New research from a study done by Stanford University School of Medicine has discovered that people with a gene variant, ApoE4, that puts them at high risk for Alzheimer’s disease are protected from its debilitating effects if they also carry a combating variant of a completely different gene.
The Stanford study
Michael Greicius, MD, PhD, senior author of the study, and postdoctoral scholar Michael Belloy, PhD, the lead author, are heading the Stanford study. Their findings, published in JAMA Neurology, suggest that a substantial fraction of the estimated 15 percent of Americans carrying the high-risk gene variant are protected to some degree from Alzheimer’s disease by a variant of the other gene.
Of 5 million Americans, roughly 1 in 10 people (age 65 or older) and one-third of those (age 85 or older) have symptomatic Alzheimer’s disease.
Even larger numbers have a subtler precursor called mild cognitive impairment (MCI). Almost half with MCI move on to full-blown Alzheimer’s. There are medications that can slow development of cognitive symptoms somewhat, but no available drugs prevent the disease’s progression or extend patients’ lives.
The ApoE4 gene variant
What causes Alzheimer’s is still unknown. There have been many theories, but the only certainty that scientists have known for three decades is a main contributor to the disorder– a gene variant, ApoE4. The gene variant has been found more than three times as frequent in Alzheimer’s patients than among people without the disease.
“While 15 percent of healthy people have the ApoE4 gene variant, it’s present in more than 50 percent 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.”
ApoE4 gene variant does not promise Alzheimer’s
“Having one or two copies of ApoE4 moves the age at which you get sick earlier by five to ten years,” Greicius said. “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.”
Yet even having two copies of ApoE4 by no means ensures that a person will develop Alzheimer’s. Some such people live to age 85 or 90 without symptoms; they’re protected, somehow, from the debilitating effects of this gene variant.
The study was born when Greicius wondered, “Why do some of these people share genetic variants that protect them?”
A hallmark of Alzheimer’s is the aggregation in the brain of plaque deposits composed of a protein called beta-amyloid. Amyloid aggregation is an early sign of the disease, but is sneaky, because it starts more than 10 years before symptoms appear.
“By the time someone is symptomatic, the amyloid horse is out of the barn,” Greicius said.
Recent technological advances have enabled the early prediction of Alzheimer’s onset by analyzing beta-amyloid levels and other protein levels in cerebrospinal fluid, and by detecting the buildup of Alzheimer’s plaques in the brain via imaging.
These biomarkers make it possible to predict the disorder’s onset before outward symptoms become apparent, or to confirm diagnoses already reached on the basis of behavioral observations.
The study focused on a variant of a gene for a protein called klotho. High blood levels of klotho have been used to predict longevity in animal studies. There is also evidence for this in human studies.
For complicated reasons, 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.
To understand the relationship between klotho-variant status and ApoE4-associated Alzheimer’s risk, the researchers combed through publicly available databases for data on almost 23,000 ApoE4 carriers with and without symptoms of Alzheimer’s disease. All subjects were age 60 or older and of Northwestern European ancestry.
The researchers tallied the likelihood of those subjects with or without a single copy of the klotho variant winding up with Alzheimer’s symptoms versus remaining asymptomatic. 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 also analyzed about 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.
“In this ApoE4 carrier group, carrying one copy — but not two — of the klotho variant reduced Alzheimer’s risk by 30 percent,” Belloy said. It substantially slowed the progression from symptom-free status to signs of mild cognitive impairment or outright Alzheimer’s disease. And it lowered the beta-amyloid burden in the brains of ApoE4 carriers who had not yet progressed to dementia.
Some 25 percent of Americans are heterozygous (have two different alleles of a particular gene or genes) for the protective klotho variant. Note: A much smaller share has two copies, and the rest have none.
Promising Alzheimer’s research
“Genetic testing for klotho status among ApoE4 carriers could provide a better predictor of Alzheimer’s risk in people with the ApoE4 variant,” Greicius said.
“In addition, drug companies will want to consider excluding patients with a single klotho copy in their clinical trials to maximize the contrast in outcomes among ApoE4-positive participants receiving or not receiving an experimental treatment,” Greicius said.
The findings should aid drug developers to better identify clinical trial participants and treatments for what, despite having billions of dollars invested into research, remains a disease without a cure.
“Learning more about how the protective gene variant works may also lead to a more sophisticated understanding of ApoE4’s debilitating effect on cognition — and, importantly, help researchers to zero in on therapeutic targets for the prevention or mitigation of those effects,” Greicius said.