APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do they have a later age of onset, milder clinical course, and less severe neuropathological findings than others with Alzheimer disease. The contrast is especially stark in comparison to the phenotype associated with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, as well as a more aggressive clinical course and notably more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Even one APOE ε2 allele improves phenotype, but it is uncertain if that is due to the replacement of a more toxic allele by APOE ε2, or if APOE ε2 has a protective, neuro-modulatory effect. Here, we demonstrate that brain exposure to APOE2 via a gene therapy approach which bathes the entire cortical mantle in the gene product after transduction of the ependyma, rapidly ameliorates established Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE4. This result suggests a promising protective effect of exogenous APOE2, revealing a cell non-autonomous effect of the protein on microglial activation. We also show that plaque associated microglia in the brain of patients who inherit APOE2 similarly have less microglial reactivity to plaques. These data raise the potential that an APOE2 therapeutic could be effective in Alzheimer disease even in individuals born with the risk ε4 allele. One Sentence Summary Introduction of ApoE2 using an AAV that transduces the ependymal cells of the ventricle causes a reduction in amyloid load and plaque associated synapse loss, and reduces neuroinflammation by modulating microglial responsiveness to plaques. ### Competing Interest Statement D.M.H. is on the scientific advisory board of C2N diagnostics and has equity. D.M.H. is on the scientific advisory board of Denali Therapeutics, Genentech, and Cajal Therapeutics and consults for Asteroid. B.L.D. serves an advisory role with equity in Latus Biosciences, Patch Bio, Voyager Therapeutics, Carbon Biosciences, Spirovant Biosciences, Resilience, Panorama Medicines, Saliogen and Homology Medicines. She has sponsored research from Novartis, Roche, Latus, Homology Medicines, Saliogen and Spirovant. B.T.H. is on the scientific advisory board of Latus Bio and has an equity interest. B.T.H.has a family member who works at Novartis, and owns stock in Novartis; he serves on the SAB of Dewpoint and owns stock. He serves on a scientific advisory board or is a consultant for AbbVie, Aprinoia Therapeutics, Arvinas, Avrobio, Axial, Biogen, BMS, Cure Alz Fund, Cell Signaling, Dewpoint, Eisai, Genentech, Ionis, Latus, Novartis, Sangamo, Sanofi, Seer, Takeda, the US Dept of Justice, Vigil, Voyager. M.S.K., L.T., Y.H.C., and P.T.R. are founders and shareholders in Latus Biosciences