Exploiting a gene that protects against Alzheimer’s

Anyone who gets tested for their genetic risk for Alzheimer’s disease likely knows about ApoE4. Having one copy of this variation of the ApoE (apolipoprotein E) gene increases the risk for developing Alzheimer’s by two to three times, while having two copies increases the risk by 12 times. But there’s another story behind ApoE, one that is protective for Alzheimer’s and enhances longevity.  It involves one of the other ApoE gene variants: ApoE2. Given the societal and personal fears about Alzheimer’s, the vast majority of scientific attention has been focused on ApoE4; ApoE2 gets short shrift in research.  Not so at the Buck.  Professor Lisa Ellerby has received a $4.4 million federal grant to explore how ApoE2 can be exploited to support healthspan and protect against Alzheimer’s.

The skinny on a gene involved in cholesterol and lipid metabolism

The ApoE gene provides instructions for making a protein called apolipoprotein E. This protein combines with fats in the body to form lipoproteins which are responsible for packaging cholesterol and other fats and carrying them through the bloodstream. 

There are at least three different versions, or alleles, of the ApoE gene: E2, E3 and E4. Given that everyone has two copies of the gene, there are six possible combinations that determine one’s ApoE “genotype”.  The most common allele is E3, which is found in more than half of the population and does not appear to impact Alzheimer’s risk. The E4 allele, present in approximately 10 to 15 percent of people increases the risk for Alzheimer’s and lowers the age of onset. Ellerby says previous research indicates that E4 alters lipid metabolism in a way that negatively impacts brain plasticity.

The E2 allele is the rarest form of ApoE, present in only seven percent of the population.  Carrying even one copy of E2 appears to reduce the risk of developing Alzheimer’s by up to 40 percent.  “ApoE2 has lots of beneficial properties,” says Ellerby. “Those who carry the allele are likely to be exceptionally long-lived and there is evidence that E2 directly impacts brain health. There are theories about why that occurs, but no one really understands what E2 does in the body. My focus is to find out what’s special about ApoE2, so that we can use it therapeutically for Alzheimer’s.”

Utilizing stem cell technology to hone in on differences

Ellerby’s team is reprogramming skin cells from individuals with genetic backgrounds involving each of the ApoE alleles (E2/E3/E4). Researchers will look at the resulting induced pluripotent stem cells (iPSCs) and characterize their cellular and functional differences. “There is a body of evidence that suggests that ApoE genotypes affect brain structure and gene expression beginning in prenatal development so this is the right place to start our inquiry,” said Ellerby.  “In addition, we are making a point to get skin cells from both males and females. Women are more likely to develop Alzheimer’s and we hope this work will help explain why that happens.”  

Researchers will also grow brain cells – neurons, astrocytes and microglial cells - from the stem cells in order to determine whether ApoE2 enhances stress response and survival in the cells, and if it does, to identify the molecular pathways relevant to the protection. “The latest generation of stem cell tools and technology are enabling this research,” said Ellerby. “This would not have been possible 5 years ago.”

Moving the work into mammals

And finally, researchers plan on moving the research into aging mice, to test whether an overexpression of ApoE2 or a treatment with factors produced by E2 increases healthspan in the animals. “E2 is a very small protein,” says Ellerby, “We have been able to get it to cross the blood-brain barrier.  If it is beneficial in mice, it would provide a proof-of-concept that would open the door for drug development for humans.”

Responding to a desperate need for new approaches for a disease affecting 5.7 million Americans

Despite decades of research there is no cure or effective treatment for Alzheimer’s; at best, existing drugs temporarily blunt the symptoms of cognitive decline. The National Institutes of Health, through the National Institute on Aging, is funding research that takes new approaches to the disease, adding $425 million this year for basic studies on Alzheimer’s and related dementias.  Ellerby’s grant award is among them, as is a $3.4 million grant to Julie Andersen to look at a fruit-derived metabolite as a possible treatment for the disease.