{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T08:27:28Z","timestamp":1769588848189,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,23]]},"group-title":"Genetic and Genomic Medicine","reference-count":84,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis. Given that a clinical diagnosis of Alzheimer\u2019s disease (AD) dementia often results from interplay between multiple underlying neuropathologic co-morbidities, previous genome-wide association studies (GWAS) of clinically diagnosed AD are restricted in their ability to translate genetic associations to potential targeted therapeutics. The current study seeks to address these limitations by presenting the largest GWAS to date (n=12,509) of neuropathologic hallmarks of AD and AD related dementias (ADRDs). We further performed a candidate-variant analysis using loci previously identified in GWAS of clinically diagnosed AD dementia and Parkinson\u2019s disease (PD). Finally, we conducted heritability and genetic correlation analyses using linkage disequilibrium (LD) score regression. We found broad genome-wide significant associations with\n                  <jats:italic>APOE<\/jats:italic>\n                  across AD and ADRDs but not cerebrovascular disease and vascular brain injury. We further identified 12 significant loci across 10 neuropathologic phenotypes, including 5 loci previously implicated in GWAS of clinical AD and ADRDs (variants on\n                  <jats:italic>BIN1, PICALM \/ EED, TMEM106B, GRN,<\/jats:italic>\n                  and\n                  <jats:italic>SNCA \/ SNCA-AS1<\/jats:italic>\n                  ) and 7 novel genome-wide associations (variants on\n                  <jats:italic>EPHA5, PSMG1, LINC00276, VAPA, LINC00290, DOCK4<\/jats:italic>\n                  and\n                  <jats:italic>SLAIN2 \/ SLC10A4<\/jats:italic>\n                  ). Our analysis of AD and PD clinical candidate variants demonstrated several that were associated with AD neuropathologic change and Lewy body disease, as well as substantial overlap with neuropathologic lesions other than the primary neuropathologic hallmarks of these diseases. Heritability analyses demonstrated heritability that was high for amyloid plaques (78%) relative to prior clinical AD heritability analyses, intermediate for TDP-43 inclusions (41%), and low for remaining AD and ADRD pathologic features. This study underscores the importance of investigating the underlying neuropathologic hallmarks of AD and ADRDs as a step toward refining the translation of genetic associations to biomarker interpretation and development of targeted therapeutics.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>Clinically diagnosed Alzheimer\u2019s disease (AD) dementia is commonly associated with its hallmark pathologic changes plus neuropathologic features of prevalent co-morbid diseases such as cerebrovascular disease, Lewy body disease, and more recently discovered abnormalities in protein called TDP-43 (collectively, AD related dementias; ADRD). As a result, previous studies that associated clinical diagnosis of AD with specific genes may not tell us the whole story. For this study, we gathered autopsy and genetic data to identify relationships between genes and dementia-associated brain changes. We found some relationships between these diseases and genes that had been previously identified as contributing to clinical dementia, as well as some new relationships that had been previously unknown. We also found that some genes that had previously been identified in relation to AD were associated with different dementia-associated brain lesions. Finally, we found that the various brain lesions differ in the proportion that can be attributed to genetic vs. environmental differences. These results support that the pathway to a diagnosis of dementia can be caused by multiple factors and are an important step in beginning to identify individually based dementia treatments.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.22.26344634","type":"posted-content","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T21:45:15Z","timestamp":1769204715000},"source":"Crossref","is-referenced-by-count":0,"title":["Genome wide association study meta-analysis of neuropathologic lesions of Alzheimer\u2019s disease and related dementias in a multi-site autopsy cohort"],"prefix":"10.64898","author":[{"given":"Brenna","family":"Cholerton","sequence":"first","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Godrich","sequence":"additional","affiliation":[{"name":"Dr. John T Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"Pasteris","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joe","family":"Rivero","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eden R.","family":"Martin","sequence":"additional","affiliation":[{"name":"Dr. John T Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL USA"},{"name":"John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian W.","family":"Kunkle","sequence":"additional","affiliation":[{"name":"Dr. John T Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL USA"},{"name":"John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam C.","family":"Naj","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kara L.","family":"Hamilton-Nelson","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan-Ping","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Logan","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory & Alzheimer\u2019s Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy J.","family":"Hohman","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory & Alzheimer\u2019s Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"name":"Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Mayeux","sequence":"additional","affiliation":[{"name":"Taub Institute on Alzheimer\u2019s Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA"},{"name":"Gertrude H. 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