<i>APOE</i> genotype regulates pathology and disease progression in synucleinopathy.

Abstract

Apolipoprotein E (<i>APOE</i>) ε4 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 α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. <i>APOE</i> ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether <i>APOE</i> genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on <i>Apoe</i> knockout (A53T/EKO) or human <i>APOE</i> knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other <i>APOE</i> genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn 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, <i>APOE</i> ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that <i>APOE</i> genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that <i>APOE</i> ε4 exacerbates pathology, and suggest that <i>APOE</i> ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.