APOE

APOE gene gateway to halting the disease's progression

An increasing number of studies demonstrate that the APOE gene, responsible for encoding a protein called apolipoprotein E, dramatically raises the risk of Alzheimer's, partly by encouraging amyloid beta to collect into damaging plaques, a key component of the disease.

There are three types of the APOE gene, called alleles: APOE2, E3 and E4. Everyone has two copies of the gene and the combination determines your APOE "genotype". There are six APOE genotypes: E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, and E4/E4. 

The E4 variant of the gene is "the most prevalent genetic risk factor" for Alzheimer's, with over half of people with the condition having this gene expressed. Studies also show that people who have both copies of the gene have a 12-fold higher risk of developing Alzheimer's disease.

A study led by Dr. David Holtzman, head of the Department of Neurology at the Washington University School of Medicine in St. Louis, MO, Research was conducted to understand the role of APOE in the formation of Alzheimer's disease. 

A Ph.D. student named Tien-Phat Huynh, Dr. Holtzman and colleagues, targeted the APOE protein using a kind of DNA-based molecule created by co-author Tracy Cole, PhD, and others at Ionis Pharmaceuticals. The molecule – known as an antisense oligonucleotide – interferes with the instructions for building the APOE protein. The findings are now published in the journal Neuron.

The researchers injected the compound into the fluid surrounding the brains of newborn mice. For comparison, they gave other newborn mice either saltwater or a placebo “oligo” that does not interfere with the APOE instructions.

Levels of APOE protein dropped by about half in mice given the APOE compound as compared with those that received the placebo oligo or saltwater. 

Dr. Holtzman said about his findings, "If you wanted to target APOE to affect the amyloid process, the best thing would be to start before the plaques form."

Gene and drug therapy are in the works, but more work is needed before the compound could be evaluated in people.

To learn more about these programs and other APOE-related drug discovery programs, investigate the  Alzheimer's Drug Discovery Foundation research portfolio with a filter for "APOE4."