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Dementia with Lewy bodies and Parkinson disease dementia — the same or different and is it important?

Nature Reviews Neurology volume 21, pages 394–403 (2025)Cite this article

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Abstract

Biological definitions of neurological diseases are now becoming a reality, although still in the research phase. This development will recategorize neurological diseases, providing objective diagnostics and the promise of therapeutics that target biological mechanisms — similar to the strategy that has proven successful in tumours and other conditions. In this Perspective article, we discuss this development for dementias with dominant Lewy pathology, as the availability of biological assays for this pathology has sparked new interest in a single disease diagnosis for all individuals positive for α-synuclein. On the basis of current evidence, we argue that an α-synuclein assay alone is unlikely to be a specific criterion for a spectrum of clinical syndromes with Lewy pathology or a definitive diagnostic marker for Lewy body dementia. We advocate that one biological assay will not reflect the complex spatiotemporal features of brain pathology. Diverse sequential mechanisms underpin the highly heterogeneous phenotypes and clinicopathological processes of Lewy body dementias. Disease modification, if possible, will be most effective when it targets the early underlying mechanisms, especially those leading to aggressive phenotypes.

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Fig. 1: Main neuropathologies in PDD and DLB and their biomarkers.
Fig. 2: Overview of clinical trajectories and findings across disease stages.

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Acknowledgements

G.M.H. discloses support for the research and publication of this work from a National Health and Medical Research Council senior leadership fellowship (1176607) and Y.F. is supported by the University of Sydney (BISA-FRP2022). Both authors have been supported in part by Aligning Science Across Parkinson’s (020529 and 020505) through the Michael J. Fox Foundation for Parkinson’s Research.

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  1. Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia

    YuHong Fu & Glenda M. Halliday

  2. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA

    YuHong Fu & Glenda M. Halliday

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Fu, Y., Halliday, G.M. Dementia with Lewy bodies and Parkinson disease dementia — the same or different and is it important?. Nat Rev Neurol 21, 394–403 (2025). https://doi.org/10.1038/s41582-025-01090-x

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