genotype regulates pathology and disease progression in synucleinopathy.

Apolipoprotein E () 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. ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on knockout (A53T/EKO) or human 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 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, ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that ε4 exacerbates pathology, and suggest that ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.