{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T10:54:09Z","timestamp":1780916049061,"version":"3.54.1"},"posted":{"date-parts":[[2024,9,4]]},"group-title":"Neurology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>In recent years, proposals have been advanced to redefine or reclassify Lewy body disorders by merging the long-established entities of Parkinson\u2019s disease (PD), Parkinson\u2019s disease dementia (PDD) and dementia with Lewy bodies (DLB). These proposals reject the International DLB Consortium classification system that has evolved over three decades of consensus collaborations between neurologists, neuropsychologists and neuropathologists. While the Consortium\u2019s \u201cone year rule\u201d for separating PD and DLB has been criticized as arbitrary, it has been a pragmatic and effective tool for splitting the continuum between the two entities. In addition to the decades of literature supporting the non-homogeneity of PD and DLB, it has become increasingly apparent that Lewy body disorders may fundamentally differ in their etiology. Most PD subjects, as well as most clinically-presenting DLB subjects, might best be classified as having a \u201cprimary synucleinopathy\u201d while most clinically-unidentified DLB subjects, who also have concurrent neuropathology-criteria AD (AD\/DLB), as well as those with neuropathological AD and amygdala-predominant LBD insufficient for a DLB diagnosis, may best be classified as having a \u201csecondary synucleinopathy. Importantly, the DLB Consortium recognized the importance of comorbid AD pathology by defining \u201cLow\u201d, \u201cIntermediate\u201d and \u201cHigh\u201d subdivisions of DLB based on the relative brain stages of both Lewy body and AD pathology. If the one-year rule for separating PD from DLB, and for then dividing DLB into subtypes based on the presence and severity of comorbid AD pathology, is effective, then the divided groups should statistically differ in important ways. In this study we used the comprehensive clinicopathological database of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) to empirically test this hypothesis. Furthermore, we used multivariable statistical models to test the hypothesis that comorbid AD neuropathology is a major predictor of the presence and severity of postmortem Lewy synucleinopathy. The results confirm the clinicopathological heterogeneity of Lewy body disorders as well as the profound influence of comorbid AD pathology.<\/jats:p>","DOI":"10.1101\/2024.08.30.24312864","type":"posted-content","created":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T21:15:25Z","timestamp":1725484525000},"source":"Crossref","is-referenced-by-count":6,"title":["Clinicopathological Heterogeneity of Lewy Body Diseases: The Profound Influence of Comorbid Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"given":"Thomas G.","family":"Beach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9527-2011","authenticated-orcid":false,"given":"Geidy E.","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika D.","family":"Driver-Dunckley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia I.","family":"Sue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly A.","family":"Shill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyamal H.","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Belden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Tremblay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parichita","family":"Choudhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Atri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles H.","family":"Adler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024090601050952000_2024.08.30.24312864v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25844"},{"key":"2024090601050952000_2024.08.30.24312864v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26424"},{"key":"2024090601050952000_2024.08.30.24312864v1.3","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-225111"},{"key":"2024090601050952000_2024.08.30.24312864v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00405-2"},{"key":"2024090601050952000_2024.08.30.24312864v1.5","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-240002"},{"key":"2024090601050952000_2024.08.30.24312864v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00404-0"},{"key":"2024090601050952000_2024.08.30.24312864v1.7","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.47.5.1113"},{"key":"2024090601050952000_2024.08.30.24312864v1.8","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.53.5.902"},{"key":"2024090601050952000_2024.08.30.24312864v1.9","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000187889.17253.b1"},{"key":"2024090601050952000_2024.08.30.24312864v1.10","doi-asserted-by":"publisher","DOI":"10.3233\/jad-2006-9s347"},{"key":"2024090601050952000_2024.08.30.24312864v1.11","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004058"},{"key":"2024090601050952000_2024.08.30.24312864v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(02)00006-0"},{"key":"2024090601050952000_2024.08.30.24312864v1.13","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.61.12.1915"},{"key":"2024090601050952000_2024.08.30.24312864v1.14","doi-asserted-by":"publisher","DOI":"10.1097\/01.jnen.0000225908.90052.07"},{"key":"2024090601050952000_2024.08.30.24312864v1.15","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-009-0538-8"},{"key":"2024090601050952000_2024.08.30.24312864v1.16","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-010-0664-3"},{"key":"2024090601050952000_2024.08.30.24312864v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25776"},{"key":"2024090601050952000_2024.08.30.24312864v1.18","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-150680"},{"key":"2024090601050952000_2024.08.30.24312864v1.19","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14698"},{"key":"2024090601050952000_2024.08.30.24312864v1.20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0217566"},{"key":"2024090601050952000_2024.08.30.24312864v1.