{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T06:58:08Z","timestamp":1792825088693,"version":"4.5.0"},"reference-count":52,"publisher":"SAGE Publications","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2022,5,17]]},"abstract":"<jats:p>Background: Down syndrome (DS) is frequently associated with Alzheimer\u2019s disease (AD)-related neuropathological changes. There are few observations on the spectrum of mixed proteinopathies in DS patients. Objective: This study aimed to evaluate multiple disease-associated proteinopathies in a series of DS cases. Methods: We analyzed the distribution of neurodegenerative disease associated proteins in postmortem brain samples from 11 DS cases (6 females, median age 57, range 38\u201366 years). Sections were stained for phosphorylated tau, 3-repeat and 4-repeat tau, amyloid-\u03b2, alpha synuclein, phosphorylated TDP-43, and p62. A comprehensive anatomical mapping and staging were applied for all proteins. Results: Tau and amyloid-\u03b2 pathology was prevalent in all cases and compatible with that typically seen in AD with some subtle deviations. Four of 11 cases presented with Lewy-related pathology (LRP). Two cases followed the Braak staging (stage 4 and 5) whereas 2 cases presented with an atypical distribution. Two cases showed limbic predominant age-related TDP-43 encephalopathy (LATE) (stage 1 and stage 2) neuropathologic change. Two cases exhibited aging-related tau astrogliopathy (ARTAG). Conclusion: In addition to subtle deviations from AD regarding the morphology of amyloid-\u03b2 deposition and distribution of neuronal tau pathology, we find that the spectrum of mixed-pathologies in DS show distinctive features such as deviations from the Braak staging of LRP and that LATE neuropathologic change and ARTAG pathology can be seen in individuals younger than in sporadic AD cases. Our observations support the notion that DS has distinctive pathogenic pathways from sporadic AD.<\/jats:p>","DOI":"10.3233\/jad-215675","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T12:15:58Z","timestamp":1647346558000},"page":"595-607","source":"Crossref","is-referenced-by-count":22,"title":["Patterns of Mixed Pathologies in Down Syndrome"],"prefix":"10.1177","volume":"87","author":[{"given":"Shojiro","family":"Ichimata","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada"},{"name":"Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada"},{"name":"Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi P.","family":"Visanji","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada"},{"name":"Edmund J. Safra Program in Parkinson\u2019s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony E.","family":"Lang","sequence":"additional","affiliation":[{"name":"Edmund J. Safra Program in Parkinson\u2019s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Nishida","sequence":"additional","affiliation":[{"name":"Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor G.","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada"},{"name":"Edmund J. Safra Program in Parkinson\u2019s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital, Toronto, Canada"},{"name":"Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-215675_ref1","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1056\/NEJMra1706537","article-title":"Down syndrome","volume":"382","author":"Bull","year":"2020","journal-title":"N Engl J Med"},{"key":"10.3233\/JAD-215675_ref2","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s40478-018-0559-4","article-title":"The age of onset and evolution of Braak tangle stage and Thal amyloid pathology of Alzheimer\u2019s disease in individuals with Down syndrome","volume":"6","author":"Davidson","year":"2018","journal-title":"Acta Neuropathol Commun"},{"key":"10.3233\/JAD-215675_ref3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s00401-019-01965-6","article-title":"Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia","volume":"137","author":"Perez","year":"2019","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref4","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1001\/archneur.1995.00540280059019","article-title":"Neuropathological changes in Down\u2019s syndrome hippocampal formation. Effect of age and apolipoprotein E genotype","volume":"52","author":"Hyman","year":"1995","journal-title":"Arch Neurol"},{"key":"10.3233\/JAD-215675_ref5","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1001\/archneur.1995.00540280065020","article-title":"Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down\u2019s syndrome. Quantitative regional analysis and comparison with Alzheimer\u2019s disease","volume":"52","author":"Hof","year":"1995","journal-title":"Arch