{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:10:05Z","timestamp":1791925805034,"version":"4.3.4"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T00:00:00Z","timestamp":1682121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"UK-ADRC","award":["1RF1AG057754-01"],"award-info":[{"award-number":["1RF1AG057754-01"]}]},{"name":"UK-ADRC","award":["1F31AG069372-01"],"award-info":[{"award-number":["1F31AG069372-01"]}]},{"name":"UK-ADRC","award":["P30-AG028383"],"award-info":[{"award-number":["P30-AG028383"]}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>APOE is the largest genetic risk factor for late-onset Alzheimer disease (AD) with E4 conferring an increased risk for AD compared to E3. The ApoE protein can impact diverse pathways in the brain including neuroinflammation but the precise impact of ApoE isoforms on inflammation remains unknown. As microglia are a primary source of neuroinflammation, this study determined whether ApoE isoforms have an impact on microglial morphology and activation using immunohistochemistry and digital analyses. Analysis of ionized calcium-binding adaptor molecule 1 (Iba1) immunoreactivity indicated greater microglial activation in both the hippocampus and superior and middle temporal gyrus (SMTG) in dementia participants versus non-demented controls. Further, only an increase in activation was seen in E3-Dementia participants in the entire SMTG, whereas in the grey matter of the SMTG, only a diagnosis of dementia impacted activation. Specific microglial morphologies showed a reduction in ramified microglia in the dementia group. For rod microglia, a reduction was seen in E4-Control patients in the hippocampus whereas in the SMTG an increase was seen in E4-Dementia patients. These findings suggest an association between ApoE isoforms and microglial morphologies and highlight the importance of considering ApoE isoforms in studies of AD pathology.<\/jats:p>","DOI":"10.1093\/jnen\/nlad031","type":"journal-article","created":{"date-parts":[[2023,4,23]],"date-time":"2023-04-23T00:28:16Z","timestamp":1682209696000},"page":"620-630","source":"Crossref","is-referenced-by-count":16,"title":["Association between APOE genotype and microglial cell morphology"],"prefix":"10.1093","volume":"82","author":[{"given":"Courtney M","family":"Kloske","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary D","family":"Gearon","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica M","family":"Weekman","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Rogers","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ela","family":"Patel","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, College of Medicine, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Bachstetter","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, College of Medicine, Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, College of Medicine, Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna M","family":"Wilcock","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,22]]},"reference":[{"key":"2024032523515893000_nlad031-B1","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1152\/physrev.00011.2010","article-title":"Physiology of microglia","volume":"91","author":"Kettenmann","year":"2011","journal-title":"Physiol Rev"},{"key":"2024032523515893000_nlad031-B2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1083\/jcb.201709069","article-title":"Microglia in Alzheimer\u2019s disease","volume":"217","author":"Hansen","year":"2018","journal-title":"J Cell Biol"},{"key":"2024032523515893000_nlad031-B3","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1093\/brain\/awh531","article-title":"LPS receptor (CD14): A receptor for phagocytosis of Alzheimer\u2019s amyloid peptide","volume":"128","author":"Liu","year":"2005","journal-title":"Brain"},{"key":"2024032523515893000_nlad031-B4","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0896-6273(00)80187-7","article-title":"Microglial cells internalize aggregates of the Alzheimer\u2019s disease amyloid beta-protein via a scavenger receptor","volume":"17","author":"Paresce","year":"1996","journal-title":"Neuron"},{"key":"2024032523515893000_nlad031-B5","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1523\/JNEUROSCI.23-07-02665.2003","article-title":"A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation","volume":"23","author":"Bamberger","year":"2003","journal-title":"J Neurosci"},{"key":"2024032523515893000_nlad031-B6","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/0304-3940(90)90748-X","article-title":"Morphologic