Implications and opportunities regarding biological frameworks in overt and prodromal dementia with Lewy bodies

doi:10.1002/alz.70470

Review

. 2025 Jul;21(7):e70470.

doi: 10.1002/alz.70470.

Implications and opportunities regarding biological frameworks in overt and prodromal dementia with Lewy bodies

Jennifer G Goldman^{1

2}, Bradley F Boeve³, Douglas Galasko⁴, John-Paul Taylor⁵, James E Galvin⁶, James B Leverenz⁷, Frederic Blanc⁸, Glenda Halliday⁹, Kejal Kantarci¹⁰, Afina W Lemstra¹¹, Iracema Leroi¹², Simon J G Lewis¹³, Irene Litvan¹⁴, Helen Medsger¹⁵, John O'Brien¹⁶, Sonja W Scholz^{17

18}, Dag Aarsland^{19

20}, Manabu Ikeda²¹, Ian McKeith⁵, Angela Taylor²²

Affiliations

¹ Medical Division, JPG Enterprises LLC, Chicago, Illinois, USA.
² Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.
³ Department of Neurology and Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Department of Neurosciences, UC San Diego, La Jolla, California, USA.
⁵ Biomedical Research Building, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
⁶ Comprehensive Center for Brain Health, Department of Neurology, University of Miami Miller School of Medicine, Boca Raton, Florida, USA.
⁷ Department of Neurology, VA-Puget Sound Health Care System, University of Washington, Seattle, Washington, USA.
⁸ HdR, CM2R (Centre de Mémoire Ressources Et Recherche), Service de Gérontologie Mobile-Neuro-Psy-Recherche, GeRMINED Department, University Hospital of Strasbourg, and ICube Laboratory UMR-7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), IMIS Team, University of Strasbourg and CNRS, Strasbourg, France.
⁹ Parkinson's Disease Research Clinic, Macquarie University Faculty of Medicine and Health Sciences, Sydney, New South Wales, Australia.
¹⁰ Department of Radiology, Division of Neuroradiology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, the Netherlands.
¹² Global Brain Health Institute and School of Medicine, Trinity College Dublin, College Green, Dublin, Ireland.
¹³ Parkinson's Disease Research Clinic, Macquarie Medical School, Macquarie University, Sydney, New South Wales, Australia.
¹⁴ Department of Neurosciences, Parkinson and Other Movement Disorders Center, UC San Diego, La Jolla, California, USA.
¹⁵ North Bay Lewy Body Dementia Caregiver Support Group, Santa Rosa, California, USA.
¹⁶ Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK.
¹⁷ Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹⁸ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA.
¹⁹ Old Age Psychiatry Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁰ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
²¹ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
²² Lewy Body Dementia Association, Atlanta, Georgia, USA.

PMID: 40684248
PMCID: PMC12276075
DOI: 10.1002/alz.70470

Review

Implications and opportunities regarding biological frameworks in overt and prodromal dementia with Lewy bodies

Jennifer G Goldman et al. Alzheimers Dement. 2025 Jul.

. 2025 Jul;21(7):e70470.

doi: 10.1002/alz.70470.

Authors

Affiliations

¹ Medical Division, JPG Enterprises LLC, Chicago, Illinois, USA.
² Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.
³ Department of Neurology and Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Department of Neurosciences, UC San Diego, La Jolla, California, USA.
⁵ Biomedical Research Building, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
⁶ Comprehensive Center for Brain Health, Department of Neurology, University of Miami Miller School of Medicine, Boca Raton, Florida, USA.
⁷ Department of Neurology, VA-Puget Sound Health Care System, University of Washington, Seattle, Washington, USA.
⁸ HdR, CM2R (Centre de Mémoire Ressources Et Recherche), Service de Gérontologie Mobile-Neuro-Psy-Recherche, GeRMINED Department, University Hospital of Strasbourg, and ICube Laboratory UMR-7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), IMIS Team, University of Strasbourg and CNRS, Strasbourg, France.
⁹ Parkinson's Disease Research Clinic, Macquarie University Faculty of Medicine and Health Sciences, Sydney, New South Wales, Australia.
¹⁰ Department of Radiology, Division of Neuroradiology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, the Netherlands.
¹² Global Brain Health Institute and School of Medicine, Trinity College Dublin, College Green, Dublin, Ireland.
¹³ Parkinson's Disease Research Clinic, Macquarie Medical School, Macquarie University, Sydney, New South Wales, Australia.
¹⁴ Department of Neurosciences, Parkinson and Other Movement Disorders Center, UC San Diego, La Jolla, California, USA.
¹⁵ North Bay Lewy Body Dementia Caregiver Support Group, Santa Rosa, California, USA.
¹⁶ Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK.
¹⁷ Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹⁸ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA.
¹⁹ Old Age Psychiatry Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁰ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
²¹ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
²² Lewy Body Dementia Association, Atlanta, Georgia, USA.

