Gene that boosts Alzheimer’s risk might protect against it too

Carrying a specific version of the apolipoprotein E, or APOE, gene is one of the most important genetic risk factors for late-onset Alzheimer’s disease. But another form of the gene is not a risk factor. What is the difference? How do the proteins made by these genes, which normally transport cholesterol, affect Alzheimer’s? And if we find out, can we use them to fight the disease?

Eloise Hudry and a group of scientists at Harvard Medical School set out to understand how different versions of APOE can affect the amyloid beta proteins, plaques and synapse loss that are associated with Alzheimer’s disease. They used viruses to transfer genes for different types of human APOE — APOE2 and APOE3, as well as APOE4, the variant associated with increased Alzheimer’s risk — into mice with an Alzheimer’s-like disease. They then looked at how the different versions of APOE affected the signs of Alzheimer’s in the mice’s brains.

In a study published in the November 21 issue of Science Translational Medicine, Hudry and her colleagues showed that a 10 percent increase in APOE4 increased plaque formation and amyloid beta in the brains of the mice. In contrast, increasing APOE2 by 10 percent decreased amyloid beta and plaque density. Increasing APOE4 was associated with decreases in synapses, the connections between neurons, while increasing APOE2 protected those connections. APOE3 is the odd one out, with no significant effects on any of the Alzheimer’s markers.

The changes are small ones, but the results are intriguing. It’s possible that a bigger effect could be obtained if we could get more APOE2 into the brain, for example. Or if we could both increase APOE2 and decrease APOE4, to boost the possible beneficial effects of APOE2 as well as block the harmful effects of APOE4.

If it these effects hold up, it could be meaningful for patients. About 14 percent of the population carries APOE4, putting them at increased risk of developing late-onset Alzheimer’s. Only 7 percent carries the possibly protective APOE2. The authors suggest the findings could one day be turned into gene therapy that inhibits APOE4 and increases APOE2. It’s also possible that drugs could be developed to provide these effects. But first it’s important to make sure that the effects of both kinds of APOE are significant, first in mice, and then in humans. It’s early days yet. But if it all works out, it’s possible that we could use APOE targets to hit Alzheimer’s where it hurts.