The significance of alpha-synuclein, amyloid-beta and tau pathologies in Parkinson's disease progression and related dementia

Dementia is one of the milestones of advanced Parkinson s disease (PD), with its neuropathological substrate still being a matter of debate, particularly regarding its potential mechanistic implications. Objective: The aim of this study was to review the relative importance of Lewy-related a-synuclein and Alzheimer s tau and amyloid-? (A?) pathologies in disease progression and dementia in PD. Methods: We reviewed studies conducted at the Queen Square Brain Bank, Institute of Neurology, University College London, using large PD cohorts. Results: Cortical Lewy- and Alzheimer-type pathologies are associated with milestones of poorer prognosis and with non-tremor predominance, which have been, in turn, linked to dementia. The combination of these pathologies is the most robust neuropathological substrate of PD-related dementia, with cortical A? burden determining a faster progression to dementia. Conclusion: The shared relevance of these pathologies in PD progression and dementia is in line with experimental data suggesting synergism between a-synuclein, tau and A? and with studies testing these proteins as disease biomarkers, hence favouring the eventual testing of therapeutic strategies targeting these proteins in PD.