Previous studies have described that APOE4 is the most common genetic risk factor for Alzheimer's disease (AD) that can also play a role in the accumulation of amyloid-beta and tau. Two recent articles, published simultaneously in the journal Science Translational Medicine, showed that APOE4 is directly linked to Lewy body dementia such as Parkinson’s disease. APOE4 has been found to directly regulate levels of alpha-synuclein, an unfolded protein that can accumulate and form fibrils in pathological conditions such as dementia with Lewy body and Parkinson’s disease.
In each of these studies, researchers tested the APOE2, APOE3 and APOE4 genes in different groups of mouse models of Lewy body dementia. In the first study, Davis and colleagues from Washington University, St. Louis, found that APOE4 mouse models had more alpha-synuclein than APOE3 or APOE2 mouse models, at 12 months of age. In addition, they showed that alpha-synuclein spread more rapidly through the brains of mouse models that have APOE4. Mouse models carrying the APOE2 gene survived longer and had improved motor performance compared to other APOE genotypes. In the second study, Zhao and colleagues from US Mayo Clinic, found that the mouse models expressing APOE4, but not APOE2 and APOE3, had increased alpha-synuclein pathology at 9 months of age. These APOE4 mouse models also had impaired behaviour, greater neuronal and synaptic loss.