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How do multiple genetic factors, including different variations of the APOE gene, combine to increase Alzheimer’s risk?
Renzo Mancuso, Ph.D.
Flanders Institute for Biotechnology, VIB
Ghent, Belgium
Background
Genes play an important role in Alzheimer’s, but for most individuals who have late-onset Alzheimer’s (the most common form of the disease), the genetic mechanisms are not well understood. One dementia-related gene, APOE, provides instructions for making ApoE, a protein that helps carry fats throughout the brain and body. There are several variations of APOE, each of which has different impacts on Alzheimer’s risk. APOE-e4 is associated with increased risk for Alzheimer’s in some populations, APOE-e3 is neutral, and APOE-e2 is protective for some populations. In addition, many other genetic variations likely impact one’s risk for Alzheimer’s – and many of these variations have been identified through large-scale studies looking at specific areas of genes (called GWAS, or Genome-wide Association Studies). These studies use datasets from large groups of individuals to identify genetic factors associated with diseases.
Many GWAS-identified risk genes are linked to inflammation in the brain, particularly through microglia, the brain’s primary immune system cell. Microglia serve as one of the first defenses against nerve cell damage and help remove unwanted proteins from the brain. Genes related to microglia could interact with APOE to increase Alzheimer’s risk. Therefore, understanding the interactions between risk genes related to microglia and APOE is important to better clarify how APOE is implicated in Alzheimer’s progression.
Research Plan
Dr. Renzo Mancuso and colleagues received additional funding to build upon their 2022 APOE Biology in Alzheimer’s (ABA) grant to expand their work on genes, microglia, and Alzheimer’s risk. The researchers will use extensive GWAS data to identify and study particular combinations of genes that may increase or decrease one’s risk of developing Alzheimer’s. This process involves adding the genes to microglia grown in a laboratory dish and testing how the genetic alterations affect microglial activity, including phagocytosis (a process during which the microglial cells engulf (or “swallow”) the unwanted proteins). Next, the investigators will add their genetically-altered microglia into the brains of Alzheimer’s-like mice in order to determine how different gene combinations affect the health and function of living brains. This supplemental grant will enable Dr. Mancuso and team to work with microglia that have the “neutral” APOE-e3 variation, as well as the “protective” APOE-e2 variant and the risk-associated APOE-e4 variant.
Impact
Overall, Dr. Mancuso’s project may work to uncover new genes, proteins and biological pathways involved in Alzheimer’s. It also has the potential to promote further investigation into how risk genes impact microglia in the early stages of the disease.
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