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Locus coeruleus pathology has been linked to clinical conditions such as cognitive impairment and behavioral and psychiatric symptoms of dementia (BPSD). However, phosphorylated TDP-43 (pTDP-43) pathology in the LC has been understudied, particularly in the contexts of aging and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Here, a convenience sample (n\u2009=\u2009134) of autopsied participants from the University of Kentucky Alzheimer\u2019s Disease Research Center community-based cohort was analyzed for LC pTDP-43 and phosphorylated tau (pTau) pathologies. Locus coeruleus pTDP-43 pathology was found in 28\/134 (20.9%) brains and was generally sparse when present. Locus coeruleus pTDP-43 lesions typically appeared as round granular structures that measured \u223c3-12\u00a0\u00b5m in diameter. Locus coeruleus pTDP-43 pathology was increased with aging and was imperfectly correlated with LATE-NC staging; it showed no correlation with cortical pTau pathology in ADNC or PART. In terms of clinical-pathological correlations, LC pTDP-43 pathology was associated with depressive symptoms but not with global cognition or with other BPSDs. Locus coeruleus pTau pathology was positively correlated with cortical pTau pathologic severity and with LATE-NC stages. In conclusion, LC pTDP-43 pathology is a common feature of brain aging, associated with LATE-NC.<\/jats:p>","DOI":"10.1093\/jnen\/nlag035","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:35:00Z","timestamp":1774355700000},"page":"842-856","source":"Crossref","is-referenced-by-count":2,"title":["Locus coeruleus TDP-43 pathology in a community-based cohort: Clinical and pathological correlates"],"prefix":"10.1093","volume":"85","author":[{"given":"Allison M","family":"Neltner","sequence":"first","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan K","family":"Shahidehpour","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan E","family":"Hall","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]},{"name":"Department of Biostatistics, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Ning","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]},{"name":"Department of Epidemiology and Environmental Health, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuling","family":"Fister","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Kang","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya","family":"Anderson","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A","family":"Jicha","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]},{"name":"Department of Neurology, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany L","family":"Lee","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin L","family":"Abner","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]},{"name":"Department of Epidemiology and Environmental Health, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W","family":"Fardo","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]},{"name":"Department of Biostatistics, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6161-1265","authenticated-orcid":false,"given":"Peter T","family":"Nelson","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United States"]},{"name":"Department of Pathology, University of Kentucky , Lexington, KY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"2026080515014729500_nlag035-B1","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/s41583-020-0360-9","article-title":"Locus coeruleus: a new look at the blue spot","volume":"21","author":"Poe","year":"2020","journal-title":"Nat Rev Neurosci"},{"key":"2026080515014729500_nlag035-B2","doi-asserted-by":"crossref","first-page":"808590","DOI":"10.3389\/fnbeh.2022.808590","article-title":"Age-and sex-dependent changes in locus coeruleus physiology and anxiety-like behavior following acute stressor exposure","volume":"16","author":"Borodovitsyna","year":"2022","journal-title":"Front Behav Neurosci"},{"key":"2026080515014729500_nlag035-B3","doi-asserted-by":"crossref","first-page":"1236335","DOI":"10.3389\/fnagi.2023.1236335","article-title":"Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function","volume":"15","author":"Chen","year":"2023","journal-title":"Front Aging Neurosci"},{"key":"2026080515014729500_nlag035-B4","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/s43587-023-00469-z","article-title":"The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance","volume":"3","author":"Dahl","year":"2023","journal-title":"Nat Aging"},{"key":"2026080515014729500_nlag035-B5","doi-asserted-by":"crossref","first-page":"e29808","DOI":"10.7554\/eLife.29808","article-title":"Functional dichotomy in spinal-vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats","volume":"6","author":"Hirschberg","year":"2017","journal-title":"elife."