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To investigate how plaques, tangles, age and apolipoprotein E \u03b54 (APOE \u03b54) interact with co-pathologies in Alzheimer\u2019s disease, we analysed 522 participants \u226550 years of age with and without dementia from the Center for Neurodegenerative Disease Research (CNDR) autopsy program and 1340 participants in the National Alzheimer's Coordinating Center (NACC) database. Consensus criteria were applied for Alzheimer\u2019s disease using amyloid phase and Braak stage. Co-pathology was staged for CAA (neocortical, allocortical, and subcortical), LATE-NC (amygdala, hippocampal, and cortical), and Lewy bodies (brainstem, limbic, neocortical, and amygdala predominant). APOE genotype was determined for all CNDR participants. Ordinal logistic regression was performed to quantify the effect of independent variables on the odds of having a higher stage after checking the proportional odds assumption. We found that without dementia, increasing age associated with all pathologies including CAA (odds ratio 1.63, 95% confidence interval 1.38\u20131.94, P\u2009&amp;lt;\u20090.01), LATE-NC (1.48, 1.16\u20131.88, P\u2009&amp;lt;\u20090.01), and Lewy bodies (1.45, 1.15\u20131.83, P\u2009&amp;lt;\u20090.01), but APOE \u03b54 only associated with CAA (4.80, 2.16\u201310.68, P\u2009&amp;lt;\u20090.01). With dementia, increasing age associated with LATE-NC (1.30, 1.15\u20131.46, P\u2009&amp;lt;\u20090.01), while Lewy bodies associated with younger ages (0.90, 0.81\u20131.00, P\u2009=\u20090.04), and APOE \u03b54 only associated with CAA (2.36, 1.52\u20133.65, P\u2009&amp;lt;\u20090.01). A longer disease course only associated with LATE-NC (1.06, 1.01\u20131.11, P\u2009=\u20090.01). Dementia in the NACC cohort associated with the second and third stages of CAA (2.23, 1.50\u20133.30, P\u2009&amp;lt;\u20090.01), LATE-NC (5.24, 3.11\u20138.83, P\u2009&amp;lt;\u20090.01), and Lewy bodies (2.41, 1.51\u20133.84, P\u2009&amp;lt;\u20090.01). Pathologically, increased Braak stage associated with CAA (5.07, 2.77\u20139.28, P\u2009&amp;lt;\u20090.01), LATE-NC (5.54, 2.33\u201313.15, P\u2009&amp;lt;\u20090.01), and Lewy bodies (4.76, 2.07\u201310.95, P\u2009&amp;lt;\u20090.01). Increased amyloid phase associated with CAA (2.27, 1.07\u20134.80, P\u2009=\u20090.03) and Lewy bodies (6.09, 1.66\u201322.33, P\u2009=\u20090.01). In summary, we describe widespread distributions of CAA, LATE-NC and Lewy bodies that progressively accumulate alongside plaques and tangles in Alzheimer\u2019s disease dementia. CAA interacted with plaques and tangles especially in APOE \u03b54 positive individuals; LATE-NC associated with tangles later in the disease course; most Lewy bodies associated with moderate to severe plaques and tangles.<\/jats:p>","DOI":"10.1093\/brain\/awaa438","type":"journal-article","created":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T20:09:41Z","timestamp":1606594181000},"page":"953-962","source":"Crossref","is-referenced-by-count":211,"title":["The development and convergence of co-pathologies in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"144","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 Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon X","family":"Xie","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvannia, Philadelphia, PA, USA"},{"name":"Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EunRan","family":"Suh","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvannia, Philadelphia, PA, 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 Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Alfaro","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4459-0896","authenticated-orcid":false,"given":"Nicholas","family":"Loh","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4868-8479","authenticated-orcid":false,"given":"Matias","family":"Porras-Paniagua","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey J","family":"Nirschl","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Wolk","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia M -Y","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvannia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-1180","authenticated-orcid":false,"given":"Edward B","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Q","family":"Trojanowski","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 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