Alpha-synuclein is a major constituent of Lewy bodies, the fibrillar aggregates that form within neurons in Parkinson's disease and dementia with Lewy bodies (DLB). Recent biochemical data show that alpha-synuclein accumulates in Parkinson's disease in a detergent insoluble form. We now examine the relationship between detergent insoluble alpha-synuclein and the presence of Lewy bodies, clinical measures of dementia and biochemical parameters in a series of individuals with DLB. We found that Triton X-100 insoluble alpha-synuclein enriched nearly twofold in the temporal cortex of patients with DLB compared to age-matched controls. By contrast the total amount of alpha-synuclein protein was unchanged. Surprisingly, the degree of Triton X-100 insoluble alpha-synuclein did not correlate with either the duration of illness or the number of Lewy bodies counted using stereological methods from an adjacent block of tissue. However, the Triton X-100 soluble fraction of alpha-synuclein did correlate strongly with the expression of several heat shock proteins (HSPs) in DLB but not control cases, suggesting a coordinated HSP response in DLB neocortex.