APOE is the strongest genetic factor for late-onset Alzheimer's disease (AD). A specific conformation of the ApoE protein is present in amyloid-β (Aβ) containing plaques. Immunotherapy targeting ApoE in plaques reduces brain Aβ deposits in mice. Here, we evaluated the effects of the anti-human APOE antibody HAE-4 on amyloid plaques, Aβ-mediated tau seeding and spreading, and neuritic dystrophy in the 5XFAD amyloid mice expressing human ApoE4. HAE-4 reduced Aβ plaques as well as Aβ-driven tau seeding/spreading and neuritic dystrophy. These results demonstrate that HAE-4 may provide therapeutic effects on amyloid removal and Aβ driven downstream consequences such as tauopathy. ANN NEUROL 2022;91:847–852.