Advances in the Genetics and Pathology of Lewy Body Dementia

Abstract

Lewy body dementia is a heterogeneous disease that is underdiagnosed and poorly understood. Pathologically, Lewy body dementia is characterized by the accumulation of intraneuronal aggregates of misfolded α-synuclein, known as Lewy bodies and Lewy neurites. The genetic architecture of Lewy body dementia is complex, involving both common genetic variants with small risk effects and rare genetic variants with large effects. Alzheimer’s disease pathology frequently coexists with Lewy body pathology and influences the clinical presentation. A deeper understanding of the pathophysiological pathways, including mitochondrial dysfunction, lysosomal dysfunction, and neuroinflammation, can enhance disease modeling, and this knowledge will ultimately facilitate the development of therapeutic interventions. The biological relationships that Lewy body dementia shares with other neurodegenerative and psychiatric disorders may also prove crucial for the development of therapeutic strategies.