},{"key":"2026080515014729500_nlag035-B6","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s13195-021-00902-8","article-title":"Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer\u2019s disease plasma biomarkers: a 7T MRI study","volume":"13","author":"Van Egroo","year":"2021","journal-title":"Alzheimers Res Ther"},{"key":"2026080515014729500_nlag035-B7","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.neuron.2015.07.002","article-title":"CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety","volume":"87","author":"McCall","year":"2015","journal-title":"Neuron"},{"key":"2026080515014729500_nlag035-B8","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/0361-9230(94)90170-8","article-title":"Depression and anxiety: role of the locus coeruleus and corticotropin-releasing 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subtypes","volume":"89","author":"Matti","year":"2022","journal-title":"J Alzheimers Dis"},{"key":"2026080515014729500_nlag035-B18","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1097\/NEN.0b013e318232a379","article-title":"Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years","volume":"70","author":"Braak","year":"2011","journal-title":"J Neuropathol Exp Neurol"},{"key":"2026080515014729500_nlag035-B19","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1111\/j.1365-2990.2011.01244.x","article-title":"Correlations between cortical and subcortical tau pathology","volume":"38","author":"Attems","year":"2012","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2026080515014729500_nlag035-B20","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/nan.12387","article-title":"Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer\u2019s disease","volume":"43","author":"Ehrenberg","year":"2017","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2026080515014729500_nlag035-B21","doi-asserted-by":"crossref","first-page":"e12965","DOI":"10.1111\/nan.12965","article-title":"Changes in the locus coeruleus during the course of Alzheimer\u2019s disease and their relationship to cortical pathology","volume":"50","author":"Beardmore","year":"2024","journal-title":"Neuropathol App Neurobiol."},{"key":"2026080515014729500_nlag035-B22","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jalz.2016.06.2362","article-title":"Locus coeruleus volume and cell population changes during Alzheimer\u2019s disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery","volume":"13","author":"Theofilas","year":"2017","journal-title":"Alzheimers Dement"},{"key":"2026080515014729500_nlag035-B23","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/s00429-024-02797-1","article-title":"The degeneration of locus coeruleus occurring during Alzheimer\u2019s disease clinical progression: a neuroimaging follow-up investigation","volume":"229","author":"Galgani","year":"2024","journal-title":"Brain Struct Funct"},{"key":"2026080515014729500_nlag035-B24","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/alz.12261","article-title":"MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction","volume":"17","author":"Elman","year":"2021","journal-title":"Alzheimers Dement"},{"key":"2026080515014729500_nlag035-B25","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40478-017-0411-2","article-title":"Locus coeruleus cellular and molecular pathology during the progression of Alzheimer\u2019s 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Alzheimer\u2019s disease","volume":"66","author":"Ehrenberg","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"2026080515014729500_nlag035-B29","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/brain\/awz099","article-title":"Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report","volume":"142","author":"Nelson","year":"2019","journal-title":"Brain"},{"key":"2026080515014729500_nlag035-B30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00401-022-02444-1","article-title":"Frequency of LATE neuropathologic change across the spectrum of Alzheimer\u2019s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts","volume":"144","author":"Nelson","year":"2022","journal-title":"Acta Neuropathol"},{"key":"2026080515014729500_nlag035-B31","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00401-013-1211-9","article-title":"Staging TDP-43 pathology in 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Neuropathol Exp Neurol"},{"key":"2026080515014729500_nlag035-B35","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13024-023-00653-0","article-title":"TDP-43 pathology is associated with increased tau burdens and seeding","volume":"18","author":"Tom\u00e9","year":"2023","journal-title":"Mol Neurodegener"},{"key":"2026080515014729500_nlag035-B36","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s00401-014-1269-z","article-title":"TDP-43 is a key player in the clinical features associated with Alzheimer\u2019s disease","volume":"127","author":"Josephs","year":"2014","journal-title":"Acta Neuropathol"},{"key":"2026080515014729500_nlag035-B37","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/bpa.12505","article-title":"Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi","volume":"28","author":"Smith","year":"2018","journal-title":"Brain 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