Would ApoE Make a Better Therapeutic Target Than Aβ?HAE-4, an anti-ApoE antibody, mopped up plaques in a [humanized ApoE4] mouse model better than did the anti-amyloid antibody aducanumab. HAE-4 also cleared amyloid deposits from blood vessel walls, where aducanumab was unable to budge those, and it improved vascular function. Notably, HAE-4 did all this without causing microhemorrhages, hinting that this approach might be safer than using anti-amyloid antibodies.
It will be years, probably, before this is ready for a Phase 1 clinical trial; but it shows that ApoE 4 is gaining front and center research attention at the earliest and most important stages of understanding pathology and treatment options once the biomarkers of actual Alzheimer's disease are present..In young AD mice expressing humanized ApoE4, treatment with HAE-4 curbed amyloid deposition without interfering with lipidated, physiological ApoE...The data suggest that aducanumab triggers a more generalized, damaging inflammation, whereas HAE-4 more narrowly targets plaque removal, Holtzman said. HAE-4 might help bust up plaques and clean out blood vessels. In contrast, aducanumab reacts with all forms of aggregated Aβ, including diffuse plaques, kindling a broader immune response.... Supporting this, inflammation stayed high over two months of aducanumab treatment, but fell back to baseline in HAE-4-treated animals....HAE-4 treatment also strengthened the blood vessels’ tone. When the authors compared vessels with similar amyloid loads in the two treatment conditions, HAE-4 restored normal dilation and contraction, while aducanumab did not. This may be because de-lipidated ApoE damages blood vessels beyond its effect on amyloid, weakening the blood-brain barrier and causing leakage, Holtzman noted... By removing this toxic ApoE, HAE-4 improved vascular function.
The next step will be to test whether HAE-4 treatment affects learning and memory, Holtzman said. It also remains to be seen what the antibody does in mouse models that develop tau pathology in addition to amyloid.