PMID: 40684248
PMCID: PMC12276075
DOI: 10.1002/alz.70470

Abstract

Dementia with Lewy bodies (DLB), a progressive neurodegenerative disease with heterogeneous clinical presentations, greatly impacts patients, caregivers, and society. Despite its frequency, diagnosing and treating DLB remains challenging. Advances in in vivo biomarker assays reflecting underlying pathology are improving disease identification, diagnostic accuracy, and therapeutic development for biologically targeted, disease-modifying agents. Consequently, definitions of Alzheimer's disease and Parkinson's disease (PD) have shifted to focus on pathological changes occurring before clinical features, with proposed frameworks for detecting pathological amyloid and tau, neurodegeneration, and other markers (National Institute on Aging-Alzheimer's Association) and alpha-synucleinopathy and dopaminergic degeneration (Neuronal α-synuclein Disease Integrated Staging System, SynNeurGe). The biological frameworks, particularly those related to alpha-synuclein (α-synuclein), have sparked debate about unifying DLB and PD under a single pathobiologic disease. This paper discusses the implications of these biological frameworks for the DLB community, addressing topics regarding multiple pathologies and neurochemical systems, clinical heterogeneity, and functional impairment, and exploring the potential impact on clinical trials and care. HIGHLIGHTS: DLB is a progressive neurodegenerative disease with varied clinical presentations. Diagnosing and treating DLB remains challenging despite its frequency. Biological frameworks are reshaping Alzheimer's and Parkinson's definitions. In vivo biomarkers are improving DLB identification and diagnostic accuracy. Debate exists regarding unifying DLB and Parkinson's under one pathobiology.

Keywords: Lewy body dementia; Parkinson's disease dementia; Parkinsonism; amyloid; biomarkers; cognitive impairment; prodromal; synuclein.

© 2025 Lewy Body Dementia Association and The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

