A hypothesis explaining Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies overlap.

Lewy body-involving diseases (LBD) are commonly associated with Parkinson's disease (PD) featuring voluntary movement inhibition, due to dopaminergic neuron dysfunction in the substantia nigra. PD is clinically tracked through Lewy bodies (LB), composed of insoluble α-synuclein aggregates sequestered with organelles, particularly inside neurons. However, α-synuclein pathology also appears in incidental LBD, Parkinson's disease dementia, and dementia with LB (DLB). Incomplete explanations address how these clinical pathologies interrelate, LBD etiology variability, and frequently overlapping α-synuclein and Alzheimer's disease (AD) pathologies. We hypothesize that (1) chronic environmental insult exposure and (2) senescence(-like) neuron accumulation contribute toward initiating and sustaining LBD; individual cell vulnerability determines either cell reactivity, death, or senescence in response to environmental insults. We predicate that parkinsonian and other neurodegenerative symptoms over LBD progression involve (3) co-occurring AD pathologies, wherein dementia symptomology develops when synergistic glial senescence, tau hyperphosphorylation, and possible α-synuclein aggregation reach into regions involved in AD progression. HIGHLIGHTS: Senescence burden is predicted to explain α-synucleinopathy progression. Senescence and cell death are hypothesized to occur in α-synucleinopathies. Sub-apoptotic stress is proposed to induce senescence in α-synucleinopathies. Neuronal senescence likely first spreads α-synucleinopathies to new regions. Glial senescence likely underlies Parkinson's disease and Alzheimer's disease overlap.