{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:54:45Z","timestamp":1790740485865,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,26]]},"group-title":"Neuroscience","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01AG069196"],"award-info":[{"award-number":["R01AG069196"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG074216"],"award-info":[{"award-number":["R01AG074216"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG077541"],"award-info":[{"award-number":["R01AG077541"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>As the strongest genetic risk factor for late-onset Alzheimer\u2019s disease (AD), the human APOE \u03b54 allele alters neuronal physiology before overt pathology. However, how aging and sex modify these effects in the anterior olfactory nucleus (AON), an early AD-affected brain region, remains unclear. Here, we performed whole-cell recordings and post hoc morphological reconstructions of pyramidal cells (PCs) and interneurons (INs) in acute AON slices from adult and aged humanized APOE3 (E3) and APOE4 (E4) knock-in mice of both sexes with identification of context-dependent remodeling across structural, intrinsic, and synaptic domains. In PCs, morphology was broadly susceptible to APOE genotype, age, sex and their interactions. Functionally, aged E4 PCs exhibited a more depolarized resting membrane potential than aged E3 PCs. Additionally, afterhyperpolarization amplitude displayed a marked age \u00d7 genotype interaction, reversing the direction of the E4\u2013E3 difference from adulthood to aging. Excitatory synaptic event frequency showed a complex genotype \u00d7 age \u00d7 sex interaction, whereas inhibitory synaptic event amplitude was elevated in E4 mice. In contrast, INs displayed far more restricted alterations. Morphological changes were limited to dendritic length, which was modulated by age and sex specifically in E4 mice. Physiologically, genotype effects were confined to action potential amplitude, while aging primarily altered membrane properties and excitatory synaptic inputs. Together, these findings demonstrate that APOE genotype cell-specifically shapes AON neuronal properties through interactions with age and sex, suggesting that APOE4 establishes altered cellular states that influence how this circuit responds to subsequent disease-related stress.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Carrying the APOE4 gene is the strongest genetic risk factor for late-onset Alzheimer\u2019s disease (AD), and its effects on brain cells are not uniform, yet how they combine with aging and biological sex is largely unknown. We examined the anterior olfactory nucleus, a region affected very early in AD, and measured the morphology, physiological properties, and synaptic inputs of both excitatory and inhibitory neurons in mice carrying the human APOE3 or APOE4 gene. Rather than making neurons uniformly more or less active, APOE4 altered different properties in different cell types, and the direction of several effects depended on age and sex. Recognizing this context dependence may be necessary before cell-level changes can be linked to early disease risk.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.21.753183","type":"posted-content","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:50:10Z","timestamp":1790484610000},"source":"Crossref","is-referenced-by-count":0,"title":["Cell Type-Specific Structural and Functional Signatures of APOE4, Age and Sex in the Mouse Anterior Olfactory Nucleus"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5265-0155","authenticated-orcid":false,"given":"Meigeng","family":"Hu","sequence":"first","affiliation":[{"name":"University of Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kershaw","sequence":"additional","affiliation":[{"name":"University of Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Brunson","sequence":"additional","affiliation":[{"name":"University of Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Li","sequence":"additional","affiliation":[{"name":"University of Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5745-8010","authenticated-orcid":false,"given":"Dan","family":"Zhao","sequence":"additional","affiliation":[{"name":"University of Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaolin","family":"Liu","sequence":"additional","affiliation":[{"name":"University of Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092919550829000_2026.09.21.753183v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24135"},{"key":"2026092919550829000_2026.09.21.753183v1.2","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1038\/s41467-018-05131-6","article-title":"Hippocampal projections to the anterior olfactory nucleus differentially convey spatiotemporal information during episodic odour memory","volume":"9","year":"2018","journal-title":"Nature communications"},{"key":"2026092919550829000_2026.09.21.753183v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2044"},{"key":"2026092919550829000_2026.09.21.753183v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature11087"},{"key":"2026092919550829000_2026.09.21.753183v1.5","doi-asserted-by":"crossref","unstructured":"Bhattarai JP , Etyemez S , Jaaro-Peled H , Janke E , Tolosa UDL , Kamiya A , Gottfried JA , Sawa A , Ma M (2022) Olfactory modulation of the medial prefrontal cortex circuitry: Implications for social cognition. In: Seminars in cell & developmental biology, pp 31-39: Elsevier.","DOI":"10.1016\/j.semcdb.2021.03.022"},{"key":"2026092919550829000_2026.09.21.753183v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2023.102486"},{"key":"2026092919550829000_2026.09.21.753183v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22293"},{"key":"2026092919550829000_2026.09.21.753183v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2005.08.005"},{"key":"2026092919550829000_2026.09.21.753183v1.9","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22662"},{"key":"2026092919550829000_2026.09.21.753183v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2620"},{"key":"2026092919550829000_2026.09.21.753183v1.11","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201500004"},{"key":"2026092919550829000_2026.09.21.753183v1.12","doi-asserted-by":"publisher","DOI":"10.1126\/science.8346443"},{"key":"2026092919550829000_2026.09.21.753183v1.13","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4026-09.2009"},{"key":"2026092919550829000_2026.09.21.753183v1.14","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03550160069041"},{"key":"2026092919550829000_2026.09.21.753183v1.15","first-page":"234","article-title":"Connectivity of pathology: the olfactory system as a model for network-driven