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    2025 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

    Decoding APOE4 in Alzheimer's: Astrocyte Cholesterol and Oxysterol Pathways

    How do Alzheimer’s-linked gene variations impact harmful products of metabolism?

    Irundika Dias, Ph.D.
    Aston University
    Birmingham, United Kingdom



    Background

    The apolipoprotein E (APOE) gene makes ApoE protein, which is thought to help carry fats throughout the body. There are several APOE gene variations, including APOE-e2, APOE-e3 and APOE-e4. Possessing the APOE-e4 variation is thought to increase the risk of developing Alzheimer’s disease in some populations. However, it remains unclear how variations of APOE may contribute to dementia risk.

    Recent studies found that APOE-e4 may impact levels of molecules in the brain such as metabolites, which the body creates when breaking down nutrients into energy, lipids (fats) and harmful variations of cholesterol called oxysterols. It is not known how APOE-e4 may impact metabolites and oxysterols in the helper cells in the brain called astrocytes.

    Research Plan

    Dr. Irundika Dias and colleagues will study the impact of APOE gene variations on changes in metabolic pathways using a specialized type of stem cell called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the body, including astrocytes, and grown in laboratory dishes. 

    Moreover, they will leverage the data they generate from iPSCs in an advanced computer science technique called machine learning. This will help them predict and simulate metabolic network changes in response to APOE gene variations. They plan to validate these predictions with laboratory experiments.

    Finally, they will use astrocyte iPSCs to test a new drug that is currently in clinical trials, which can target and extract oxysterol. They will examine its effects on oxysterol and metabolic pathways in cells with different APOE variations.

    Impact

    Results from this study could shed new light on how genes and metabolism may contribute to risk of dementia. Their data could also help inform clinical trials of a new drug.

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