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2024 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

Identification of Modifiers of APOEe4 Toxicity

How do genetic variations associated with Alzheimer’s risk impact the function of immune cells in the brain?

Beth Stevens, Ph.D.
Boston Children's Hospital
Boston, MA - United States


The apolipoprotein E (APOE) gene provides instructions for making ApoE, a protein thought to help carry lipids (fats) throughout the body. The APOE gene has several variations, including APOE-e2, APOE-e3 and APOE-e4. Possessing the APOE-e4 variation is thought in some populations to impact an individual’s risk of developing Alzheimer’s. Current research focuses on how APOE interacts with other factors, like the immune system, to increase or decrease one’s risk of Alzheimer’s. Studies have shown that genetic variations of APOE may be associated with regulating the activity of brain cells called microglia. Microglia are the primary immune cells in the brain that serve as one of the first defenses against nerve cell damage. Microglia sense and help remove unwanted proteins from the brain, in part through a process called phagocytosis, during which the microglial cells engulf (or “swallow”) the unwanted proteins. Research has shown that microglia become impaired in Alzheimer’s and may lose their ability to clear dementia-related molecules properly.

Dr. Beth Stevens and colleagues have identified specific groups (subpopulations) of microglia in the brain with distinct gene activity, suggesting that they contribute to distinct functions. However, the associations between these microglial subpopulations, APOE gene variations, and Alzheimer’s are not well understood. 

Research Plan

Dr. Stevens and team received additional funding to build upon their 2022 APOE Biology in Alzheimer’s (ABA) grant to expand their work on APOE, microglia, and dementia risk. Their work has involved a specialized type of stem cell called induced pluripotent stem cells (iPSCs). These stem cells are created from adult human skin cells and can be “reprogrammed” to turn into any cell in the body, including microglia. The research team have been generating iPSC-derived microglia to take on the characteristics of different microglial subpopulations. They have been comparing microglia with APOE-e3 or APOE-e4 to determine how different forms of APOE may impact microglial activity, including lipid processing and phagocytosis. They have also been working to identify new genetic variations that interact with APOE and affect APOE-related brain functions.

With their supplemental grant, Dr. Stevens and the team will now expand their work to examine the role of APOE-e4 in microglia derived from cells of different men and women. Specifically, they will identify how various genes interact with APOE-e4 to alter microglial phagocytosis. The researchers will also examine how sex may play a role in these processes. Next, they will inject multiple microglial cells with the APOE gene variant APOE-e4 – cells derived from men and women – into living mouse brains. They will assess how cell-to-cell interactions and other factors (including sex hormones) affect APOE-e4’s role in brain health and dementia risk.  


Results from this study may shed new light on the interactions of sex, genetic variations, and microglia in Alzheimer’s. If successful, the findings may help identify novel targets for the prevention or treatment of Alzheimer’s in men and women, especially for those with genetic risk factors.

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