{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:42:13Z","timestamp":1787730133888,"version":"build-2784847793"},"posted":{"date-parts":[[2026,3,18]]},"group-title":"Neuroscience","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Alzheimer\u2019s disease (AD) and related dementias (ADRD) are defined by molecular and cellular pathology and cognitive decline, but linking these levels requires understanding how pathology alters large-scale neuronal activity. We longitudinally tracked behavior, multi-area neuronal population activity, and fluid and histological biomarkers in a macaque model of early-stage ADRD. As pathology progressed, visually guided behavior became increasingly disorganized, reflected in less structured exploration despite preserved task performance. Guided by systems neuroscience principles linking neuronal population activity with organized goal-directed behavior, we found progressive reductions in coordinated neuronal population activity within and between visual and parietal cortices, even as single-neuron tuning and basic feature encoding remained stable. These changes emerged when tau pathology was largely confined to regions providing feedback to visual cortex. This disorganized state appears modifiable: proof-of-concept methylphenidate administration was associated with transient improvement in behavioral organization. Together, these findings identify disruption of neuronal population organization as a defining feature of early-stage ADRD and frame early dysfunction as a disorder of coordinated population activity.<\/jats:p>","DOI":"10.64898\/2026.03.18.712735","type":"posted-content","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T07:15:15Z","timestamp":1773904515000},"source":"Crossref","is-referenced-by-count":2,"title":["Loss of neuronal population organization links pathology to behavior in a model of Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7228-8822","authenticated-orcid":false,"given":"Douglas A.","family":"Ruff","sequence":"first","affiliation":[{"name":"Department of Neurobiology, University of Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4198-4619","authenticated-orcid":false,"given":"Drew E.G.","family":"Sheets","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1832-7250","authenticated-orcid":false,"given":"Ramanujan","family":"Srinath","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2020-2289","authenticated-orcid":false,"given":"Giovanne B.","family":"Diniz","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California Davis, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7059-7699","authenticated-orcid":false,"given":"Devon J.","family":"Griggs","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California Davis, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9584-4411","authenticated-orcid":false,"given":"Danielle","family":"Beckman","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California Davis, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8792-7236","authenticated-orcid":false,"given":"Sean","family":"Ott","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California Davis, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla","family":"Schwartz","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California Davis, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8933-8125","authenticated-orcid":false,"given":"Carissa","family":"Erices","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California Davis, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5379-1331","authenticated-orcid":false,"given":"Scott","family":"Muller","sequence":"additional","affiliation":[{"name":"ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, Arizona, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5524-2044","authenticated-orcid":false,"given":"Jeffrey H.","family":"Kordower","sequence":"additional","affiliation":[{"name":"ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, Arizona, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8292-0964","authenticated-orcid":false,"given":"John H.","family":"Morrison","sequence":"additional","affiliation":[{"name":"California National Primate Research Center, University of California Davis, Davis, California, USA"},{"name":"Department of Neurology, School of Medicine, University of California Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8583-4300","authenticated-orcid":false,"given":"Marlene R.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032302000656000_2026.03.18.712735v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.27003"},{"key":"2026032302000656000_2026.03.18.712735v1.2","doi-asserted-by":"publisher","DOI":"10.1159\/000057702"},{"key":"2026032302000656000_2026.03.18.712735v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh045"},{"key":"2026032302000656000_2026.03.18.712735v1.4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-120320-082744"},{"key":"2026032302000656000_2026.03.18.712735v1.5","unstructured":"Bakotich, E.C.S. , Koenig, S. , Jutras, M.J. , Bachevalier, J. , and Buffalo, E.A. (2024). Normative aging and hippocampal lesions differentially impact viewing behaviors in monkeys. held in Chicago, IL."