Neurol"},{"key":"10.3233\/JAD-215675_ref6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0197-4580(94)90139-2","article-title":"Amyloid plaques in cerebellar cortex and the integrity of Purkinje cell dendrites","volume":"15","author":"Li","year":"1994","journal-title":"Neurobiol Aging"},{"key":"10.3233\/JAD-215675_ref7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0047-6374(88)90041-3","article-title":"The pathological association between Down syndrome and Alzheimer disease","volume":"43","author":"Mann","year":"1988","journal-title":"Mech Ageing Dev"},{"key":"10.3233\/JAD-215675_ref8","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1002\/ana.410170310","article-title":"Occurrence of neuropathological changes and dementia of Alzheimer\u2019s disease in Down\u2019s syndrome","volume":"17","author":"Wisniewski","year":"1985","journal-title":"Ann Neurol"},{"key":"10.3233\/JAD-215675_ref9","first-page":"457","article-title":"The development of the pathologic changes of Alzheimer\u2019s disease and senile dementia in patients with Down\u2019s syndrome","volume":"73","author":"Burger","year":"1973","journal-title":"Am J Pathol"},{"key":"10.3233\/JAD-215675_ref10","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s00401-013-1157-y","article-title":"Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: A community-based autopsy series","volume":"126","author":"Kovacs","year":"2013","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref11","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1093\/brain\/awy146","article-title":"Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated","volume":"141","author":"Robinson","year":"2018","journal-title":"Brain"},{"key":"10.3233\/JAD-215675_ref12","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/neup.12427","article-title":"Molecular mechanisms of the co-deposition of multiple pathological proteins in neurodegenerative diseases","volume":"38","author":"Nonaka","year":"2018","journal-title":"Neuropathology"},{"key":"10.3233\/JAD-215675_ref13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5114\/fn.2020.94001","article-title":"Cortical laminar distribution of beta-amyloid deposits in five neurodegenerative disorders","volume":"58","author":"Armstrong","year":"2020","journal-title":"Folia Neuropathol"},{"key":"10.3233\/JAD-215675_ref14","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1093\/brain\/awab099","article-title":"Comorbid neuropathological diagnoses in early versus late-onset Alzheimer\u2019s disease","volume":"144","author":"Spina","year":"2021","journal-title":"Brain"},{"key":"10.3233\/JAD-215675_ref15","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s00441-004-0956-9","article-title":"Stages in the development of Parkinson\u2019s disease-related pathology","volume":"318","author":"Braak","year":"2004","journal-title":"Cell Tissue Res"},{"key":"10.3233\/JAD-215675_ref16","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/j.1365-2990.2007.00874.x","article-title":"Parkinson\u2019s disease: A dual-hit hypothesis","volume":"33","author":"Hawkes","year":"2007","journal-title":"Neuropathol Appl Neurobiol"},{"key":"10.3233\/JAD-215675_ref17","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00401-015-1526-9","article-title":"Pathological alpha-synuclein distribution in subjects with coincident Alzheimer\u2019s and Lewy body pathology","volume":"131","author":"Toledo","year":"2016","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref18","doi-asserted-by":"crossref","first-page":"S78","DOI":"10.1002\/mds.22637","article-title":"Evidence in favor of Braak staging of Parkinson\u2019s disease","volume":"25","author":"Dickson","year":"2010","journal-title":"Mov Disord"},{"key":"10.3233\/JAD-215675_ref19","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00401-020-02255-2","article-title":"Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: A multi-centre study","volume":"141","author":"Attems","year":"2021","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref20","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1002\/mds.26605","article-title":"Neuropathological basis of nonmotor manifestations of Parkinson\u2019s disease","volume":"31","author":"Adler","year":"2016","journal-title":"Mov Disord"},{"key":"10.3233\/JAD-215675_ref21","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3233\/JPD-202481","article-title":"The alpha-synuclein origin and connectome model (SOC Model) of Parkinson\u2019s disease: Explaining motor asymmetry, non-motor phenotypes, and cognitive decline","volume":"11","author":"Borghammer","year":"2021","journal-title":"J Parkinsons