APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid

The apolipoprotein E (APOE)epsilon 4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by driving amyloid-beta 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 alpha-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of alpha-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased alpha-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing alpha-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on alpha-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating alpha-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.