Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model.

Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimer's disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation-the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target.