Dis"},{"key":"10.3233\/JAD-215675_ref22","doi-asserted-by":"crossref","first-page":"105557","DOI":"10.1016\/j.nbd.2021.105557","article-title":"Neuropathological evidence of body-first vs. brain-first Lewy body disease","volume":"161","author":"Borghammer","year":"2021","journal-title":"Neurobiol Dis"},{"key":"10.3233\/JAD-215675_ref23","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/1531-8249(199903)45:3<353::AID-ANA11>3.0.CO;2-4","article-title":"Antibodies to alpha-synuclein detect Lewy bodies in many Down\u2019s syndrome brains with Alzheimer\u2019s disease","volume":"45","author":"Lippa","year":"1999","journal-title":"Ann Neurol"},{"key":"10.3233\/JAD-215675_ref24","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1212\/WNL.44.1.159","article-title":"A case of Down\u2019s syndrome with diffuse Lewy body disease and Alzheimer\u2019s disease","volume":"44","author":"Bodhireddy","year":"1994","journal-title":"Neurology"},{"key":"10.3233\/JAD-215675_ref25","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1136\/jnnp.52.6.701","article-title":"A pathological study of the association between Lewy body disease and Alzheimer\u2019s disease","volume":"52","author":"Gibb","year":"1989","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"10.3233\/JAD-215675_ref26","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1136\/jnnp.62.3.289","article-title":"Down\u2019s syndrome and Parkinson\u2019s disease","volume":"62","author":"Hestnes","year":"1997","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"10.3233\/JAD-215675_ref27","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/nan.12406","article-title":"The physiological phosphorylation of tau is critically changed in fetal brains of individuals with Down syndrome","volume":"44","author":"Milenkovic","year":"2018","journal-title":"Neuropathol Appl Neurobiol"},{"key":"10.3233\/JAD-215675_ref28","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s00401-015-1509-x","article-title":"Aging-related tau astrogliopathy (ARTAG): Harmonized evaluation strategy","volume":"131","author":"Kovacs","year":"2016","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref29","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s40478-018-0552-y","article-title":"Sequential stages and distribution patterns of aging-related tau astrogliopathy (ARTAG) in the human brain","volume":"6","author":"Kovacs","year":"2018","journal-title":"Acta Neuropathol Commun"},{"key":"10.3233\/JAD-215675_ref30","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":"10.3233\/JAD-215675_ref31","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1093\/jnen\/63.9.911","article-title":"Staging of argyrophilic grains: An age-associated tauopathy","volume":"63","author":"Saito","year":"2004","journal-title":"J Neuropathol Exp Neurol"},{"key":"10.3233\/JAD-215675_ref32","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1111\/ene.14321","article-title":"Argyrophilic grain disease in individuals younger than 75 years: Clinical variability in an under-recognized limbic tauopathy","volume":"27","author":"Wurm","year":"2020","journal-title":"Eur J Neurol"},{"key":"10.3233\/JAD-215675_ref33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00401-012-0964-x","article-title":"An antibody with high reactivity for disease-associated \u03b1-synuclein reveals extensive brain pathology","volume":"124","author":"Kovacs","year":"2012","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref34","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00401-006-0127-z","article-title":"Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry","volume":"112","author":"Braak","year":"2006","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref35","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","article-title":"Phases of A beta-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"10.3233\/JAD-215675_ref36","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1212\/WNL.41.4.479","article-title":"The Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer\u2019s disease","volume":"41","author":"Mirra","year":"1991","journal-title":"Neurology"},{"key":"10.3233\/JAD-215675_ref37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","article-title":"National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: A practical approach","volume":"123","author":"Montine","year":"2012","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref38","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/jnen\/61.3.282","article-title":"Two types of sporadic cerebral amyloid angiopathy","volume":"61","author":"Thal","year":"2002","journal-title":"J Neuropathol Exp Neurol"},{"key":"10.3233\/JAD-215675_ref39","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1093\/jnen\/62.12.1287","article-title":"Vascular