Dementia in Parkinson's disease (PD) is a frequent complication that often limits the efficacy of pharmacotherapy and may decrease survival. We propose that the majority of demented patients have Alzheimer's disease (AD) and dementia will be associated with the risk factors for the development of Alzheimer's disease (AD). Dementia in the remaining patients is a late effect of PD and may be due to increased exposure or a critical period of exposure to the risk factors responsible for PD. Using a case-control approach, we will collect genetic and environmental risk factor information in 150 demented PD patients, 150 nondemented PD patients and 300 healthy elderly patients, all previously identified and examined neurologically and neuropsychologically. Reliable interviews for putative environmental risk factors for both PD and dementia in PD will be developed. All patients will have their blood screened for mutations in the coding and the promoter regions of the amyloid precursor protein (APP) gene and for low level mosaicism for trisomy 21. A cell bank will be established for future investigations. A reliable family history interview will be completed in all participants for ascertainment of AD and PD in first-degree relatives of PD patients and controls. Familial aggregation of AD and PD will be assessed by comparing cumulative incidence of AD and PD in first-degree relatives of PD patients with and without dementia, with and without APP gene mutations and with onset of motor manifestations <65 and >65. Potential gene-environment interactions will be explored by comparing PD patients with and without a family history of AD and PD, and the effects of environmental factors on the development of dementia. Statistical methods will be used to develop models to predict the development of dementia based on the significant risk factors from the preliminary analysis. Cumulative incidence of AD and PD in relatives will be examined with life table methods and rate ratios will be calculated using Cox proportional hazards modeling.
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