Genetic susceptibility and environmental factors in dementia with Lewy bodies: Converging pathogenic mechanisms

Dementia with Lewy bodies (DLB) is a heterogeneous neurodegenerative disorder characterized by cognitive decline, neuropsychiatric symptoms, and parkinsonism, with α-synuclein pathology as a central hallmark. Despite growing recognition of its clinical and biological complexity, the determinants underlying susceptibility to DLB remain incompletely defined and are frequently extrapolated from Parkinson's disease. This review integrates recent evidence on genetic susceptibility and environmental and metabolic factors implicated in DLB, with emphasis on the biological mechanisms that may link these domains. Genetic studies support a moderate heritability and identify key risk loci, including APOE, GBA, and SNCA, which delineate biologically distinct subgroups and influence lipid metabolism, lysosomal function, mitochondrial quality control, and neuroinflammatory responses, with additional modulation by epigenetic and sex-specific factors. Environmental exposures, including pesticides, air pollution, heavy metals, and endocrine-disrupting chemicals, are associated with α-synuclein aggregation, mitochondrial dysfunction, neuroinflammation, and disruption of the gut-brain axis, largely based on experimental and observational evidence. Rather than defining a unified pathogenic cascade, current data support a framework in which genetic background constrains biological vulnerability, while environmental and metabolic exposures modulate disease expression and heterogeneity in DLB.