Drug Development.

Background: The Apolipoprotein E4 isoform (ApoE4), encoded by the APOE gene, stands out as the most influential genetic factor in late-onset Alzheimer's disease (LOAD). The ApoE4 isoform contributes to metabolic and neuropathological abnormalities during brain aging, with a strong correlation observed in APOE4-positive Alzheimer's disease cases between phosphorylated tau burden and amyloid deposition. Despite compelling evidence of APOE-mediated neuroinflammation influencing the progression of tau-mediated neurodegeneration, the molecular mechanisms underlying these phenomena remain largely unknown.

Method: Utilizing Tau-P301S mice crossed to APOE4-knockin mice expressing human APOE4 (TauP301S/APOE4), the investigation tested the impact of anti-mouse ApoE4 antibody, ADEL-Y04, on memory enhancement and tau pathology reduction.

Result: We developed ADEL-Y04, an anti-mouse ApoE4 antibody specifically recognizing human ApoE4. Administration of ADEL-Y04 in TauP301S/APOE4 mice demonstrated improvements in memory impairment. Synapse loss and pathological tau accumulation was also inhibited by ADEL-Y04 administration.

Conclusion: Our findings suggest the potential for improving APOE4-mediated tau pathology and memory impairment through the modulation of ApoE4. This provides avenues for intervention, indicating the possibility of ameliorating tau pathology and memory deficits by targeting APOE4.