pathology in Alzheimer disease: Correlation of cerebral amyloid angiopathy and arteriosclerosis\/lipohyalinosis with cognitive decline","volume":"62","author":"Thal","year":"2003","journal-title":"J Neuropathol Exp Neurol"},{"key":"10.3233\/JAD-215675_ref40","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/nan.12208","article-title":"Invited review: Neuropathology of tauopathies: Principles and practice","volume":"41","author":"Kovacs","year":"2015","journal-title":"Neuropathol Appl Neurobiol"},{"key":"10.3233\/JAD-215675_ref41","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1212\/WNL.0000000000004058","article-title":"Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium","volume":"89","author":"McKeith","year":"2017","journal-title":"Neurology"},{"key":"10.3233\/JAD-215675_ref42","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s00401-018-1866-3","article-title":"Patterns and severity of vascular amyloid in Alzheimer\u2019s disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer\u2019s disease","volume":"136","author":"Mann","year":"2018","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref43","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1111\/neup.12662","article-title":"Amyloid-beta plaques may be reduced in advanced stages of cerebral amyloid angiopathy in the elderly","volume":"40","author":"Okamoto","year":"2020","journal-title":"Neuropathology"},{"key":"10.3233\/JAD-215675_ref44","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1093\/jnen\/nlx099","article-title":"The amygdala as a locus of pathologic misfolding in neurodegenerative diseases","volume":"77","author":"Nelson","year":"2018","journal-title":"J Neuropathol Exp Neurol"},{"key":"10.3233\/JAD-215675_ref45","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s40478-019-0708-4","article-title":"How to demix Alzheimer-type and PSP-type tau lesions out of their mixture -hybrid approach to dissect comorbidity","volume":"7","author":"Ebashi","year":"2019","journal-title":"Acta Neuropathol Commun"},{"key":"10.3233\/JAD-215675_ref46","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s00401-020-02158-2","article-title":"Distribution patterns of tau pathology in progressive supranuclear palsy","volume":"140","author":"Kovacs","year":"2020","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref47","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/BF00688170","article-title":"Spectrum of morphological appearance of amyloid deposits in Alzheimer\u2019s disease","volume":"78","author":"Wisniewski","year":"1989","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref48","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/BF00687584","article-title":"Diffuse type of senile plaques in the cerebellum of Alzheimer-type dementia demonstrated by beta protein immunostain","volume":"77","author":"Yamaguchi","year":"1989","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref49","doi-asserted-by":"crossref","first-page":"645334","DOI":"10.3389\/fnagi.2021.645334","article-title":"Cerebellar calcium-binding protein and neurotrophin receptor defects in Down syndrome and Alzheimer\u2019s disease","volume":"13","author":"Miguel","year":"2021","journal-title":"Front Aging Neurosci"},{"key":"10.3233\/JAD-215675_ref50","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1007\/BF00294651","article-title":"The prevalence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down\u2019s syndrome and Alzheimer\u2019s disease","volume":"80","author":"Mann","year":"1990","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref51","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00401-002-0664-z","article-title":"Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt-Jakob disease","volume":"105","author":"Jarius","year":"2003","journal-title":"Acta Neuropathol"},{"key":"10.3233\/JAD-215675_ref52","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.3233\/JAD-215065","article-title":"A primer on the evolution of Aducanumab: The first antibody approved for treatment of Alzheimer\u2019s disease","volume":"83","author":"Mukhopadhyay","year":"2021","journal-title":"J Alzheimers Dis"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-215675","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:05:49Z","timestamp":1777370749000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-215675"}},"subtitle":[],"editor":[{"given":"Giorgio","family":"Giaccone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,5,17]]},"references-count":52,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.3233\/jad-215675","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,17]]}}}