},{"key":"2026032302000656000_2026.03.18.712735v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2019.02.021"},{"key":"2026032302000656000_2026.03.18.712735v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12318"},{"key":"2026032302000656000_2026.03.18.712735v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13868"},{"key":"2026032302000656000_2026.03.18.712735v1.9","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00370"},{"key":"2026032302000656000_2026.03.18.712735v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-006-0127-z"},{"key":"2026032302000656000_2026.03.18.712735v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2026032302000656000_2026.03.18.712735v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1919895116"},{"key":"2026032302000656000_2026.03.18.712735v1.13","doi-asserted-by":"publisher","DOI":"10.1101\/lm32100"},{"key":"2026032302000656000_2026.03.18.712735v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/nature20412"},{"key":"2026032302000656000_2026.03.18.712735v1.15","doi-asserted-by":"publisher","DOI":"10.3233\/jad-160641"},{"key":"2026032302000656000_2026.03.18.712735v1.16","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.15636"},{"key":"2026032302000656000_2026.03.18.712735v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2021.10.010"},{"key":"2026032302000656000_2026.03.18.712735v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2501"},{"key":"2026032302000656000_2026.03.18.712735v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2842"},{"key":"2026032302000656000_2026.03.18.712735v1.20","doi-asserted-by":"publisher","DOI":"10.1177\/1533317509332093"},{"key":"2026032302000656000_2026.03.18.712735v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3776"},{"key":"2026032302000656000_2026.03.18.712735v1.22","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.42.2.320"},{"key":"2026032302000656000_2026.03.18.712735v1.23","doi-asserted-by":"publisher","DOI":"10.1101\/2025.09.22.677855"},{"key":"2026032302000656000_2026.03.18.712735v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0231(20000430)14:8<619::AID-RCM916>3.0.CO;2-2"},{"key":"2026032302000656000_2026.03.18.712735v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jagp.2012.12.018"},{"key":"2026032302000656000_2026.03.18.712735v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.02.002"},{"key":"2026032302000656000_2026.03.18.712735v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.07.011"},{"key":"2026032302000656000_2026.03.18.712735v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42834-x"},{"key":"2026032302000656000_2026.03.18.712735v1.29","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-vision-030320-041115"},{"key":"2026032302000656000_2026.03.18.712735v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02018-x"},{"key":"2026032302000656000_2026.03.18.712735v1.31","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.61.1.95"},{"key":"2026032302000656000_2026.03.18.712735v1.32","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2010.00166"},{"key":"2026032302000656000_2026.03.18.712735v1.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0223792"},{"key":"2026032302000656000_2026.03.18.712735v1.34","unstructured":"Hof, P.R. , and Morrison, J.H . (1994). The Cellular basis of cortical disconnection in Alzheimer\u2019s disease and related dementing conditions. In Alzheimer Disease, R. Terry , R. Katzman , and K. Bick , eds. (Raven Press), pp. 197\u2013229."},{"key":"2026032302000656000_2026.03.18.712735v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2011.05.012"},{"key":"2026032302000656000_2026.03.18.712735v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2022.11.006"},{"key":"2026032302000656000_2026.03.18.712735v1.37","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13859"},{"key":"2026032302000656000_2026.03.18.712735v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2014.01.001"},{"key":"2026032302000656000_2026.03.18.712735v1.39","doi-asserted-by":"publisher","DOI":"10.1055\/a-1076-8228"},{"key":"2026032302000656000_2026.03.18.712735v1.40","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz151"},{"key":"2026032302000656000_2026.03.18.712735v1.41","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2016.0205"},{"key":"2026032302000656000_2026.03.18.712735v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-021-00502-3"},{"key":"2026032302000656000_2026.03.18.712735v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2011.06.027"},{"key":"2026032302000656000_2026.03.18.712735v1.44","doi-asserted-by":"publisher","DOI":"10.1162\/jocn_a_01544"},{"key":"2026032302000656000_2026.03.18.712735v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1348"},{"key":"2026032302000656000_2026.03.18.712735v1.46","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-vision-082114-035431"},{"key":"2026032302000656000_2026.03.18.712735v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.08.006"},{"key":"2026032302000656000_2026.03.18.712735v1.48","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222313168"},{"key":"2026032302000656000_2026.03.18.712735v