Alzheimer's researchers and drug companies have for years concentrated on one hallmark of Alzheimer's disease: the production of toxic shards of a protein that accumulate in plaques on the brain.
But now, in a surprising coincidence, two groups of researchers working from entirely different starting points have converged on a mutated gene involved in another aspect of Alzheimer's disease: the immune system's role in protecting against the disease. The mutation is suspected of interfering with the brain's ability to prevent the buildup of plaque.
The discovery, researchers say, provides clues to how and why the disease progresses. The gene, known as TREM2, is only the second found to increase Alzheimer's risk substantially in older people.
"It points very specifically to a potential metabolic pathway that you could intervene in to change the course of Alzheimer's disease," said William Thies, chief medical and scientific officer of the Alzheimer's Association.
Much work remains to be done before scientists understand precisely how the newly discovered gene mutation leads to Alzheimer's, but already there are some indications from studies in mice. When the gene is not mutated, white blood cells in the brain spring into action, gobbling up and eliminating the plaque-forming toxic protein, beta amyloid. As a result, Alzheimer's can be staved off or averted.
But when the gene is mutated, the brain's white blood cells are hobbled, making them less effective in their attack on beta amyloid.
People with the mutated gene have a threefold to fivefold increase in the likelihood of developing Alzheimer's disease in old age.
The intact gene, says John Hardy of University College London, "is a safety net." And those with the mutation, he adds, "are living life without a safety net." Dr. Hardy is lead author of one of the papers.
The discovery also suggests that a new type of drug could be developed to enhance the gene's activity, perhaps allowing the brain's white blood cells to do their work.
"The field is in desperate need of new therapeutic agents," said Alison Goate, an Alzheimer's researcher at Washington University in St. Louis who contributed data to Dr. Hardy's study. "This will give us an alternative approach."
The fact that two research groups converged on the same gene gives experts confidence in the findings. Both studies were published online Wednesday in The New England Journal of Medicine. "Together they make a good case that this really is an Alzheimer's gene," said Gerard Schellenberg, an Alzheimer's researcher at the University of Pennsylvania who was not involved with the work.
The other gene found to raise the odds that a person will get Alzheimer's, ApoE4, is much more common and confers about the same risk as the mutated version of TREM2. But it is still not clear why ApoE4, discovered in 1993, makes Alzheimer's more likely.
Because the mutations in the newly discovered gene are rare, occurring in no more than 2 percent of Alzheimer's patients, it makes no sense to start screening people for them, Dr. Thies said. Instead, the discovery provides new clues to the workings of Alzheimer's disease.
To find the gene, a research group led by Dr. Kari Stefansson of deCODE Genetics of Iceland started with a simple question.
"We asked, 'Can we find anything in the genome that separates those who are admitted to nursing homes before the age of 75 and those who are still living at home at 85?' " he said.
Scientists searched the genomes of 2,261 Icelanders and zeroed in on TREM2. Mutations in that gene were more common among people with Alzheimer's, as well as those who did not have an Alzheimer's diagnosis but who had memory problems and might be on their way to developing Alzheimer's.
The researchers confirmed their results by looking for the gene in people with and without Alzheimer's in populations studied at Emory University, as well as in Norway, the Netherlands and Germany.
The TREM2 connection surprised Dr. Stefansson. Although researchers have long noticed that the brain is inflamed in Alzheimer's patients, he had dismissed inflammation as a major factor in the disease.
"I was of the opinion that the immune system would play a fairly small role, if any, in Alzheimer's disease," Dr. Stefansson said. "This discovery cured me of that bias."
Meanwhile, Dr. Hardy and Rita Guerreiro at University College London, along with Andrew Singleton at the National Institute on Aging, were intrigued by a strange, rare disease. Only a few patients had been identified, but their symptoms were striking. They had crumbling bones and an unusual dementia, sclerosing leukoencephalopathy.
"It's a weird disease," Dr. Hardy said.
He saw one patient in her 30s whose brain disease manifested in sexually inappropriate behavior. Also, her bones kept breaking. The disease was caused by mutations that disabled both the copy of TREM2 that she had inherited from her mother and the one from her father.
Eventually the researchers searched for people who had a mutation in just one copy of TREM2. To their surprise, it turned out that these people were likely to have Alzheimer's disease.
They then asked researchers around the world who had genetic data from people with and without Alzheimer's to look for TREM2 mutations.
"Sure enough, they had good evidence," Dr. Hardy said. The mutations occurred in one-half of 1 percent of the general population but in 1 to 2 percent of patients with Alzheimer's disease.
"That is a big effect," Dr. Hardy said.
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