Doctors have long known that people with genes that produce a cholesterol transporter molecule called APOE4 are at especially high risk for Alzheimer's disease. Now they think they know why.
Researchers say they've discovered key molecular pathways at work inside brain cells that appear to be altered by the presence of APOE4.
The finding might someday lead to practical applications for patients, because it points to potential new drug targets for Alzheimer's disease. The brain-robbing illness currently affects an estimated 5 million Americans and has no effective treatment.
The newly discovered brain pathways also help explain why APOE4 carriers -- who have somewhere between a three and 10 times higher risk of developing Alzheimer's compared to people who don't carry the gene -- don't always go on to develop memory loss, in spite of their predisposition.
"We're really excited, but a lot more needs to be done before this can be used clinically," said study author Dr. Asa Abeliovich, a neuroscientist at Columbia University in New York City.
For the research, Abeliovich and his team applied big data tools to science to look for patterns in changes in gene activity in 100 people who carried APOE4 genes and 100 people who did not.
To keep the genetic changes caused by the disease itself from skewing their results, they only looked at tissue samples from people who had not yet developed symptoms.
Abeliovich's team found changes in the expression of 215 genes between carriers and noncarriers of APOE4. Out of those, they identified 20 that appeared to be "master regulators" of key processes inside cells.
"These are candidates that connect the dots for us. They are somewhat modified in the way they work in the context of the disease," Abeliovich explained.
At least two of those -- SV2A and RNF219 -- appear to change how they work depending on the kind of apolipoprotein E they encounter inside cells.
Apolipoprotein E, or APOE, is a molecule that ferries cholesterol around the body. There are three major forms of this cholesterol carrier -- APOE2, APOE3 and APOE4. People who make APOE4 are at increased risk for Alzheimer's disease, people who make
APOE3 have a neutral or intermediate risk, and people who make APOE2 appear to be at lower risk for developing the disease. No one has understood why these molecules appear to be so important to the development of the disease.
When APOE attaches to a receptor on the surface of cells, the receptor also grabs a molecule called the "amyloid precursor protein" and moves the entire package inside the cell.
In the presence of APOE4, the new research shows, the cell appears to change how it processes the amyloid precursor protein.
"APOE4 changes the behavior of [the genes] SV2A and RFN219," said Abeliovich. "They go from good cops to bad cops, and amyloid precursor protein and other proteins end up in unfortunate parts of the cell, where they are processed into amyloid beta," he said.
A build-up of amyloid beta protein in the brain is a well-known hallmark of Alzheimer's disease.
One expert not involved in the research said the findings give scientists an important new clue to the Alzheimer's puzzle.
"The role of APOE4 in enhancing Alzheimer's risk has been a vexing problem for 20 years. The gene robustly increases amyloid buildup in mouse models but no consistent molecular or cellular explanation has emerged," explained Dr. Sam Gandy, director of the Mount Sinai Center for Cognitive Health in New York City.
Gandy said the new study now shows that APOE4 causes perturbations in the processing of amyloid precursor proteins inside cells and these perturbations "apparently cause nerve cells to make too much amyloid."
In an extra step, researchers tried blocking the action of SV2A with a drug called levetiracetam, which is used to treat seizures. In that experiment, cells in a petri dish processed the amyloid precursor protein more normally -- even in the presence of APOE4.
The finding suggests the medication could play a role in the prevention of the disease, though researchers say much more research is needed to confirm their results.