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01925-w"},{"key":"2026032302000656000_2026.03.18.712735v1.50","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.3356"},{"key":"2026032302000656000_2026.03.18.712735v1.51","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2013.2080"},{"key":"2026032302000656000_2026.03.18.712735v1.52","doi-asserted-by":"publisher","DOI":"10.3233\/jad-141173"},{"key":"2026032302000656000_2026.03.18.712735v1.53","doi-asserted-by":"publisher","DOI":"10.1159\/000106957"},{"key":"2026032302000656000_2026.03.18.712735v1.54","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1234-18.2018"},{"key":"2026032302000656000_2026.03.18.712735v1.55","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2120529119"},{"key":"2026032302000656000_2026.03.18.712735v1.56","first-page":"463","article-title":"Learning and attention reveal a general relationship between population activity and behavior","volume":"35S","year":"2018","journal-title":"Science"},{"key":"2026032302000656000_2026.03.18.712735v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2016.06.019"},{"key":"2026032302000656000_2026.03.18.712735v1.58","doi-asserted-by":"publisher","DOI":"10.1007\/s11065-021-09495-3"},{"key":"2026032302000656000_2026.03.18.712735v1.59","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2017.17030316"},{"key":"2026032302000656000_2026.03.18.712735v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-022-00606-4"},{"key":"2026032302000656000_2026.03.18.712735v1.61","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.21.1.227"},{"key":"2026032302000656000_2026.03.18.712735v1.62","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-vision-030320-041306"},{"key":"2026032302000656000_2026.03.18.712735v1.63","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2021.23"},{"key":"2026032302000656000_2026.03.18.712735v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.011"},{"key":"2026032302000656000_2026.03.18.712735v1.65","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.12m08099"},{"key":"2026032302000656000_2026.03.18.712735v1.66","doi-asserted-by":"publisher","DOI":"10.1037\/0894-4105.14.3.398"},{"key":"2026032302000656000_2026.03.18.712735v1.67","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhj076"},{"key":"2026032302000656000_2026.03.18.712735v1.68","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2750-14.2014"},{"key":"2026032302000656000_2026.03.18.712735v1.69","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0477-1"},{"key":"2026032302000656000_2026.03.18.712735v1.70","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-080317-061936"},{"key":"2026032302000656000_2026.03.18.712735v1.71","doi-asserted-by":"publisher","DOI":"10.1111\/1467-9280.00288"},{"key":"2026032302000656000_2026.03.18.712735v1.72","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28552-w"},{"key":"2026032302000656000_2026.03.18.712735v1.73","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3071-06.2006"},{"key":"2026032302000656000_2026.03.18.712735v1.74","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4542-08.2008"},{"key":"2026032302000656000_2026.03.18.712735v1.75","first-page":"940","article-title":"Laminar dependence of neuronal correlations in visual cortex","volume":"10S","year":"2013","journal-title":"Journal of Neurophysiology"},{"key":"2026032302000656000_2026.03.18.712735v1.76","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.31.060407.125627"},{"key":"2026032302000656000_2026.03.18.712735v1.77","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.119"},{"key":"2026032302000656000_2026.03.18.712735v1.78","doi-asserted-by":"publisher","DOI":"10.1101\/2024.09.30.615928"},{"key":"2026032302000656000_2026.03.18.712735v1.79","doi-asserted-by":"publisher","DOI":"10.1101\/2024.07.10.602774"},{"key":"2026032302000656000_2026.03.18.712735v1.80","doi-asserted-by":"publisher","DOI":"10.1101\/2024.08.30.610535"},{"key":"2026032302000656000_2026.03.18.712735v1.81","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51695"},{"key":"2026032302000656000_2026.03.18.712735v1.82","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.06.028"},{"key":"2026032302000656000_2026.03.18.712735v1.83","doi-asserted-by":"publisher","DOI":"10.1016\/j.jagp.2020.04.026"},{"key":"2026032302000656000_2026.03.18.712735v1.84","doi-asserted-by":"publisher","DOI":"10.1101\/2024.03.04.583375"},{"key":"2026032302000656000_2026.03.18.712735v1.85","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4244"},{"key":"2026032302000656000_2026.03.18.712735v1.86","doi-asserted-by":"publisher","DOI":"10.1177\/1533317512470484"},{"key":"2026032302000656000_2026.03.18.712735v1.87","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-01-00451.2000"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.18.712735","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:00:20Z","timestamp":1774256420000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.18.712735"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,18]]},"references-count":87,"URL":"https:\/\/doi.org\/10.64898\/2026.03.18.712735","relation":{},"subject":[],"published":{"date-parts":[[2026,3,18]]},"subtype":"preprint"}}