","author":"Wu","year":"2016","journal-title":"Nat Neurosci"},{"key":"2025061306114194900_ref55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2012.02.002","article-title":"Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease","volume":"97","author":"Xu","year":"2012","journal-title":"Prog Neurobiol"},{"key":"2025061306114194900_ref56","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1084\/jem.20131685","article-title":"Neuronal activity regulates extracellular tau in vivo","volume":"211","author":"Yamada","year":"2014","journal-title":"J Exp Med"},{"key":"2025061306114194900_ref57","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.stem.2019.12.015","article-title":"Interneuron accumulation of phosphorylated tau impairs adult hippocampal neurogenesis by suppressing GABAergic transmission","volume":"26","author":"Zheng","year":"2020","journal-title":"Cell Stem Cell"},{"key":"2025061306114194900_ref58","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1126\/science.aay0198","article-title":"A vicious cycle of \u03b2 amyloid-dependent neuronal hyperactivation","volume":"365","author":"Zott","year":"2019","journal-title":"Science"}],"container-title":["Cerebral Cortex"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cercor\/article-pdf\/35\/3\/bhaf053\/62411666\/bhaf053.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cercor\/article-pdf\/35\/3\/bhaf053\/62411666\/bhaf053.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T10:11:46Z","timestamp":1749809506000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cercor\/article\/doi\/10.1093\/cercor\/bhaf053\/8077889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":58,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3,6]]}},"URL":"https:\/\/doi.org\/10.1093\/cercor\/bhaf053","relation":{},"ISSN":["1047-3211","1460-2199"],"issn-type":[{"value":"1047-3211","type":"print"},{"value":"1460-2199","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,3]]},"published":{"date-parts":[[2025,3]]},"article-number":"bhaf053"}}