{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T11:35:27Z","timestamp":1794569727858,"version":"4.9.1"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pathologies that are causative for neurodegenerative disease (ND) are also frequently present in unimpaired, older individuals. In this retrospective study of 1647 autopsied individuals, we report the incidence of 10 pathologies across ND and normal ageing in attempt to clarify which pathological combinations are disease-associated and which are ageing-related. Eight clinically defined groups were examined including unimpaired individuals and those with clinical Alzheimer\u2019s disease, mixed dementia, amyotrophic lateral sclerosis, frontotemporal degeneration, multiple system atrophy, probable Lewy body disease or probable tauopathies. Up to seven pathologies were observed concurrently resulting in a heterogeneous mix of 161 pathological combinations. The presence of multiple additive pathologies associated with older age, increasing disease duration, APOE e4 allele and presence of dementia across the clinical groups. Fifteen to 67 combinations occurred in each group, with the unimpaired group defined by 35 combinations. Most combinations occurred at a &amp;lt;5% prevalence including 86 that were present in only one or two individuals. To better understand this heterogeneity, we organized the pathological combinations into five broad categories based on their age-related frequency: (i) \u2018Ageing only\u2019 for the unimpaired group combinations; (ii) \u2018ND only\u2019 if only the expected pathology for that individual\u2019s clinical phenotype was present; (iii) \u2018Other ND\u2019 if the expected pathology was not present; (iv) \u2018ND + ageing\u2019 if the expected pathology was present together with ageing-related pathologies at a similar prevalence as the unimpaired group; and (v) \u2018ND + associated\u2019 if the expected pathology was present together with other pathologies either not observed in the unimpaired group or observed at a greater frequency. ND only cases comprised a minority of cases (19\u201345%) except in the amyotrophic lateral sclerosis (56%) and multiple system atrophy (65%) groups. The ND + ageing category represented 9\u201328% of each group, but was rare in Alzheimer\u2019s disease (1%). ND + associated combinations were common in Alzheimer\u2019s disease (58%) and Lewy body disease (37%) and were observed in all groups. The Ageing only and Other ND categories accounted for a minority of individuals in each group. This observed heterogeneity indicates that the total pathological burden in ND is frequently more than a primary expected clinicopathological correlation with a high frequency of additional disease- or age-associated pathologies.<\/jats:p>","DOI":"10.1093\/brain\/awad059","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T05:47:35Z","timestamp":1677822455000},"page":"2557-2569","source":"Crossref","is-referenced-by-count":196,"title":["Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated"],"prefix":"10.1093","volume":"146","author":[{"given":"John L","family":"Robinson","sequence":"first","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon 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School of Medicine , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivianna M","family":"Van Deerlin","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Loh","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5599-5098","authenticated-orcid":false,"given":"David J","family":"Irwin","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"},{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey T","family":"McMillan","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"},{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Wolk","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"},{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Chen-Plotkin","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"},{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Weintraub","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania Perelman School of Medicine , 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