Understanding the genetic interplay between human ApoE4 and novel <i>App</i> ^NL‐F knock‐in in Alzheimer's Disease male mouse model

Combining ApoE4 and App^NL-F mutations produces distinct phenotypes, including hypoactivity, Aβ plaque burden, heightened neuroinflammation, and impaired glial function. Reduced Aβ plaques in E4NLF compared to NLF mice highlight species-specific differences in Aβ clearance, underscoring functional differences between mouse ApoE and human ApoE4 isoforms. These findings emphasize the limitations of mouse ApoE in accurately modeling human ApoE biology and reinforce the necessity of humanized models to investigate ApoE isoform-specific roles in AD.