Elucidating the Protective Effects of APOE2 in the Presence of APOE4 Gene Allele in Animal Models

The APOE gene plays a crucial role in Alzheimer’s disease (AD), with three variations in humans: APOE2, APOE3 and APOE4. APOE4 is known to increase AD risk, while APOE2 offers protection compared with APOE3. But what happens when someone carries both APOE2 and APOE4? Some human studies suggest that APOE2/4 individuals face higher AD risk closer to that of APOE4 carriers, indicating that APOE4’s risk might outweigh APOE2’s protection, but the mechanism is unclear. To solve this biological puzzle, we turn to mouse models that provide a controlled environment for AD research. We found that APOE2/4 mice have lower levels of amyloid deposits, a hallmark of AD pathology, resembling levels in APOE2/3 mice and significantly lower than APOE3/4 mice. This contrasts with observations in humans. We speculate that APOE2 effectively slows amyloid buildup but may not halt other harmful processes that APOE4 triggers, such as tau accumulation, another AD hallmark. To explore this further, we developed two plans. First, we will continue studying these mice at different stages of amyloid buildup, analyzing how APOE2 and APOE4 affect amyloid, changes in lipids, inflammation and blood vessels. Second, we will introduce tau into the disease context, examining whether APOE2 can protect against tau’s damage and its impact on the brain’s immune system when APOE4 is present. We will employ advanced tools to investigate cellular and molecular aspects. Our goal is to gain a deeper understanding of how APOE2 and APOE4 influence AD. This knowledge could open doors to innovative treatments for more APOE-targeted AD management.