APOE genotype regulates pathology and disease progression in synucleinopathy.

Apolipoprotein E (APOE) epsilon 4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of alpha-synuclein (alpha Syn), amyloid-beta (A beta), and tau pathologies. APOE epsilon 4 exacerbates brain A beta pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates alpha Syn pathology. In this study, we generated A53T alpha Syn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated alpha Syn compared to A53T/EKO and A53T/E3; detergent-insoluble alpha Syn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated alpha Syn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of alpha Syn spreading, striatal injection of alpha Syn preformed fibrils induced greater accumulation of alpha Syn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE epsilon 4/epsilon 4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates alpha Syn pathology independent of its established effects on A beta and tau, corroborate the finding that APOE epsilon 4 exacerbates pathology, and suggest that APOE epsilon 2 may protect against alpha Syn aggregation and neurodegeneration in synucleinopathies.