<scp>APOE4</scp> Exacerbates Alzheimer‐Like Pathologies and Cognitive Deficits Induced by Blood‐Derived Aβ in a Mouse Model

Apolipoprotein E4 (APOE4) is a significant risk for both familial Alzheimer's disease (AD) and sporadic AD with elusive mechanisms. Previous studies mainly focused on the role of APOE4 in familial AD, with less attention to sporadic AD. Our previous study demonstrated that blood cell-derived amyloid-β (Aβ) can enter the brain and induce AD-like pathologies, providing a novel animal model to study sporadic AD to a certain extent. The impacts of APOE4 on Alzheimer-like pathologies and cognitive deficits induced by blood-derived Aβ remain unknown. In the present study, we found that APOE4 prompted the entry of blood Aβ into the brain. APOE4 recipient mice showed impaired integrity of the blood-brain barrier and higher Aβ levels in the brain after transplantation of bone marrow cells from APP/PS1•APOE4 mice. In addition, we observed that the APOE4 recipient mice displayed aggravated tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits at the age of 12 months. Our study demonstrates that APOE4 is capable of facilitating the entry of blood-derived Aβ into the brain and enhancing the AD-like pathologies triggered by blood-derived Aβ. Our findings provide a possible way by which APOE4 elevates the risk of sporadic AD.