Neuropathology of Lewy body dementia: Lewy-related pathology, α-synuclein oligomers, and comorbid pathologies

Abstract Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer’s disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson’s disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer’s disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.