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0231720"},{"key":"2024090601050952000_2024.08.30.24312864v1.22","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27867"},{"key":"2024090601050952000_2024.08.30.24312864v1.23","doi-asserted-by":"publisher","DOI":"10.3390\/bs11070094"},{"key":"2024090601050952000_2024.08.30.24312864v1.24","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-019-02129-2"},{"key":"2024090601050952000_2024.08.30.24312864v1.25","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14698"},{"key":"2024090601050952000_2024.08.30.24312864v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/S1353-8020(13)70017-8"},{"key":"2024090601050952000_2024.08.30.24312864v1.27","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-130175"},{"key":"2024090601050952000_2024.08.30.24312864v1.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0852-9"},{"key":"2024090601050952000_2024.08.30.24312864v1.29","doi-asserted-by":"publisher","DOI":"10.1159\/000375363"},{"key":"2024090601050952000_2024.08.30.24312864v1.30","doi-asserted-by":"publisher","DOI":"10.1017\/S1041610208008600"},{"key":"2024090601050952000_2024.08.30.24312864v1.31","doi-asserted-by":"publisher","DOI":"10.1017\/S1041610208008624"},{"key":"2024090601050952000_2024.08.30.24312864v1.32","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000256715.13907.d3"},{"key":"2024090601050952000_2024.08.30.24312864v1.33","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab402"},{"key":"2024090601050952000_2024.08.30.24312864v1.34","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26721"},{"key":"2024090601050952000_2024.08.30.24312864v1.35","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13357"},{"key":"2024090601050952000_2024.08.30.24312864v1.36","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1526-9"},{"key":"2024090601050952000_2024.08.30.24312864v1.37","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-02071-3"},{"key":"2024090601050952000_2024.08.30.24312864v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49402-x"},{"key":"2024090601050952000_2024.08.30.24312864v1.39","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-014-0073-2"},{"key":"2024090601050952000_2024.08.30.24312864v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.10.010"},{"key":"2024090601050952000_2024.08.30.24312864v1.41","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-00914-9"},{"key":"2024090601050952000_2024.08.30.24312864v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(02)00006-0"},{"key":"2024090601050952000_2024.08.30.24312864v1.43","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.61.12.1915"},{"key":"2024090601050952000_2024.08.30.24312864v1.44","doi-asserted-by":"publisher","DOI":"10.1097\/01.jnen.0000225908.90052.07"},{"key":"2024090601050952000_2024.08.30.24312864v1.45","doi-asserted-by":"publisher","DOI":"10.31083\/j.fbl2810255"},{"key":"2024090601050952000_2024.08.30.24312864v1.46","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-024-12314-3"},{"key":"2024090601050952000_2024.08.30.24312864v1.47","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012418-012936"},{"key":"2024090601050952000_2024.08.30.24312864v1.48","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlx099"},{"key":"2024090601050952000_2024.08.30.24312864v1.49","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00476-x"},{"key":"2024090601050952000_2024.08.30.24312864v1.50","doi-asserted-by":"publisher","DOI":"10.1101\/2023.08.14.23294081"},{"key":"2024090601050952000_2024.08.30.24312864v1.51","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/jnen\/nlv028","article-title":"Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database","volume":"75","year":"2016","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024090601050952000_2024.08.30.24312864v1.52","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nly049"},{"key":"2024090601050952000_2024.08.30.24312864v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(97)00294-2"},{"key":"2024090601050952000_2024.08.30.24312864v1.54","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20393"},{"key":"2024090601050952000_2024.08.30.24312864v1.55","doi-asserted-by":"publisher","DOI":"10.1007\/s004019900155"},{"key":"2024090601050952000_2024.08.30.24312864v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(94)90666-1"},{"key":"2024090601050952000_2024.08.30.24312864v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65722-7"},{"key":"2024090601050952000_2024.08.30.24312864v1.58","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.63.3.370"},{"key":"2024090601050952000_2024.08.30.24312864v1.59","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4244-07.2007"},{"key":"2024090601050952000_2024.08.30.24312864v1.60","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00702-018-1850-z","article-title":"Neuropathology and biochemistry of early onset familial Alzheimer\u2019s disease caused by presenilin-1 missense mutation Thr116Asn","volume":"125","year":"2018","journal-title":"J Neural Transm (Vienna)"},{"key":"2024090601050952000_2024.08.30.24312864v1.61","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2009.277"},{"key":"2024090601050952000_2024.08.30.24312864v1.62","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0197-4580(91)90007-7","article-title":"Gelsolin variant and beta-amyloid co-occur in a case of Alzheimer\u2019s with Lewy bodies","volume":"12","year":"1991","journal-title":"Neurobiol Aging"},{"key":"2024090601050952000_2024.08.30.24312864v1.63","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0029(20000701)50:1<10::AID-JEMT3>3.0.CO;2-6"},{"key":"2024090601050952000_2024.08.30.24312864v1.64","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-201213"},{"key":"2024090601050952000_2024.08.30.24312864v1.65","doi-asserted-by":"publisher","DOI":"10.1111\/neup.12189"},{"key":"2024090601050952000_2024.08.30.24312864v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(97)00057-2"},{"key":"2024090601050952000_2024.08.30.24312864v1.67","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0910-3"},{"issue":"10-12","key":"2024090601050952000_2024.08.30.24312864v1.68","first-page":"19","article-title":"Olfactory Dysfunction in Incidental Lewy Body Disease and Parkinson\u2019s Disease: An Update","volume":"19","year":"2022","journal-title":"Innov Clin Neurosci"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.08.30.24312864","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:10:46Z","timestamp":1768507846000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.08.30.24312864"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,4]]},"references-count":68,"URL":"https:\/\/doi.org\/10.1101\/2024.08.30.24312864","relation":{},"subject":[],"published":{"date-parts":[[2024,9,4]]},"subtype":"preprint"}}