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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Dementia with Lewy Bodies (DLB) is the most common neurodegenerative dementia after Alzheimer\u2019s disease (AD), but it remains challenging to diagnose due to overlapping symptoms and mixed pathologies. This pilot study tested whether DLB has different metabolic blood proteomic profiles compared to AD and controls. Serum was analysed from people with DLB (n = 20), a group with AD (either with Alzheimer\u2019s disease dementia or Mild Cognitive Impairment with a positive amyloid positron emission tomography scan (MCI+\/AD) (n = 15), and similarly aged controls (n = 15) using the Olink Metabolism panel encompassing 92 proteins. Six proteins (PILRB, LRIG1, NECTIN2, TINAGL1, SSC4D, and FKBP4) were significantly different in DLB compared with the controls, and one protein (SERPINB8) was differentially expressed when compared with MCI+\/AD. Receiver operating characteristic curves for biologically relevant proteins that have previously established roles in neurodegenerative and cognitive properties showed that RNASE3 levels could differentiate DLB from MCI+\/AD (area under the curve (AUC) = 0.717, sensitivity = 0.850, and specificity = 0.600). A multimarker model incorporating RNASE3 with phosphorylated tau 217 (pTau217) and polygenic risk scores for LBD achieved improved accuracy in discriminating DLB from MCI+\/AD (AUC = 0.963, sensitivity = 1.000, and specificity = 0.900). Pathway analyses revealed dysregulation in cortisol signalling, inflammation resolution, and ErbB4-mediated neuroplasticity, which point towards peripheral protein alterations related to the adaptation to stress, immune regulation, and synaptic integrity in DLB. The present exploratory study highlights potential pathophysiological mechanisms implicated in DLB, suggesting that a multimodal biomarker panel may perform better compared to single proteins. Considering the small sample sizes, the findings will need to be replicated in larger cohorts.<\/jats:p>","DOI":"10.3390\/ijms27156875","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:02:01Z","timestamp":1785510121000},"page":"6875","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolism Pathway Blood Proteomic Differences in Lewy Body Dementia Compared to Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Ariana N.","family":"Pritha","sequence":"first","affiliation":[{"name":"Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas","family":"Chouliaras","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK"},{"name":"Specialist Dementia and Frailty Service, Essex Partnership University NHS Foundation Trust, St Margaret\u2019s Hospital, Epping CM16 6TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Swann","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Prats-Sedano","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"McKeever","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Heslegrave","sequence":"additional","affiliation":[{"name":"Dementia Research Institute, University College London, London NW1 3BT, UK"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Ashton","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, University of Gothenburg, 405 30 Gothenburg, Sweden"},{"name":"Banner Alzheimer\u2019s Institute, University of Arizona, Phoenix, AZ 85004, USA"},{"name":"Banner Sun Health Research Institute, Sun City, AZ 85351, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Dementia Research Institute, University College London, London NW1 3BT, UK"},{"name":"Department of Psychiatry and Neurochemistry, University of Gothenburg, 405 30 Gothenburg, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 413 45 M\u00f6lndal, Sweden"},{"name":"Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China"},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6347-3986","authenticated-orcid":false,"given":"Li","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Malpetti","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK"},{"name":"Dementia Research Institute, Cambridge CB2 0AH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Rowe","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK"},{"name":"Dementia Research Institute, Cambridge CB2 0AH, UK"},{"name":"UK Dementia Research Institute at Cambridge, University of Cambridge, Cambridge CB2 0SP, UK"},{"name":"Medical Research Council Cognition and Brain Sciences Unit, Cambridge CB2 7EF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0837-5080","authenticated-orcid":false,"given":"John T.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Medical Research Council Cognition and Brain Sciences Unit, Cambridge CB2 7EF, 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