Researchers have found the first gene mutation that protects against Alzheimer’s disease, a finding that supports a now-controversial theory about the cause of the disease and that could eventually lead to the development of new drugs to treat the disorder. The gene mutation also protects against normal dementia of aging, suggesting that the two diseases have mechanisms in common.
Alzheimer’s affects an estimated 5.4 million Americans, and the prevalence increases with age: 13% of those older than 65 and 45% of those over the age of 85 have it. The disease is characterized by the buildup in the brain of particles called amyloid plaque, which are composed of a protein called amyloid beta. Amyloid beta is produced by the breakdown of a larger protein called amyloid precursor protein, or APP. Researchers have so far identified at least two dozen variants of APP that produce early-onset Alzheimer’s disease in people younger than 65. The new variant, reported online Wednesday in the journal Nature, is the first that protects against Alzheimer’s.
The idea that breakdown of APP causes Alzheimer’s has led many pharmaceutical companies to search for drugs that could delay Alzheimer’s by inhibiting the breakdown. Unfortunately, clinical trials of those drugs have been almost uniformly unsuccessful, leading many critics to doubt the theory. The new findings, however, tend to place it on firmer ground.
A team led by Dr. Kari Stefansson of deCode Genetics in Reykjavik, Iceland, deciphered the whole genome of 1,795 Icelanders looking for rare variants associated with Alzheimer’s and found the new mutation, which is present in about 0.45% of the population there. Unpublished data show that it is even rarer in the United States, found in only about 1 in every 10,000 people. That suggests the mutation arose relatively recently in Northern Europe, Stefansson said.
The data showed that the mutant gene was present in 0.13% of those with a diagnosis of Alzheimer’s, but in 0.62% of those over 85 who did not have the disease. The variant was also present in 0.79% of those over age 85 whose brain functions were normal. Furthermore, those with the variant performed significantly better in tests of cognitive functioning.
Surprisingly, the variant also seems to protect against other risk factors for the disease. At least 90% of people with two copies of a gene called ApoE4 normally get Alzheimer’s by age 80. But Stefansson observed 25 people in the study with the new variant and two ApoE4 genes, and none had Alzheimer’s.
Stefansson predicted that pharmaceutical companies will now accelerate their search for new drugs that can somehow mimic the action of the gene variant.