Alzheimer’s Disease (AD) is the most common type of dementia, with a common underlying genetic factor called apolipoprotein E (APOE). Most people have APOE3, which is the neutral form of APOE. One in six people have the bad form of APOE, called APOE4, which increases the risk of developing AD. Nobody knows exactly why and how APOE4 is bad for the brain. The bold new direction this project will undertake is exploring how APOE4 creates a network of changes in the body’s immune system during aging that may accelerate changes in the brain that lead to AD. Using a state-of-the-art technology called NULISA in mice engineered to express APOE3 or APOE4, they recently made the landmark discovery that the combination of APOE4 and aging led to marked changes in key properties of the immune system called immune checkpoints. Immune checkpoints control how aggressive the immune system becomes. This is an entirely new way of thinking about AD and may explain how brain cells become attacked and die. In this project, the team will first replicate their discovery in a different mouse model of APOE to prove that their initial findings are robust. Next, they will use a sophisticated method to profile the entire immune system in mice, including the brain, spleen and bone marrow cells, to understand how the presence of APOE4 alters immune cell populations during aging. Together, these results will enable the design of future larger experiments in mice and in humans to understand how APOE4 may trick the immune system into attacking brain cells in AD patients.
