{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:21:16Z","timestamp":1782930076128,"version":"3.54.5"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE \u03b54 genotype, co-pathology including concomitant Alzheimer\u2019s disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear.<\/jats:p>\n                  <jats:p>To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinson\u2019s disease, Parkinson\u2019s disease dementia and dementia with Lewy bodies, and controls, integrating APOE genotype, clinical data and assessment of ischaemic pathology alongside large-scale digital pathology quantification. We established an image analysis pipeline utilising machine learning to enable automated, standardised measurement of \u03b1-synuclein, amyloid-\u03b2, and phosphorylated tau burden across multiple brain regions.<\/jats:p>\n                  <jats:p>Quantitative pathology strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE \u03b53 and \u03b54 carriers showed distinct dementia risk profiles. APOE \u03b53 carriers developed dementia at lower quantitative \u03b1-synuclein and amyloid-\u03b2 thresholds than \u03b54 carriers, although overall dementia risk was dominated by \u03b54 genotype, consistent with \u03b54 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in \u03b53 carriers with low Lewy and Alzheimer\u2019s proteinopathy burden, while male sex further modulated dementia risk for this subgroup. The Subtype and Stage Inference (SuStaIn) algorithm identified four trajectories of Lewy pathology progression. Two corresponded to recognised patterns, one brainstem-first and the other with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement, one with early cingulate cortex involvement together with brainstem pathology and the other starting in neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-\u03b2, phosphorylated tau, or \u03b1-synuclein, and showed that Lewy subtypes follow two propagation trajectories in opposite directions.<\/jats:p>\n                  <jats:p>Together, these findings demonstrate that integrating quantitative pathology with genotype and clinical data reveals distinct yet overlapping pathways to dementia in LBD, refining disease progression models and providing a basis for genotype- and pathology-informed patient stratification in therapeutic trials.<\/jats:p>","DOI":"10.1093\/brain\/awag114","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T12:45:30Z","timestamp":1774529130000},"source":"Crossref","is-referenced-by-count":1,"title":["Quantitative pathology and\n                    <i>APOE<\/i>\n                    genotype reveal dementia risk and progression in Lewy body disease"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2407-4517","authenticated-orcid":false,"given":"Hemanth R","family":"Nelvagal","sequence":"first","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase , MD 20815 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8383-5717","authenticated-orcid":false,"given":"Nancy","family":"Chiraki","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase , MD 20815 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3277-7813","authenticated-orcid":false,"given":"Toby","family":"Curless","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase , MD 20815 ,","place":["USA"]},{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4360-2680","authenticated-orcid":false,"given":"Patrick W","family":"Cullinane","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]},{"name":"Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Movement Disorders Centre, UCL Queen Square Institute of Neurology , London, WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Rockliffe","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samarth","family":"Pimparkar","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Ollerenshaw","sequence":"additional","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isha","family":"Elahi","sequence":"additional","affiliation":[{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9821-0342","authenticated-orcid":false,"given":"Sebastian","family":"Brandner","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London, WC1N 3BG ,","place":["UK"]},{"name":"Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust , London, NW1 2PB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-5603","authenticated-orcid":false,"given":"Lesley","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8117-742X","authenticated-orcid":false,"given":"Raquel","family":"Real","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase , MD 20815 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Fernandez","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]},{"name":"Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology , London, WC1N 3BG ,","place":["UK"]},{"name":"Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University London , London, E1 4NS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6195-6995","authenticated-orcid":false,"given":"Thomas T","family":"Warner","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]},{"name":"Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Movement Disorders Centre, UCL Queen Square Institute of Neurology , London, WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5473-3774","authenticated-orcid":false,"given":"Huw R","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase , MD 20815 ,","place":["USA"]},{"name":"Queen Square Movement Disorders Centre, UCL Queen Square Institute of Neurology , London, WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yau Mun","family":"Lim","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase , MD 20815 ,","place":["USA"]},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London, WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zane","family":"Jaunmuktane","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London, WC1N 3BG ,","place":["UK"]},{"name":"Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology , London, WC1N 1PJ ,","place":["UK"]},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase , MD 20815 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