Genetic Variant Could Protect People from Alzheimer’s Disease

Researchers at Stanford University have found that a significant fraction of Americans carrying a genetic variant that puts people at high risk for Alzheimer’s disease are protected to some degree by a variant of a different gene.

The findings may help drug developers identify treatments for the condition, which impacts five million Americans.

Even larger numbers of people have a subtler precursor to Alzheimer’s disease, called mild cognitive impairment. About half of individuals with this condition move on to develop full-blown Alzheimer’s. While there are medications to somewhat slow the development of cognitive symptoms, no available drugs can prevent the progression of the disease or extend patients’ lives.

Researchers have not yet discovered the root cause of Alzheimer’s, but they know that the genetic variant ApoE4 is more than three times as frequent in Alzheimer’s patients than in people without the disease.

"While 15 percent of healthy people have the ApoE4 gene variant, it's present in more than 50% of Alzheimer's patients," said Michael Greicius, MD, MPH, associate professor of neurology and director of the Stanford Center for Memory Disorders. "One copy of ApoE4 triples or quadruples your risk, compared with no copies. If you're carrying two copies, your risk goes up tenfold."

"Having one or two copies of ApoE moves the age at which you get sick earlier by five to ten years. But it turns out, not all ApoE4 carriers are destined to develop the disease. The gene variant we studied protects you from getting Alzheimer's."

A principle indicator of Alzheimer’s is the aggregation of gummy deposits or plaques in the brain. These plaques are composed of a protein called beta-amyloid, and the aggregation starts ten years before Alzheimer’s symptoms appear.

“By the time someone is symptomatic, the amyloid horse is out of the barn,” Greicius said.

Recent advances in technology have enabled researchers to analyze beta-amyloid levels and other protein levels in cerebrospinal fluid, and to detect the buildup of Alzheimer’s plaques in the brain via imaging.

These biomarkers make it possible to predict the disease’s onset before symptoms become apparent, or to confirm diagnoses already reached on the basis of behavioral observations. However, researchers noticed that some people can have two copies of ApoE4 and still not develop Alzheimer’s. The team set out to determine whether these individuals share genetic variants that protect them from the disease.

Stanford researchers focused on a variant of a gene for a protein called klotho. High blood levels of klotho predict longevity in animal studies, and there is evidence for this in humans as well. Carrying a single copy of the klotho variant, a genetic status referred to as heterozygous, but not two copies increases circulating levels of the klotho protein.

The group examined data on 22,748 ApoE4 carriers with and without symptoms of Alzheimer’s disease. They tracked asymptomatic ApoE4 carriers over time to determine whether those with a single copy of klotho were less likely to have developed Alzheimer’s symptoms.

They then examined 650 subjects to see if those with a single copy were less likely to develop cerebrospinal beta-amyloid levels or beta-amyloid brain deposits predicting the disease’s onset.

The results showed that carrying one copy of the klotho variant significantly slowed the progression from symptom-free status to signs of mild cognitive impairment or signs of outright Alzheimer’s disease. Carrying one copy of the variant also lowered the beta-amyloid burden in the brains of ApoE4 carriers who had not yet progressed to dementia.

"In this ApoE4 carrier group, carrying one copy -- but not two -- of the klotho variant reduced Alzheimer's risk by 30 percent," Belloy, the study's lead author, said. 

Some 25 percent of Americans are heterozygous for the protective klotho variant, researchers noted. Genetic testing for klotho status among ApoE4 carriers could provide a better predictor of Alzheimer’s risk in people with the ApoE4 variant.

Researchers also said that clinical trials may want to consider excluding patients with a single klotho copy to maximize the contrast in outcomes among ApoE4-positive participants receiving or not receiving an experimental treatment. This can help researchers get a clearer picture of a test drug’s value, leading to more targeted therapies and improved patient outcomes in the future.