Caution Greets Report of New Gene for Alzheimer Disease

Neurology Today
1 July 2010; Volume 10(13); p 25

HURLEY, DAN

A genome-wide association study (GWAS), involving 2,269 people with the disease and 3,107 controls, is the first to identify the MTHFD1L gene on chromosome six as a risk factor for late-onset AD.

TORONTO—Adults with late-onset Alzheimer disease (AD) are twice as likely to have a variation in a gene linked to homocysteine levels as are people without the disorder, according to a study presented at the AAN annual meeting here.

The genome-wide association study (GWAS), involving 2,269 people with the disease and 3,107 controls, is the first to identify the MTHFD1L gene on chromosome six as a risk factor for late-onset AD. Because other, larger GWAS studies have not reported the association, researchers not involved with the study interpreted the new finding with caution.

Lindsay A. Farrer, PhD, chief of the genetics program and professor in the departments of medicine, neurology, and genetics and genomics at Boston University School of Medicine, said that Dr. Pericak-Vance's team had a reputation in the field for being careful in their research and cautious in their conclusions.

“It's certainly important for them to report such findings,” said Dr. Farrer, who was not involved with the study. But, he added, “One has to be conservative in interpreting the study until other groups attempt to replicate it. The findings will be either confirmed or not fairly quickly. That's the way the field is now.”

The fact that the gene is in a pathway previously implicated in Alzheimer disease is “encouraging,” Dr. Farrer said. But, he noted, “the investigators haven't identified any functional variants yet.”

“There are a lot of merits to this new study, but there are also a number of concerns,” said Nilufer Ertekin-Taner, MD, PhD, a neurogeneticist and neurologist in the departments of neurology and neuroscience at the Mayo Clinic in Jacksonville, FL, who was not involved with the study.

One of the strengths of the study, Dr. Ertekin-Taner said, was that it replicated the MTHDF1L gene finding in two separate data sets. The study initially identified the gene's significance in a set of 931 patients compared to 1,104 controls, then replicated it in another 1,338 patients and 2,003 controls.

Figure. DR. MARGARET PERICAK-VANCE:“Usually when you do a GWAS, you find a gene, and then you have to find the biological reason behind its significance. What's so exciting is that this is a gene known to be involved in influencing the body's levels of homocysteine, and high levels of homocysteine are strong risk factor for late-onset Alzheimer disease.”

[ Click here to enlarge ]

In a press conference here, the principal investigator of the study emphasized the gene's previously documented influence on homocysteine levels, higher levels of which have been linked to an increased risk of cardiovascular disease, stroke, and AD. Elevated blood levels of this amino acid damage the lining of arteries and contribute to the accumulation of plaques in the brain that are the hallmark of Alzheimer disease (AD).

“Usually when you do a GWAS, you find a gene, and then you have to find the biological reason behind its significance,” said Margaret Pericak-Vance, PhD, director of the University of Miami Miller School of Medicine John P. Hussman Institute for Human Genomics. “What's so exciting is that this is a gene known to be involved in influencing the body's levels of homocysteine, and high levels of homocysteine are strong risk factor for late-onset Alzheimer disease.”

But the fact that the gene plays some role in homocysteine metabolism, said Dr. Ertekin-Taner, is still not proof that what it does directly raises the risk of AD.

“What we don't know is whether the variants in the gene alter the protein in such a way that it also affects Alzheimer's risk,” she said. “The true functional effect of the mutation will have to be shown.”

Of even greater concern, Dr. Ertekin-Taner said, is that the MTHFD1L gene did not show up in two larger GWAS papers published last October in Nature Genetics. A French team studied 2,032 cases and 5,328 controls, while a British team analyzed a total of over 16,000 individuals. Both studies identified novel genes associated with AD, but not the MTHFD1L gene.

It may well be, Dr. Ertekin-Taner said, that different genes play varying roles in the risk of developing AD in different populations.

“That's a possibility that needs to be taken very seriously,” said Dr. Ertekin-Taner. “Both the genetics and the Alzheimer's disease communities should not dismiss these findings.”

Stronger doubts about the new findings were expressed by John Hardy, PhD, former head of neurogenetics at the National Institute of Aging and now professor of neuroscience at the Reta Lila Weston Institute of Neurological Studies at the University College London, England.

Noting that the MTHFLD1L gene had not shown up in last year's French and British GWAS papers, he said the finding was “very likely to be wrong.”

But Dr. Pericak-Vance said she expects her findings to be replicated by other groups. “I feel relatively confident,” she said. “We found it in over a thousand cases and controls, then replicated it in another 2,000 controls and more cases.”

Still, she said, the gene's effect on the risk of developing Alzheimer's is likely to be far less than that of the apolipoprotein (APOE) gene.

“It's a mild risk factor at best,” she said. As other genes playing similarly modest roles in the risk of AD are replicated, she said, researchers might be able to assess them as a group of factors, much the way that smoking, weight, and other lifestyle factors are combined to assess the risk of heart disease.

For now, she said, her group has plans to conduct functional studies of the gene's variant, and to measure plasma homocysteine levels in patients and controls in light of their MTHFLD1L gene status.

Figure. DR. LINDSAY A. FARRER:“One has to be conservative in interpreting the study until other groups attempt to replicate it. The findings will be either confirmed or not fairly quickly. That's the way the field is now.”

[ Click here to enlarge ]

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Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. 2009;41(10):1088–1093. E-pub 2009 Sep 6.

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