November 25, 2014
For about 20 years, the gene known as APOE has been recognized as a risk factor for Alzheimer’s disease. People who inherit a variant of the APOE gene known as APOE-E4 from a parent are at up to five times higher risk of developing Alzheimer’s in old age compared to those who carry other forms of the APOE gene. Those who inherit two copies of APOE-E4, one from each parent, are at up to 15 times higher risk of developing Alzheimer’s.
Now doctors have studied a 40-year-old man from California who was born with no APOE gene at all, an extremely rare genetic occurrence. The man had very high levels of cholesterol, not surprising since APOE is known to be involved in maintaining the balance of cholesterol and other blood fats in the body. High cholesterol levels are known to increase the risk of heart attacks and strokes. He also had skin lesions related to the buildup of blood fats in the skin.
But remarkably, the man had normal memory and thinking skills, and otherwise appeared generally healthy.
In years past, scientists have identified other people who had no APOE gene at all. But this is the first case in which a patient underwent extensive brain scans and other tests to assess cognitive function and other effects throughout the body.
The findings, published in the journal JAMA Neurology, from the American Medical Association, show that you can have normal neurological function without any APOE in the brain.
The scientists studying the man said the results open up possible new avenues for developing therapies for Alzheimer’s disease. By developing drugs that block the effects of APOE-E4, the findings suggest, it might be possible to block its destructive effects on the brain without causing other serious health problems.
“In light of APOE as the primary risk factor for Alzheimer’s disease, the lack of neurological findings in this patient would appear to answer the question of whether APOE is necessary for brain function with a resounding no,” conclude researchers from the University of Texas Southwestern Medical Center in Dallas, in an editorial accompanying the case study.
Studies in mice that have been bred to develop a disease that resembles Alzheimer’s in people show that immune therapies that block APOE lead to less buildup of amyloid plaque in the brain, a hallmark of Alzheimer’s disease. Drugs that block APOE are currently being tested in monkeys.
But drugs that would block the harmful effects of APOE-E4 on the brain in people are still likely years away. The drug would have to block the effects of APOE-E4 in the brain without blocking its effects elsewhere in the body, where it might produce dangerously high cholesterol levels and pose heart risks.
Another form of APOE, known as APOE-E2, is known to decrease the risk of developing Alzheimer’s. Scientists are also investigating agents that might mimic the healthful effects of this variant of the APOE gene.
Sources: Angel C. Y. Mak, PhD, et al: “Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function.” JAMA Neurology, published online August 11, 2014.
Courtney Lane-Donovan, SB; Joachim Herz, MD: “Is Apolipoprotein E Required for Cognitive Function in Humans? Implications for Alzheimer Drug Development” (editorial). JAMA Neurology, published online August 11, 2014.