APOE and scrapie: To control for these variables we used APOE targeted replacement (APOE-TR) mice, where both murine Apoe alleles are replaced by human APOE alleles [110], and infected them with 22L mouse adapted scrapie strain, which is an established and reliable laboratory model of prion disease featuring limited variability in disease latency and neuropathological metrics [8, 9, 77, 93].