PubMed Disclaimer

Conflict of interest statement

Jennifer G. Goldman, MD, MS, has received grant/research support from Acadia, Michael J. Fox Foundation; honoraria from International Parkinson Disease and Movement Disorders Society, Parkinson's Foundation, and Parkinson Study Group; and consulting fees from EIP Pharma/CervoMed, GE Healthcare, KeifeRx, Lewy Body Dementia Association, InMuneBio, and SAGE. Dag Aarsland has received research support and/or honoraria from AstraZeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, GE Health, and Sanofi; and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, Eli Lilly, Cognetivity, Enterin, Acadia, EIP Pharma, Biogen, and Takeda. Frederic Blanc, MD, PhD was the national coordinator for France for the Eisai Delphia (E2027), Axovant Headway‐DLB, Roche Graduate, and EIP Pharma/CervoMed therapeutic trials; he has received honoraria from Roche, Eisai, and Biogen for oral presentations and from Eisai and Novo‐Nordisk for serving on a board; and grant support from National PHRC, Inter‐regional PHRC, Memento cohort, Vaincre Alzheimer, Alzheimer Research Foundation, and A2MCL. Bradley F. Boeve, MD, has received honoraria for SAB activities for the Tau Consortium, funded by the Rainwater Charitable Foundation; institutional research grant support for clinical trials from Alector, Transposon, Cognition Therapeutics, and EIP Pharma/CervoMed; and grant support from NIH (P30 AG062677, U01 NS100620, U19 AG071754), Lewy Body Dementia Association, American Brain Foundation, Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Little Family Foundation, the Ted Turner and Family Foundation. Douglas Galasko, MD, has received consulting fees from Eisai, Inc., GE Healthcare, and Artery Therapeutics and grant support from NIH U01NS100610, P30AG062429, and the Michael J. Fox Foundation. James E. Galvin, MD, MPH, receives grants from the US National Institutes of Health (NIH) (U01 AG084528, T32 AG081170, P30 AG059295, R01 AG078214, RF1 AG075901, R56 AG074889, R01 AG071514, R01 AG071643, R01 AG069765, R01 AG057681, R01 NS101483) and Lewy Body Dementia Association. He is the Chief Scientific Officer for Cognivue, Inc., and receives consulting fees. He is a consultant for Biogen, Beckman‐Coulter, BMS, Cognition Therapeutics, CervoMed, Eisai, Eli Lilly, GE Healthcare, Lobe Sciences, Lundbeck, and Roche. Glenda Halliday, PhD, has received grant/research support from Aligning Science Across Parkinson's, Defeat MSA Canada and Australia‐New Zealand, National Health and Medical Research Council of Australia, NIH, Michael J. Fox Foundation for Parkinson's Research, and Medical Research Future Fund of Australia Australian Parkinson's Mission; Royalties from Elsevier, Academic Press, and Oxford University Press; consulting fees from the Australian Government Department of Health and Aged Care and National Health and Medical Research Council; support for attending meetings from International Parkinson Disease and Movement Disorders Society, Australian Academy of Science, New Zealand Winter Brain Conference, Fight Parkinson's, and University of Tasmania; owns stock in Cochlear Pty Ltd and NIB Health Insurance. Manabu Ikeda, MD, PhD, has received grant support from Eisai, Otsuka, Sumitomo, and Takeda as the chairman of the department; grant from MHLW Program (Grant Number JPMH20CA2088), the Health Labour Sciences Research Grant (grant number:22GB1001), Innovation Platform for Society 5.0 at MEXT, Japan; honoraria from Eisai, Otsuka, Sumitomo, Lilly, Kowa; consulting fees from Otsuka, Ono, Lilly, Shionogi, K‐pharma, and Novo Nordisk. Kejal Kantarci, MD, MS, has received grant support from the NIH (P30 AG062677, U01 NS100620, U19 AG071754, and R01 NS124065) and ADDF and received research support from Eli Lilly. She consults for Biogen without personal compensation. Afina W. Lemstra, MD, PhD, has received institutional grant support from Hersenstichting, Gieske Strijbis Fonds, Stichting Dioraphte, Combinostics, and Michael J. Fox Foundation. Iracema Leroi, MD, has received grant support from the European Commission, the Health Research Board (Ireland), and the Irish Research Foundation, as well as honoraria from Boeringher, Roche, and Novo Nordisk. James B. Leverenz, MD, has received grant/research support from the NIH (NIA, National Institute of Neurological Disorders and Stroke), Lewy Body Dementia Association, Michael J. Fox Foundation, GE Healthcare, and Amprion. Simon Lewis, FRCP, MD, is supported by a National Health and Medical Research Council Leadership Fellowship (1195830) and has received research funding from the Michael J. Fox Foundation and the Australian Research Council, as well as honoraria from International Parkinson Disease and Movement Disorders Society, and the Parkinson's Foundation and consulting fees from Pharmaxis Ltd. Irene Litvan, MD, is supported by NIH grants U01NS112010, U01NS100610, R01AG063911, R61NS141119‐01; U01NS112010; P30AG062429‐06; and R25NS10893; the Michael J. Fox Foundation, Parkinson's Foundation, Lewy Body Dementia Association, CurePSP, Roche, AbbVie, Lundbeck, EIP‐Pharma, Alterity, Novartis, and UCB. She is a member of the scientific advisory board of the Rossy PSP Program at the University of Toronto, Aprinoia, and Amydis. She receives her salary from the University of California, San Diego, and is the Chief Editor of Frontiers in Neurology. Ian McKeith, F Med Sci, MD, FRC Psych, has no disclosures. Helen Medsger is a Special Government Employee in the US Department of Health & Human Services as a Member of the NAPA Advisory Council on Alzheimer's Research, Care, and Services. John O'Brien, DM, FMedSci, has acted as a consultant for TauRx, Novo Nordisk, Biogen, Roche, Lilly, GE Healthcare, and Okwin and received grants or academic in‐kind support from Avid/ Lilly, Merck, UCB, and Alliance Medical. John O'Brien is supported by the NIHR Cambridge Biomedical Research Centre and the Medical Research Council‐funded Dementias Platform UK. Sonja W. Scholz, MD, PhD, has received research support from Cerevel Therapeutics. SWS has been supported by the Intramural Research Program of the NINDS, NIH (Program No. ZIANS003154). Angela Taylor is employed by the Lewy Body Dementia Association. John‐Paul Taylor, MBBS(hons) MRCPsych, PhD, is supported by the Newcastle NIHR Biomedical Research Centre and has received speaker fees from GE Healthcare and Bial, consultant fees from EIP Pharma/CervoMed, and grant funding and consultancy from Sosei‐Heptares. Author disclosures are available in the Supporting Information

