Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?

The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of alpha-synuclein, tau and amyloid-beta accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-beta scores were obtained, while tau and alpha-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-beta scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak alpha-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P < 0.05), with all the pathologies showing a significant positive correlation to each other (P < 0.05). A combination of pathologies [area under the receiver-operating characteristic curve = 0.95 (0.88-1.00); P < 0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-beta scores (r = -0.62; P = 0.043) and Braak tau stages (r = -0.52; P = 0.028), but not Lewy body scores (r = -0.25; P = 0.41) or Braak alpha-synuclein stages (r = -0.44; P = 0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n = 15). High cortical amyloid-beta score (P = 0.017) along with an older age at onset (P = 0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak alpha-synuclein stages. Cortical amyloid-beta and age at disease onset seem to determine the rate to dementia.