LRRK2 and GBA1 in Lewy body diseases: neuropathological subtypes at opposite ends of a spectrum?

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Lewy body diseases (LBDs), including Parkinson’s disease (PD), are defined by the presence of pathological intraneuronal α-synuclein aggregates but exhibit considerable heterogeneity in clinical course, neuropathology, and underlying mechanisms. This review summarizes neuropathological findings in PD associated with pathogenic variants in GBA1 and LRRK2 – the two most common genetic risk factors for PD – and highlights how these genetic forms represent neuropathological subtypes at opposite ends of a spectrum. GBA1-associated PD typically shows widespread Lewy pathology with cortical involvement and relatively limited Alzheimer-type co-pathology, while LRRK2-associated PD may occur with or without Lewy bodies and displays variability in tau and TDP-43 aggregates. We also examine how these genetic forms may serve as models for subtypes within idiopathic PD, including the potential existence of Lewy body-negative idiopathic PD. We propose a conceptual framework in which idiopathic PD encompasses GBA1-like and LRRK2-like subtypes, as well as intermediate forms with mixed pathologies. This perspective supports a shift toward biomarker-informed, mechanism-based classification of PD, beyond genetic labels alone, that may ultimately enable broader application of targeted therapeutic strategies.

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