Research Advances: Study Reveals Pathology and Genetic Associations with Dementia in Parkinson’s

Parkinson’s disease (PD) was originally described as "the shaking palsy that spared the intellect." But research has revealed that the opposite is actually true. Nearly 80 percent of older adults diagnosed with Parkinson’s disease are likely to progress to dementia within 15 years of diagnosis. New research indicates that the severity of Lewy body pathology in the cortex at autopsy and presence of the APOE4 gene variant were each associated with progression to dementia in PD.

In a collaboration of researchers at the University of Pennsylvania and University of Washington Udall Centers of Excellence for Parkinson’s Disease Research (David J. Irwin, MD, lead author), 140 individuals with a clinical diagnosis of Parkinson’s disease and brain autopsy were studied. Those who were diagnosed with dementia with Lewy bodies or who developed dementia within 2 years of PD motor symptom onset were excluded from the study.

Sixty-five percent of those studied had developed dementia prior to death, with a median onset of dementia eight years after motor symptom onset. Forty-five percent of those with dementia were carriers of the APOE4 genetic variation, a genetic variation previously linked primarily to Alzheimer’s disease (AD), compared to only nine percent of those who did not progress to dementia. Importantly, this association of the AD genetic risk factor was independent of AD changes in the brain, suggesting this risk factor is driving dementia in Parkinson’s through other pathways.

Thirty-eight percent of those with dementia were found to have co-existing AD upon autopsy. Older age at onset of motor symptoms was also associated with higher levels of co-existing AD. The presence of Alzheimer’s pathology was associated with a shorter progression to dementia in PD. Interestingly, nine percent of those with PD and no dementia had high levels of AD changes in the brain.

When the investigators analyzed the factors that were most strongly linked to the dementia they found that age, severity of the typical PD pathologic changes (Lewy bodies), and the APOE4 gene best predicted the presence of dementia during life.

Dr. James Leverenz, co-author of the paper and chair of LBDA’s Scientific Advisory Council, commented that the results are significant for several reasons. “While the data clearly dispel the commonly held belief that dementia in Parkinson’s disease is just due to co-existent Alzheimer’s disease, there is a sizeable portion of these patients that do have significant Alzheimer’s disease brain changes, in addition to the Parkinson’s disease changes (Lewy bodies). This has important ramifications for future treatments, in that some Parkinson’s patients with dementia may require additional treatment with Alzheimer’s disease-specific drugs,” he said

Leverenz also noted that the data raises some important new questions, such as “Why does carrying the APOE4 gene variation increase the risk of dementia in PD?” and concluded, “There is much more work to be done to understand dementia in PD, but this is an important step in clarifying the processes that underlie this common and devastating complication of PD.”