LAUSR

APOE4 exacerbates α-synuclein pathology in a synucleinopathy mouse model, and APOE4 genotype associates with increased α-synuclein pathology in humans. APOE4 beyond amyloid Although several genetic risk factors for neurodegenerative disorders have been identified, often the mechanistic aspect is not clear. Now, Zhao et al. and Davis et al. investigated whether apolipoprotein E4 (APOE4) genotype, a major genetic risk factor for neurodegenerative diseases, affected α-synuclein pathology in mouse models and Parkinson’s disease (PD) patients. Zhao et al. generated a mouse model of α-synucleinopathy and showed that APOE4 exacerbated α-synuclein pathology in the absence of amyloid. Davis et al. used a mouse model of PD and analyzed cognition in patients with PD to demonstrate that APOE4 directly regulated α-synuclein pathology and was associated with faster cognitive decline. These results provide insight into the mechanisms linking APOE genotype to neurodegenerative disorders. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson’s disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased α-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing α-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on α-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.