Scientists Discover Four New Alzheimer’s Risk Genes

While most Alzheimer’s cases aren’t directly caused by genetic mutations, genes still play an important role. Carrying one or two copies of the ApoE4 gene confers a substantially higher risk of developing Alzheimer’s — those who carry two copies have a 60 percent lifetime risk. 

There are also a handful of other genetic variants that have a relatively small effect on disease risk, but provide important clues about the proteins and molecular pathways that misfire in Alzheimer’s.

A new study published in Science Translational Medicine looked at the protein signatures of people with Alzheimer’s for clues about genes that were previously missed. Their analysis implicated four genes that regulate inflammation outside the brain. 

“Almost all of them are involved in how immune cells recognize things and decide whether to attack or clear them,” Pascal Schlosser at the University of Freiburg in Germany told Being Patient. “Think of them as checkpoints or brakes on the immune system.”

The implications are that the immune system, including parts outside the brain, could play a larger role in Alzheimer’s disease than previously thought. 

Using proteins to find clues in DNA

In the past, researchers relied on a technique called genome-wide association studies (GWAS) to find regions of the DNA that are different in those with a disease compared to the healthy population. “The problem is that those regions are like a street address with no name on the door,” said Schlosser. “They tell you roughly where to look, but not which gene, or what it’s actually doing. But this strategy could overlook many important differences.“ 

Instead, his team used a different approach, called a protein-wide association study, which looks at the proteins in the blood rather than the DNA. Genes encode the instructions for building proteins and small differences in a person’s genetic code could shift the levels of these proteins higher or lower. 

The researchers measured roughly 1,300 proteins from over 9,000 participants, of whom about one in five were African American, to identify the genes that may be responsible for these differences.

Then they cross-referenced these genes and proteins in a separate, larger dataset which included people with and without Alzheimer’s, to see if any appeared more often in people with the disease. Among European Americans, the researchers identified 18 proteins and their associated genes that were linked to Alzheimer’s. Of these 18 genes, four were never spotted by scientists in the past. 

“The two standout new ones, called LILRB1 and SIRPA, are both regulators of the immune system,” said Schlosser. Among the African Americans, they only found an association between one protein and disease risk. Schlosser emphasized that this reflects the underrepresentation of these populations in genetic studies rather than the underlying biology. 

Erik Johnson, an assistant professor at Emory University who wasn’t involved in the research, told Being Patient that these kinds of studies are helpful for understanding how genes affect the levels of proteins in the body. 

“Because proteins carry out most biological functions in the body and are the targets of most drugs, bridging the gap between genetic risk and downstream protein changes will help to advance diagnostic and therapeutic development for Alzheimer’s,” he said.

Next steps for LILRB1 and SIRPA

Now the race is on to prove that these genes are in fact implicated in Alzheimer’s. 

“We need laboratory and model-system work to confirm that these proteins genuinely cause changes in disease risk and in which direction,” said Schlosser. He believes that changes in the DNA might affect the protein structure of LILRB1 and SIRPA, affecting their function.

This study adds more evidence that cancer-related genes might contribute to Alzheimer’s. Since SIRPA, and another genetic risk factor identified in this study, CD55, are already targeted by existing cancer drugs, we may not need to wait long for trials. Schlosser said,“That opens a genuine opportunity to repurpose existing compounds rather than start from scratch.”