mechanisms of Alzheimer\u2019s disease pathogenesis","volume":"7","year":"2015","journal-title":"Frontiers in aging neuroscience"},{"key":"2026092919550829000_2026.09.21.753183v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(77)90978-7"},{"key":"2026092919550829000_2026.09.21.753183v1.17","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A3601"},{"key":"2026092919550829000_2026.09.21.753183v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2014.08.025"},{"key":"2026092919550829000_2026.09.21.753183v1.19","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00111"},{"key":"2026092919550829000_2026.09.21.753183v1.20","doi-asserted-by":"crossref","first-page":"97","DOI":"10.14283\/jpad.2023.61","article-title":"Burden of illness in people with Alzheimer\u2019s disease: a systematic review of epidemiology, comorbidities and mortality","volume":"11","year":"2024","journal-title":"The journal of prevention of Alzheimer\u2019s disease"},{"key":"2026092919550829000_2026.09.21.753183v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2009.10.015"},{"key":"2026092919550829000_2026.09.21.753183v1.22","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","article-title":"Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy","volume":"9","year":"2013","journal-title":"Nature Reviews Neurology"},{"key":"2026092919550829000_2026.09.21.753183v1.23","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3389\/fncel.2020.00181","article-title":"Dopamine Suppresses Synaptic Responses of Fan Cells in the Lateral Entorhinal Cortex to Olfactory Bulb Input in Mice","volume":"14","year":"2020","journal-title":"Front Cell Neurosci"},{"key":"2026092919550829000_2026.09.21.753183v1.24","doi-asserted-by":"publisher","DOI":"10.1113\/JP275511"},{"key":"2026092919550829000_2026.09.21.753183v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/J.CMET.2018.05.011"},{"key":"2026092919550829000_2026.09.21.753183v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21077"},{"key":"2026092919550829000_2026.09.21.753183v1.27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s40478-020-00986-7","article-title":"The unfolded protein response is activated in the olfactory system in Alzheimer\u2019s disease","volume":"8","year":"2020","journal-title":"Acta neuropathologica communications"},{"key":"2026092919550829000_2026.09.21.753183v1.28","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1001\/jamaneurol.2017.2188","article-title":"Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis","volume":"74","year":"2017","journal-title":"JAMA neurology"},{"key":"2026092919550829000_2026.09.21.753183v1.29","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1038\/s41467-017-01444-0","article-title":"Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer\u2019s disease-like pathology","volume":"8","year":"2017","journal-title":"Nature communications"},{"key":"2026092919550829000_2026.09.21.753183v1.30","doi-asserted-by":"crossref","first-page":"4951","DOI":"10.1002\/alz.13842","article-title":"Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction","volume":"20","year":"2024","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2026092919550829000_2026.09.21.753183v1.31","doi-asserted-by":"crossref","first-page":"778","DOI":"10.3390\/ijms24010778","article-title":"Apoe4 and Alzheimer\u2019s disease pathogenesis\u2014mitochondrial deregulation and targeted therapeutic strategies","volume":"24","year":"2023","journal-title":"International Journal of Molecular Sciences"},{"key":"2026092919550829000_2026.09.21.753183v1.32","doi-asserted-by":"crossref","first-page":"e1000850","DOI":"10.1371\/journal.pcbi.1000850","article-title":"A threshold equation for action potential initiation","volume":"6","year":"2010","journal-title":"PLoS computational biology"},{"key":"2026092919550829000_2026.09.21.753183v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2016.03.012"},{"key":"2026092919550829000_2026.09.21.753183v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/nature24016"},{"key":"2026092919550829000_2026.09.21.753183v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2003.10.011"},{"key":"2026092919550829000_2026.09.21.753183v1.36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.29.17972"},{"key":"2026092919550829000_2026.09.21.753183v1.37","doi-asserted-by":"crossref","unstructured":"Tabuena DR , Jang S-S , Grone B , Yip O , Aery Jones EA , Blumenfeld J , Liang Z , Mann RS , Li Y , Necula D (2026) Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer\u2019s disease pathogenesis. Nature Aging:1\u201319.","DOI":"10.1038\/s43587-026-01096-0"},{"key":"2026092919550829000_2026.09.21.753183v1.38","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1177\/13872877251386812","article-title":"Chimpanzee and human ApoE isoforms differ in the stimulation of neurite differentiation consistent with structural predictions with relevance to brain development and aging","volume":"108","year":"2025","journal-title":"Journal of Alzheimer\u2019s Disease"},{"key":"2026092919550829000_2026.09.21.753183v1.39","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40035-020-00200-7","article-title":"The human olfactory system in two proteinopathies: Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"9","year":"2020","journal-title":"Transl Neurodegener"},{"key":"2026092919550829000_2026.09.21.753183v1.40","doi-asserted-by":"crossref","first-page":"e70865","DOI":"10.1002\/alz.70865","article-title":"APOE \u03b54 disrupts neuronal and network-level function in the anterior olfactory nucleus: Influence of age and sex","volume":"21","year":"2025","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2026092919550829000_2026.09.21.753183v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.10.013"},{"key":"2026092919550829000_2026.09.21.753183v1.42","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41582-019-0228-7","article-title":"Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies","volume":"15","year":"2019","journal-title":"Nature Reviews Neurology"},{"key":"2026092919550829000_2026.09.21.753183v1.43","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.47177"},{"key":"2026092919550829000_2026.09.21.753183v1.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0198"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.21.753183","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:55:14Z","timestamp":1790736914000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.21.753183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,26]]},"references-count":44,"URL":"https:\/\/doi.org\/10.64898\/2026.09.21.753183","relation":{},"subject":[],"published":{"date-parts":[[2026,9,26]]},"subtype":"preprint"}}