association between microglia and senile plaque amyloid in Alzheimer\u2019s disease","volume":"119","author":"Perlmutter","year":"1990","journal-title":"Neurosci Lett"},{"key":"2024032523515893000_nlad031-B7","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.molmed.2017.03.008","article-title":"TREM2, microglia, and neurodegenerative diseases","volume":"23","author":"Yeh","year":"2017","journal-title":"Trends Mol Med"},{"key":"2024032523515893000_nlad031-B8","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1038\/ng.3916","article-title":"Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer\u2019s disease","volume":"49","author":"Sims","year":"2017","journal-title":"Nat Genet"},{"key":"2024032523515893000_nlad031-B9","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.neulet.2019.01.001","article-title":"A decade of diverse microglial-neuronal physical interactions in the brain (2008-2018)","volume":"698","author":"Uweru","year":"2019","journal-title":"Neurosci Lett"},{"key":"2024032523515893000_nlad031-B10","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.it.2015.08.008","article-title":"Microglia: Dynamic mediators of synapse development and plasticity","volume":"36","author":"Wu","year":"2015","journal-title":"Trends Immunol"},{"key":"2024032523515893000_nlad031-B11","doi-asserted-by":"crossref","first-page":"11295","DOI":"10.1038\/ncomms11295","article-title":"Untangling the brain\u2019s neuroinflammatory and neurodegenerative transcriptional responses","volume":"7","author":"Srinivasan","year":"2016","journal-title":"Nat Commun"},{"key":"2024032523515893000_nlad031-B12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00281-017-0662-9","article-title":"Complement in the pathogenesis of Alzheimer\u2019s disease","volume":"40","author":"Morgan","year":"2018","journal-title":"Semin Immunopathol"},{"key":"2024032523515893000_nlad031-B13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nrneurol.2014.38","article-title":"Microglial priming in neurodegenerative disease","volume":"10","author":"Perry","year":"2014","journal-title":"Nat Rev Neurol"},{"key":"2024032523515893000_nlad031-B14","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.ajpath.2011.05.047","article-title":"Reactive glia not only associates with plaques but also parallels tangles in Alzheimer\u2019s disease","volume":"179","author":"Serrano-Pozo","year":"2011","journal-title":"Am J Pathol"},{"key":"2024032523515893000_nlad031-B15","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.3390\/biom10101439","article-title":"Microglia in Alzheimer\u2019s disease in the context of tau pathology","volume":"10","author":"Perea","year":"2020","journal-title":"Biomolecules"},{"key":"2024032523515893000_nlad031-B16","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1002\/glia.23046","article-title":"The \u201cBig-Bang\u201d for modern glial biology: Translation and comments on Pio del Rio-Hortega 1919 series of papers on microglia","volume":"64","author":"Sierra","year":"2016","journal-title":"Glia"},{"key":"2024032523515893000_nlad031-B17","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1113\/JP272134","article-title":"Microglia across the lifespan: From origin to function in brain development, plasticity and cognition","volume":"595","author":"Tay","year":"2017","journal-title":"J Physiol"},{"key":"2024032523515893000_nlad031-B18","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41380-019-0609-8","article-title":"Microglial regional heterogeneity and its role in the brain","volume":"25","author":"Tan","year":"2020","journal-title":"Mol Psychiatry"},{"key":"2024032523515893000_nlad031-B19","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3389\/fnagi.2018.00140","article-title":"Microglia in Alzheimer\u2019s disease: Activated, dysfunctional or degenerative","volume":"10","author":"Navarro","year":"2018","journal-title":"Front Aging Neurosci"},{"key":"2024032523515893000_nlad031-B20","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.semcdb.2019.02.005","article-title":"Rod microglia and their role in neurological diseases","volume":"94","author":"Holloway","year":"2019","journal-title":"Semin Cell Dev Biol"},{"key":"2024032523515893000_nlad031-B21","doi-asserted-by":"crossref","first-page":"fcaa227","DOI":"10.1093\/braincomms\/fcaa227","article-title":"An update on the rod microglia variant in experimental and clinical brain injury and