1 May 2010. A common gene variant that puts many people at risk for obesity may also make those who have it more vulnerable to developing Alzheimer disease (AD). This finding, reported on April 19 in PNAS online by a collaboration led by researchers in the laboratory of Paul Thompson at University of California, Los Angeles, is one of the first published results from the genotyping component of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). It follows another report by the same lab, published in the journal Neuroimage online in March, that identified a variant glutamate receptor gene as a potential risk factor for AD. Together, these studies illustrate the potential of ADNI data analysis to discover some of the missing heritability of AD and to lay the groundwork for more effective pharmaceutical trials.
The fat mass and obesity-associated (FTO) gene was discovered three years ago as a contributor to the genetic basis of obesity. The gene encodes a protein that localizes to the cell nucleus and catalyzes the demethylation of nucleic acids. A common variant of the FTO gene, found in 46 percent of Western Europeans, causes those who have it to weigh about 1.2 kg more on average and have about 1 cm greater waist circumference than those without the variant. The risk allele may hinder the brain’s ability to recognize satiety, as those with the variant eat about 200 calories per day more than they otherwise might.
Thompson and colleagues hypothesized that the FTO gene might have an effect on the brain because people with a higher body mass index tend to have a loss of brain tissue volume in the frontal, occipital, and temporal lobes. The researchers analyzed the genotypes and structural MRI brain scans of 206 healthy elderly participants in the ADNI study, using tensor-based morphometry to create 3D maps of structural brain atrophy. They found that people who carried the obesity risk allele had an average volume deficit of 8 percent in the frontal lobes and 12 percent in the occipital lobes compared to those without the gene variant. The researchers found that people with higher BMI had greater volume loss, as every unit increase in BMI was associated with an average 1 to 1.5 percent loss of brain tissue. There was some evidence, according to Thompson, that people carrying the FTO risk allele who maintain a healthy BMI do not show this brain atrophy, but more data are needed.
As all of the participants were clinically normal, the brain shrinkage may provide an early marker of people at risk for developing AD, Thompson said. Brain atrophy is well documented to precede the onset of clinical AD. The FTO gene variant is not a direct cause of this disease; rather, the FTO pathway can be thought of as depleting brain reserves and making people more vulnerable to developing AD and perhaps other dementias as well. “It’s a little like a bank account. The FTO gene is spending down your bank balance, but you can top it up in other ways,” Thompson said.
Ways to stimulate the brain and alleviate the effect of the FTO risk allele include exercise, mental stimulation, and eating a healthy diet. Thompson emphasized that people can modify their genetic risk by making behavior changes. For example, walking an additional two miles per day can neutralize the effect of the FTO risk allele on body weight, Thompson said.
Because the ADNI volunteers are elderly, the study did not address the issue of whether the loss of brain tissue is progressive throughout the lifespan. Thompson and colleagues are now scanning the brains of younger people, and their preliminary results indicate that even young adults with the risk allele show subtle deficits in brain tissue. “FTO risk seems to accumulate throughout life,” Thompson said. People carrying the FTO risk allele would be good candidates for trials of new AD prevention drugs, Thompson said, because they are at elevated risk for developing the disease. By testing drugs on people whose brains are shrinking, as seen by structural MRI, and screening out people whose brains are fine, it also would be easier for promising drugs to show a statistical effect, according to Thompson.
The FTO paper “is a great example of the use of the ADNI dataset to test a hypothesis,” said Andrew Saykin, the neurogeneticist in charge of the ADNI genotyping effort and a coauthor on the paper.
In a separate project, first author Jason Stein in Thompson’s group made a different use of the ADNI data to find the variant glutamate receptor gene. In this case, the researchers analyzed the entire ADNI dataset, including healthy participants, those with AD, and those with mild cognitive impairment, reviewing more than half a million single nucleotide polymorphisms (SNPs) in each person’s genome to find any that correlated with reduced cortical volume as seen in the MRI scans. The interesting thing about this approach, according to Stein, is that they looked for genetic variance associated with imaging traits rather than with development of AD. MRI brain atrophy served as an endophenotype, that is, an inherited phenotype associated with AD. Studying the genetics of an endophenotype should be more powerful than conventional gene association studies, Stein said, because “the disease is genetically heterogeneous, whereas traits like temporal lobe volume should be closer to the underlying biology.”
Their analysis revealed that a variant of the GRIN2B gene, which codes for a subunit of the NMDA glutamate receptor, is both associated with reduced temporal lobe volume and overrepresented in people with cognitive impairment. This result needs to be replicated in a second dataset to verify its status as an Alzheimer’s risk factor, Stein said. The NMDA receptor is known to be involved in learning and memory. It is already a therapeutic target in AD in that the drug memantine acts as a low-affinity antagonist.
The Thompson lab papers represent two of the first five papers published from the ADNI genotyping data, but many more such papers are in press or in revisions, Saykin said. “ADNI provides an extraordinary opportunity because we have such a rich set of biomarkers, all collected in a longitudinal format,” Saykin said. The size of the ADNI dataset has made it possible to find Alzheimer-associated genes with small effects, such as GRIN2B, Stein said. Scientists plan to enroll twice as many cognitively normal volunteers in the next ADNI cohort. Finding even subtle genetic associations is important, Saykin said, because these genes “can give clues to the underlying pathophysiology of the disease. There’s not a single path to neurodegeneration. In fact there are many interacting pathways.”—Madolyn Bowman Rogers.
Madolyn Bowman Rogers is a freelance writer in Madison, Wisconsin.
Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, DeCarli CS, DeChairo BM, Potkin SG, Jack CR Jr, Weiner MW, Raji CA, Lopez OL, Becker JT, Carmichael OT, Thompson PM; the Alzheimer Disease Neuroimaging Initiative. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci USA. 2010 April 19. Abstract
Stein JL, Hua X, Morra JH, Lee S, Ho AJ, Leow AD, Toga AW, Sul J, Kang HM, Eskin E, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen A, Corneveaux J, Stephan DA, Webster J, DeChairo BM, Potkin SG, Jack CR, Weiner MW, Thompson PM (2010). Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease., NeuroImage, 2010 Mar 1. Abstract