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The researchers found that APOE4 mice had more alpha-synuclein clusters than APOE3 or APOE2 mice. Further experiments showed that the clumps spread more widely in APOE4 mice as well. Together, the findings showed that APOE4 was directly involved in exacerbating signs of disease in the mice's brains.
"What really stood out is how much less affected the APOE2 mice were than the others," Davis said. "It actually may have a protective effect, and we are investigating this now. If we do find that APOE2 is protective, we might be able to use that information to design therapies to reduce the risk of dementia."
To study the effect of APOE variants on dementia in people with Parkinson's, the researchers analyzed publicly available data from three separate sets of people with Parkinson's. Two of the cohorts – one from the Parkinson's Progression Markers Initiative, with 251 patients, and the other from the Washington University Movement Disorders Center, with 170 patients – had been followed for several years. In both cohorts, cognitive skills declined faster in people with APOE4 than in those with APOE3 . People with two copies of APOE2 are very rare, but none of the three patients in the group with two copies of APOE2 showed any cognitive decline over the period of the study.
The third cohort, from the NeuroGenetics Research Consortium, was made up of 1,030 people with Parkinson's whose cognitive skills had been evaluated just once. The researchers found that people with APOE4 in the cohort had developed cognitive problems at a younger age and had more severe cognitive deficits at the time they were evaluated than people with APOE3 or APOE2.
"Parkinson's is the most common, but there are other, rarer diseases that also are caused by alpha-synuclein aggregation and also have very limited treatment options," Davis said. "Targeting APOE with therapeutics might be a way to change the course of such diseases."
APOE doesn't affect the overall risk of developing Parkinson's or how quickly movement symptoms worsen, so an APOE- targeted therapy might stave off dementia without doing anything for the other symptoms. Even so, it could be beneficial, Davis said.
"Once people with Parkinson's develop dementia, the financial and emotional costs to them and their families are just enormous," Davis said. "If we can reduce their risk of dementia, we could dramatically improve their quality of life." Source:
Washington University School of Medicine in St. Louis Journal reference:
Davis, A.A., et al. (2020) APOE genotype regulates pathology and disease progression in synucleinopathy. Science Translational Medicine . doi.org/10.1126/scitranslmed.aay3069 .
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