Understanding the genetic imperfections of Lewy body dementia.

Lewy body dementia (LBD) is a clinically and pathologically complex neurodegenerative disease. Its etiology remains poorly understood and, as such, it is likely underdiagnosed in clinical practice. Clinically, LBD is defined by fluctuations in cognition, visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and motor dysfunction. The disease is pathologically defined by the presence of Lewy bodies in the brain, which are protein aggregates made up of misfolded α-synuclein; however, co-pathologies are often present and greatly complicate both symptom presentation and research interpretation. This heterogeneous pathology paired with overlapping clinical features of Alzheimer's disease and Parkinson's disease hinder diagnostic clarity. With no specific biological biomarkers currently identified, it is the hope that genetics can help with diagnosis and to clarify the pathomechanistic nature of this multifaceted disorder. Through rare familial studies, SNCA, the gene which encodes α-synuclein, was implicated in disease risk and development, underscoring its central role in α-synucleinopathies. Shortly after this discovery, a genome wide association study (GWAS) confirmed this risk, and identified two other major genes, APOE and GBA, to be associated with LBD. The APOE ε4 allele, which is a well-established risk factor for AD, is also associated with an increased risk for LBD. This common association demonstrates that APOE is implicated in a broader role in neurodegenerative disease pathogenesis. Meanwhile, GBA mutations, which are associated with lysosomal dysfunction and are also a known risk factor for PD, are linked to a more severe cognitive decline and earlier disease onset. However, even with these advances, our understanding of LBD's genetic architecture remains incomplete. Overcoming these limitations will require larger, more diverse study cohorts, comprehensive analyses, technological advances, and improved phenotyping upon clinical presentation of disease. Current clinical diagnostic strategies often struggle to capture the full spectrum of LBD symptoms and commonly lead to misdiagnosis/misclassification. By combining genetic data with improved phenotyping and the latest novel technologies, we can greatly improve our mechanistic understanding of LBD. These insights will not only improve diagnostic accuracy but will also lead to the development of disease modifying treatments specifically designed to best treat each individual patient.