{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:15:49Z","timestamp":1787008549704,"version":"build-2736575974"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Histopathological assessment has served as the gold standard for diagnosing Alzheimer\u2019s disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD.<\/jats:p>\n                  <jats:p>This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid \u03b2 (A\u03b2) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis.<\/jats:p>\n                  <jats:p>Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR\u2009=\u20091.20, 95% CI 1.14-1.26, P\u2009=\u20091.32\u2009\u00d7\u200910\u221211), CR1 (rs4844610, OR\u2009=\u20091.24, 95% CI\u2009=\u20091.16-1.32, P\u2009=\u20094.21\u2009\u00d7\u200910\u221210), APOE (rs429358, OR\u2009=\u20094.01, 95% CI\u2009=\u20093.66-4.38, P\u2009=\u20094.54\u2009\u00d7\u200910\u2212201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR\u2009=\u20091.18, 95% CI\u2009=\u20091.12-1.25, P\u2009=\u20091.47\u2009\u00d7\u200910\u22128). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased A\u03b2 burden and AD case status (PFDR &amp;lt; 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P\u2009&amp;lt;\u20096.54\u2009\u00d7\u200910\u22128) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P\u2009&amp;lt;\u20091.32\u2009\u00d7\u200910\u22127).<\/jats:p>\n                  <jats:p>Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology.<\/jats:p>\n                  <jats:p>Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem A\u03b2 measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with A\u03b2 burden.<\/jats:p>","DOI":"10.1093\/brain\/awag216","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T16:18:32Z","timestamp":1782231512000},"source":"Crossref","is-referenced-by-count":1,"title":["Combining post-mortem and neuroimaging measures of brain amyloidosis to accelerate genomic discovery"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6139-3168","authenticated-orcid":false,"given":"Ting-Chen","family":"Wang","sequence":"first","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt Health , Nashville, TN, 37203 ,","place":["USA"]},{"name":"Vanderbilt Genetics Institute, Vanderbilt Health , Nashville, TN, 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8638-0785","authenticated-orcid":false,"given":"Derek B","family":"Archer","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt Health , Nashville, TN, 37203 ,","place":["USA"]},{"name":"Vanderbilt Genetics Institute, Vanderbilt Health , Nashville, TN, 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University , St. Louis, MO, 63110 ,","place":["USA"]},{"name":"NeuroGenomics and Informatics, Washington University , St. Louis, MO, 63108 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9231-7093","authenticated-orcid":false,"given":"Yiyang","family":"Wu","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt Health , Nashville, TN, 37203 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Mormino","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University , Stanford, CA, 94305 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5356-5537","authenticated-orcid":false,"given":"Rachel F","family":"Buckley","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 ,","place":["USA"]},{"name":"Center for Alzheimer Research and Treatment, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA, 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie J","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]},{"name":"Department of Neurology, The New York Presbyterian Hospital , New York, NY, 10032 ,","place":["USA"]},{"name":"Taub Institute for Research on Alzheimer\u2019s Disease and The Aging Brain, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J","family":"Saykin","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences, Center for Neuroimaging, School of Medicine, Indiana University , Indianapolis, IN, 46202 ,","place":["USA"]},{"name":"Department of Medical and Molecular Genetics, School of Medicine, Indiana University , Indianapolis, IN, 46202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L","family":"De Jager","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]},{"name":"Department of Neurology, The New York Presbyterian Hospital , New York, NY, 10032 ,","place":["USA"]},{"name":"Taub Institute for Research on Alzheimer\u2019s Disease and The Aging Brain, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]},{"name":"Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A","family":"Schneider","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center , Chicago, IL, 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-554X","authenticated-orcid":false,"given":"David 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10032 ,","place":["USA"]},{"name":"The Institute for Genomic Medicine, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Mayeux","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]},{"name":"Department of Neurology, The New York Presbyterian Hospital , New York, NY, 10032 ,","place":["USA"]},{"name":"Taub Institute for Research on Alzheimer\u2019s Disease and The Aging Brain, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]},{"name":"The Institute for Genomic Medicine, Columbia University Medical Center , New York, NY, 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian W","family":"Kunkle","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, University of Miami School of Medicine , Miami, FL, 33136 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9729-6519","authenticated-orcid":false,"given":"William