APOE Consortium: Investigating Potential Cell Autonomous Neuroprotection of APOE Protective Variants

Alzheimer’s disease (AD) is the leading cause of dementia. Currently, 6.7 million Americans over 65 are living with AD, and the financial burden for health care, long-term care, and hospice services for this population and their families reached $345 billion in 2023. While current anti-amyloid antibodies such as Lecanemab and Donanemab have modestly delayed cognitive decline in patients with very mild dementia, more effective treatments are still needed. These antibodies target amyloid deposition, the initial pathology of AD, but do not directly address the tauopathy-driven synaptic and neuronal loss that leads to cognitive impairment. Previous studies, including those from our research team, have highlighted the critical role of microglial activation in influencing tau-mediated neurodegeneration. Recently, a case report identified a homozygous carrier of the APOE3 R136S variant (referred to as APOE3ch) with an autosomal dominant AD (ADAD) mutation PSEN1 E280A, who experienced a nearly 25-year delay in the progression from amyloid pathology to amyloid-induced tauopathy. Our research group, together with Cure Alzheimer’s Fund, developed a humanized APOE3ch mouse model and replicated the protective phenotype observed in this case. We found that the APOE3ch variant significantly reduced amyloid-induced tau seeding and spreading in vivo. Moreover, APOE3ch improved microglial responses to various AD-related pathologies, particularly to tau aggregates. The APOE3ch mutation decreased lipoprotein receptor binding but enhanced receptor binding to tau fibrils, improving microglial phagocytosis and degradation of tau aggregates. Another study also reported a protective effect of introducing the R136S mutation into an APOE4 background in a tauopathy model. These findings suggest for the first time that APOE3ch may influence microglial function in a way that is beneficial for reducing tau pathology and tau-mediated neurodegeneration. To explore this potential, we will investigate the effects of microglia expressing different APOE protective variants, including APOE3ch, using a newly developed microglial replacement approach. We will create a library of microglia-like cells expressing various APOE variants – APOE2, APOE3, APOE4, APOE3ch, and APOE4^R251G – and transplant these cells into an amyloid model and assess their effects on amyloid-induced tau seeding and spreading.  We will also use a tauopathy model, the P301S:APOE4 mouse, to assess the impact of APOE-expressing microglia-like cells on tauopathy and tau-mediated neurodegeneration. Additionally, we will conduct experiments in cells to explore the underlying cellular mechanisms. These studies will provide valuable insights into the potential of APOE-based cell therapies and other therapeutic strategies focusing on microglia-like cells to treat AD and other tauopathies.