disease","volume":"3","author":"Giordano","year":"2021","journal-title":"Brain Commun"},{"key":"2024032523515893000_nlad031-B22","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neurobiolaging.2016.12.028","article-title":"Rod-shaped microglia morphology is associated with aging in 2 human autopsy series","volume":"52","author":"Bachstetter","year":"2017","journal-title":"Neurobiol Aging"},{"key":"2024032523515893000_nlad031-B23","doi-asserted-by":"crossref","first-page":"e2115539118","DOI":"10.1073\/pnas.2115539118","article-title":"Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1","volume":"118","author":"Lituma","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024032523515893000_nlad031-B24","doi-asserted-by":"crossref","first-page":"678","DOI":"10.3390\/ijms21020678","article-title":"Patterns of expression of purinergic receptor P2RY12, a putative marker for non-activated microglia, in aged and Alzheimer\u2019s disease brains","volume":"21","author":"Walker","year":"2020","journal-title":"IJMS"},{"key":"2024032523515893000_nlad031-B25","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13024-020-00394-4","article-title":"Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice","volume":"15","author":"Fitz","year":"2020","journal-title":"Mol Neurodegener"},{"key":"2024032523515893000_nlad031-B26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13024-018-0249-5","article-title":"Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury","volume":"13","author":"Main","year":"2018","journal-title":"Mol Neurodegener"},{"key":"2024032523515893000_nlad031-B27","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.neuroscience.2019.01.049","article-title":"APOE genotype specific effects on the early neurodegenerative sequelae following chronic repeated mild traumatic brain injury","volume":"404","author":"Muza","year":"2019","journal-title":"Neuroscience"},{"key":"2024032523515893000_nlad031-B28","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s40478-019-0729-z","article-title":"APOE genotype and sex affect microglial interactions with plaques in Alzheimer\u2019s disease mice","volume":"7","author":"Stephen","year":"2019","journal-title":"Acta Neuropathol Commun"},{"key":"2024032523515893000_nlad031-B29","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1093\/jnen\/nlab085","article-title":"Inflammatory pathways are impaired in Alzheimer disease and differentially associated with apolipoprotein E status","volume":"80","author":"Kloske","year":"2021","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523515893000_nlad031-B30","doi-asserted-by":"crossref","first-page":"724","DOI":"10.2174\/156720512801322591","article-title":"University of Kentucky Sanders-Brown healthy brain aging volunteers: Donor characteristics, procedures and neuropathology","volume":"9","author":"Schmitt","year":"2012","journal-title":"Curr Alzheimer Res"},{"key":"2024032523515893000_nlad031-B31","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.3233\/JAD-180514","article-title":"Diffuse amyloid-beta plaques, neurofibrillary tangles, and the impact of APOE in elderly persons\u2019 brains lacking neuritic amyloid plaques","volume":"64","author":"Abner","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"2024032523515893000_nlad031-B32","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s40478-015-0209-z","article-title":"Disease-related microglia heterogeneity in the hippocampus of Alzheimer\u2019s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging","volume":"3","author":"Bachstetter","year":"2015","journal-title":"Acta Neuropathol Commun"},{"key":"2024032523515893000_nlad031-B33","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1037\/a0031642","article-title":"APOE epsilon4, Alzheimer\u2019s disease pathology, cerebrovascular disease, and cognitive change over the years prior to death","volume":"28","author":"Yu","year":"2013","journal-title":"Psychol Aging"},{"key":"2024032523515893000_nlad031-B34","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1038\/s41598-020-59869-5","article-title":"Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E epsilon4 genotype","volume":"10","author":"Friedberg","year":"2020","journal-title":"Sci Rep"},{"key":"2024032523515893000_nlad031-B35","doi-asserted-by":"crossref","first-page":"5644","DOI":"10.1073\/pnas.0600549103","article-title":"Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer\u2019s disease","volume":"103","author":"Mahley","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024032523515893000_nlad031-B36","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1212\/WNL.56.12.1696","article-title":"Gender