S","family":"Bush","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University , Cleveland, OH, 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Dirk Keene","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington , Seattle, WA, 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[{"name":"Department of Neurology, Chobanian and Avedisian School of Medicine, Boston University School of Medicine , Boston, MA, 02118 ,","place":["USA"]},{"name":"Glenn Biggs Institute for Alzheimer\u2019s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio , San Antonio, TX, 78229 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reisa A","family":"Sperling","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, MA, 02114 ,","place":["USA"]},{"name":"Center for Alzheimer Research and Treatment, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA, 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4286-0589","authenticated-orcid":false,"given":"Prashanthi","family":"Vemuri","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic-Minnesota , Rochester, MN, 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6591-8734","authenticated-orcid":false,"given":"Vijay K","family":"Ramanan","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic-Minnesota , Rochester, MN, 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Ilyas Kamboh","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Epidemiology and Psychiatry, University of Pittsburgh , Pittsburgh, PA, 15261 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-3496","authenticated-orcid":false,"given":"Theresa M","family":"Harrison","sequence":"additional","affiliation":[{"name":"Helen Wills Neuroscience Institute, University of California , Berkeley, Berkeley, CA, 94720 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4458-113X","authenticated-orcid":false,"given":"William J","family":"Jagust","sequence":"additional","affiliation":[{"name":"Helen Wills Neuroscience Institute, University of California , Berkeley, Berkeley, CA, 94720 ,","place":["USA"]},{"name":"Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory , Berkeley, CA, 94720 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4355-7082","authenticated-orcid":false,"given":"Simon M","family":"Laws","sequence":"additional","affiliation":[{"name":"Centre for Precision Health, Edith Cowan University , Joondalup, WA, 6027 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard D","family":"Schellenberg","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Huentelman","sequence":"additional","affiliation":[{"name":"Neurogenomics Division, Translational Genomics Research Institute , Phoenix, AZ, 85004 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Hamilton-Nelson","sequence":"additional","affiliation":[{"name":"John P. 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Hussman Institute for Human Genomics, University of Miami School of Medicine , Miami, FL, 33136 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M","family":"Goate","sequence":"additional","affiliation":[{"name":"Ronald M Loeb Center for Alzheimer\u2019s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY, 10029 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L","family":"Haines","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University , Cleveland, OH, 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Montine","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University , Stanford, CA, 94305 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Beecham","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science, Wake Forest University School of Medicine , Winston-Salem, NC, 27157 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1346-1872","authenticated-orcid":false,"given":"Jennifer E","family":"Below","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt Health , Nashville, TN, 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5261-689X","authenticated-orcid":false,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University , St. Louis, MO, 63110 ,","place":["USA"]},{"name":"NeuroGenomics and Informatics, Washington University , St. Louis, MO, 63108 ,","place":["USA"]},{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University , St. Louis, MO, 63108 ,","place":["USA"]},{"name":"Hope Center for Neurologic Diseases, Washington University , St. Louis, MO, 63110 ,","place":["USA"]},{"name":"Department of Genetics, Washington University School of Medicine , St. Louis, MO, 63110 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-7014","authenticated-orcid":false,"given":"Timothy J","family":"Hohman","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt Health , Nashville, TN, 37203 ,","place":["USA"]},{"name":"Vanderbilt Genetics Institute, Vanderbilt Health , Nashville, TN, 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9782-9944","authenticated-orcid":false,"given":"Logan","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt Health , Nashville, TN, 37203 ,","place":["USA"]},{"name":"Vanderbilt Genetics Institute, Vanderbilt Health , Nashville, TN, 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,23]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag216\/68585215\/awag216.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag216\/68585215\/awag216.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T16:18:32Z","timestamp":1782231512000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag216\/8714025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag216","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]},"article-number":"awag216"}}