The Role of α-Synuclein Pathology in Dementia: Linking Lewy Bodies, Mitochondrial Dysfunction, and Neuroinflammation- A Current Scenario

Abstract

Lewy body dementias (LBD), which include dementia with Lewy bodies and Parkinson’s disease dementia, constitute a major group of neurodegenerative disorders characterised by abnormal α-synuclein aggregation. Over the past five years (2020–2025), there has been significant progress in understanding their molecular mechanisms, clinical variability, and overlap with Alzheimer’s disease (AD). A key aspect of their pathogenesis is the misfolding of α-synuclein into toxic oligomers, protofibrils, and fibrils that build up within neurons as Lewy bodies and Lewy neurites. These inclusions interfere with synaptic transmission, mitochondrial function, and proteostasis, while provoking neuroinflammatory responses that worsen neuronal loss. Genetic mutations in SNCA, PINK1, Parkin, and GBA highlight the role of compromised lysosomal and mitochondrial pathways in disease development. Co-existing proteinopathies, especially amyloid-β and tau deposits, are increasingly recognised in neuropathologically confirmed dementia cases, influencing disease progression and response to therapy. Neuroimaging and network analyses show large-scale cortical network breakdown that correlates with key symptoms such as cognitive fluctuation, visual hallucinations, and Parkinsonism. Soluble α-synuclein species, rather than mature inclusions, are now viewed as the main drivers of toxicity, with abnormal spreading of these strains across neural circuits resembling prion-like transmission. Advances in biomarker discovery—including α-synuclein seeding assays, CSF and plasma markers, and novel PET tracers—offer hope for earlier and more accurate diagnosis. Despite these advances, treatments that alter disease progression remain unavailable, with current management limited to symptom control. This review consolidates   recent   insights  into  Lewy body   formation, molecular     disease      mechanisms, clinicopathological relationships, and emerging therapies, highlighting the role of precise biomarker techniques in shaping dementia research and treatment.