People with a gene variant that puts them at high risk for Alzheimer’s disease are protected from its debilitating effects if they also carry a variant of a completely different gene, Stanford University School of Medicine investigators report in a large new study.
Their findings, published Apr. 13 in JAMA Neurology, suggest that a substantial fraction of the estimated 15% of Americans carrying the high-risk gene variant are protected to some degree from Alzheimer’s disease by a variant of the other gene. (A gene will often come in a variety of versions, or variants, that can produce different traits.)
The study may help drug developers identify treatments for what, despite billions of dollars spent in pursuit of effective therapies, remains a disease without a cure.
About 5 million Americans — including 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. About half with this condition 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.
By the time someone is symptomatic, the amyloid horse is out of the barn.
What causes Alzheimer’s isn’t well understood. There are probably numerous factors. But scientists have known for three decades about one main contributor to the disorder: a gene variant, ApoE4, that’s more than three times as frequent in Alzheimer’s patients than among people without the disease.
More than 50% of Alzheimer’s patients have ApoE4
“While 15% 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.”
Greicius is the senior author of the study. Postdoctoral scholar Michael Belloy, PhD, is the lead author.
“Having one or two copies of ApoE4 moves the age at which you get sick earlier by five to 10 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.”
A hallmark of Alzheimer’s is the aggregation in the brain of gummy deposits, or plaques, composed of a protein called beta-amyloid. Amyloid aggregation 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.
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.