and age modify the association between APOE and AD-related neuropathology","volume":"56","author":"Ghebremedhin","year":"2001","journal-title":"Neurology"},{"key":"2024032523515893000_nlad031-B37","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1750-3639.1998.tb00136.x","article-title":"Glial-neuronal interactions in Alzheimer\u2019s disease: The potential role of a \u2018cytokine cycle\u2019 in disease progression","volume":"8","author":"Griffin","year":"1998","journal-title":"Brain Pathol"},{"key":"2024032523515893000_nlad031-B38","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1750-3639.1998.tb00166.x","article-title":"Microglial activation in Alzheimer disease: Association with APOE genotype","volume":"8","author":"Egensperger","year":"1998","journal-title":"Brain Pathol"},{"key":"2024032523515893000_nlad031-B39","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s12974-016-0601-z","article-title":"Microglial immunophenotype in dementia with Alzheimer\u2019s pathology","volume":"13","author":"Minett","year":"2016","journal-title":"J Neuroinflammation"},{"key":"2024032523515893000_nlad031-B40","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.neurobiolaging.2020.12.003","article-title":"Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain","volume":"99","author":"Shahidehpour","year":"2021","journal-title":"Neurobiol Aging"},{"key":"2024032523515893000_nlad031-B41","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1002\/glia.23523","article-title":"Traumatic brain injury-induced neuronal damage in the somatosensory cortex causes formation of rod-shaped microglia that promote astrogliosis and persistent neuroinflammation","volume":"66","author":"Witcher","year":"2018","journal-title":"Glia"},{"key":"2024032523515893000_nlad031-B42","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1186\/1742-2094-9-247","article-title":"Rod microglia: Elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury","volume":"9","author":"Ziebell","year":"2012","journal-title":"J Neuroinflammation"},{"key":"2024032523515893000_nlad031-B43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jnr.20093","article-title":"Microglia and Alzheimer\u2019s disease pathogenesis","volume":"77","author":"Streit","year":"2004","journal-title":"J Neurosci Res"},{"key":"2024032523515893000_nlad031-B44","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1001\/archneur.59.11.1737","article-title":"Dementia and Alzheimer disease incidence: A prospective cohort study","volume":"59","author":"Kukull","year":"2002","journal-title":"Arch Neurol"},{"key":"2024032523515893000_nlad031-B45","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S1474-4422(12)70291-0","article-title":"Tracking pathophysiological processes in Alzheimer\u2019s disease: An updated hypothetical model of dynamic biomarkers","volume":"12","author":"Jack","year":"2013","journal-title":"Lancet Neurol"},{"key":"2024032523515893000_nlad031-B46","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.ajpath.2015.10.010","article-title":"Plaque-associated local toxicity increases over the clinical course of Alzheimer disease","volume":"186","author":"Serrano-Pozo","year":"2016","journal-title":"Am J Pathol"},{"key":"2024032523515893000_nlad031-B47","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12974-020-01820-6","article-title":"The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer\u2019s disease: A longitudinal PET study","volume":"17","author":"Ismail","year":"2020","journal-title":"J Neuroinflammation"}],"container-title":["Journal of Neuropathology &amp; Experimental Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jnen\/article-pdf\/82\/7\/620\/50635538\/nlad031.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jnen\/article-pdf\/82\/7\/620\/50635538\/nlad031.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:40:19Z","timestamp":1711413619000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jnen\/article\/82\/7\/620\/7136723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,22]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4,22]]},"published-print":{"date-parts":[[2023,6,20]]}},"URL":"https:\/\/doi.org\/10.1093\/jnen\/nlad031","relation":{},"ISSN":["0022-3069","1554-6578"],"issn-type":[{"value":"0022-3069","type":"print"},{"value":"1554-6578","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,7,1]]},"published":{"date-parts":[[2023,4,22]]}}}