Figures

**FIGURE 1**
Diagnostic pathology for dementia with Lewy bodies.

**FIGURE 2**
Needs and future directions for applying biological frameworks to prodromal and overt dementia with Lewy bodies.

See this image and copyright information in PMC

References

1. Taylor JP, McKeith IG, Burn DJ, et al. New evidence on the management of Lewy body dementia. Lancet Neurol. 2020;19:157‐169. - PMC - PubMed
1. Goldman JG, Forsberg LK, Boeve BF, et al. Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials. Alzheimers Res Ther. 2020;12:137. - PMC - PubMed
1. Boeve BF, Dickson DW, Duda JE, et al. Arguing against the proposed definition changes of PD. Mov Disord. 2016;31:1619‐1622. - PMC - PubMed
1. Borghammer P, Okkels N, Weintraub D. Parkinson's disease and dementia with Lewy bodies: one and the same. J Parkinsons Dis. 2024;14:383‐397. - PMC - PubMed
1. McKeith IG, Ferman TJ, Thomas AJ, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94:743‐755. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

Lewy Body Dementia Association

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information

[1] Taylor JP, McKeith IG, Burn DJ, et al. New evidence on the management of Lewy body dementia. Lancet Neurol. 2020;19:157‐169. - PMC - PubMed

[2] Taylor JP, McKeith IG, Burn DJ, et al. New evidence on the management of Lewy body dementia. Lancet Neurol. 2020;19:157‐169. - PMC - PubMed

[3] Goldman JG, Forsberg LK, Boeve BF, et al. Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials. Alzheimers Res Ther. 2020;12:137. - PMC - PubMed

[4] Goldman JG, Forsberg LK, Boeve BF, et al. Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials. Alzheimers Res Ther. 2020;12:137. - PMC - PubMed

[5] Boeve BF, Dickson DW, Duda JE, et al. Arguing against the proposed definition changes of PD. Mov Disord. 2016;31:1619‐1622. - PMC - PubMed

[6] Boeve BF, Dickson DW, Duda JE, et al. Arguing against the proposed definition changes of PD. Mov Disord. 2016;31:1619‐1622. - PMC - PubMed

[7] Borghammer P, Okkels N, Weintraub D. Parkinson's disease and dementia with Lewy bodies: one and the same. J Parkinsons Dis. 2024;14:383‐397. - PMC - PubMed

[8] Borghammer P, Okkels N, Weintraub D. Parkinson's disease and dementia with Lewy bodies: one and the same. J Parkinsons Dis. 2024;14:383‐397. - PMC - PubMed

[9] McKeith IG, Ferman TJ, Thomas AJ, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94:743‐755. - PMC - PubMed

[10] McKeith IG, Ferman TJ, Thomas AJ, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94:743‐755. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Implications and opportunities regarding biological frameworks in overt and prodromal dementia with Lewy bodies

Affiliations

Implications and opportunities regarding biological frameworks in overt and prodromal dementia with Lewy bodies

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical