The Alzheimer’s gene, known as ApoE4, is one of the the largest genetic risk factors for later onset Alzheimer’s disease. Carrying one copy of the gene triples the risk of developing Alzheimer’s, while two copies increase one’s risks more than 12 times. Scientist now think they may have found a new gene known as KL-VS that may counter the elevated risk associated with ApoE4.
“What’s making [these patients] unique? What’s protecting them? The effect of APOE4 is so strong that we really would expect them to develop Alzheimer’s disease,” said Michael Belloy, postdoctoral fellow at the Department of Neurology and Neurological Sciences at Stanford University, in an interview with Being Patient.
In a new study published in JAMA Neurology, Belloy and other researchers discovered that a variant of the klotho gene KL-VS may protect older adults with ApoE4 from developing Alzheimer’s. After analyzing more than 20,000 people ages 60 and older, the team found that healthy participants who carried both ApoE4 and KL-VS are less likely to develop mild cognitive impairment (MCI) and Alzheimer’s. Healthy participants carrying both genes also had less beta-amyloid in their brains — abnormal proteins considered one of the first hallmarks of Alzheimer’s.
Everyone carries the klotho gene. Klotho is a complex hormone produced in both the kidney and the brain, named for the daughter of Zeus, Klotho, a Greek Fate who spun the thread of life, and linked to longevity. Scientists previously found that some older adults who carry one copy of the variant have greater memory and processing speed. Previous animal studies show that klotho is not only associated with improved cognition, but it’s also linked to extended life spans and may possess therapeutic benefits for mice with Alzheimer’s.
About one in five people have the variant KL-VS.
The team found no benefits for those who carried two copies of the variant. In fact, previous research shows that one copy of KL-VS increases the levels of klotho while two copies decreases the hormone.
This phenomenon is called the heterozygote advantage, where carrying one copy of a mutated gene may be beneficial while having two copies can be harmful. By way of another example is the gene variant that may cause sickle cell anemia: Previous research has indicated that one copy of the sickle cell gene variant may protect people from malaria, a life-threatening disease where parasites infect the red blood cells. They would also be safe from the blood disease sickle cell anemia. However, those who inherit two copies of the variant develop sickle cell anemia.
Exactly why KL-VS may reduce the risk of Alzheimer’s is still unknown. But what the link can tell us is that doctors who counsel their patients about genetic risk factors for Alzheimer’s should also consider the patients’ klotho variant. And scientists conducting clinical trials should also target those who carry ApoE4 without KL-VS, as they may have a greater likelihood of developing Alzheimer’s.