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doi: 10.1097/01.NT.0000360726.83579.a3

ARTICLE IN BRIEF Investigators have identified a gene, dubbed TOMM40, that may help explain why many people with the most common variant of the apolipoprotein (APOE) gene, APOEe3, develop Alzheimer disease and the age at symptom-onset.

VIENNA—A newly identified gene may help to improve predictions of who will develop Alzheimer disease (AD) and the approximate age at which symptoms of the disorder will begin to appear.

The new gene, dubbed TOMM40, may help explain why many people with the most common variant of the apolipoprotein (APOE) gene, APOEe3, develop the disease, researchers said here at the International Conference on Alzheimer's Disease in July.

TOMM40 can help predict the onset of symptoms within a five- to seven-year window among people over age 60, according to lead investigator Allen D. Roses, MD, director of the Deane Drug Discovery Institute at Duke University Medical Center in Durham, NC.

TOMM40, the protein translocase of the outer mitochondrial membrane, codes for the membrane channel through which cytoplasmic peptides and proteins traverse in order to synthesize new mitochondria, he said.

In 1993, Dr. Roses reported that people with the APOEe4 gene variant are at increased risk for AD. The APOE gene comes in one of three forms: APOEe2, APOEe3, and APOEe4.

The APOEe4 variant accounts genetically for 50 percent of late-onset cases of AD. Adding in TOMM40 may help to pinpoint up to 90 percent of inherited cases of the disease, Dr. Roses said.

If borne out through additional research, testing for the two genes could help clinicians improve calculations of a patient's estimated disease risk of getting the disease and the likely age at onset, Dr. Roses said.

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The study involved 35 patients with AD and 35 controls.

“In genome-wide scans, single nucleotide polymorphisms (SNPs) are analyzed one at a time and corrected for the number of SNP tests used. In fact this creates incredible noise. Genome-wide screening detects big blocks of DNA inherited together, but it doesn't tell us all the differences within that block,” Dr. Roses explained.

“From all the genome-wide scans that have been performed over the past four years, it was apparent that the variance within APOE could not account for the extremely high statistical significance which characterized this small block of genes, including APOE and TOMM40, which were inherited in a block,” he said.

“We conducted a phylogenetic analysis to explore the evolution of the DNA and to see what changes take place on the backbone of other changes,” he said. Phylogenetic analysis “allows you to map polymorphisms as they occur on the back of polymorphisms over time.”

The most common uses in medicine are using sequence-based phylogenetics to track changes in the influenza virus or HIV genes. Essentially it allows the role of small genetic effects to be characterized by its evolutionary history.

“With phylogenetic analyses of small defined genomic areas, like the region of LD (linkage disequilibrium) associated with AD, the mutations are analyzed to see if and where in the evolutionary pattern of changed disease or phenotypic changes relevant association occurs. Just as we can map where two species of monkey diverge, we can also map where changes associated with a common complex disease converge,” Dr. Roses explained.

“In our case, [phylogenetic analysis] led to directly defining the historical and hierarchical structure of TOMM40 and correlating the specific loci with differences in age of onset of AD,” he said.



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The Duke researchers found that a variant of TOMM40 apparently evolved independently when attached to the APOEe3 version of the gene than it did when attached to the APOEe4 version. In addition, TOMM40 linked to APOEe3 had either short or long repeated sequences, while all APOE e4-linked repeat sequences were long.

“A variable length polymorphism in the translocase of the outer mitochondrial membrane (TOMM40) gene is a significant predictor of age at onset of AD in APOEe3 carriers.

“There is also an increased length of this polymorphism carried on all APOEe4 strands. The effects of each of an individual's two strands are inherited independently, and both contribute to the phenotype or disease risk,” Dr. Roses said.

The researchers concluded that a longer version of TOMM40 is attached to both APOEe3 and APOEe4 and both are significantly associated with earlier symptom onset, while the short repeat sequences are associated with later onset.

Among people with the APOEe3 variant, those with two copies of the long version of TOMM40 develop AD at an average age of 70 years, Dr. Roses reported. Those with one copy of the short version of TOMM40 develop it at age 77. People with two short forms of TOMM40 may never develop AD, he said.

APOEe4 is uniformly associated with a long version of TOMM40 and early onset,” he said.

The Duke team now plans to validate the association of APOE genotypes and TOMM40 with age at symptom-onset and to determine how well these genes predict age at onset. They are planning a prospective, five-year study combined with a drug trial aiming to prevent or delay disease onset.

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Other researchers, not involved with the study, expressed various degrees of enthusiasm.

Samuel E. Gandy, MD, PhD, Mount Sinai Professor of Alzheimer's Disease Research, professor of neurology and psychiatry, and associate director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine in New York, said that, if confirmed, “this would give us a better idea of risk in people who don't carry the APOEe4 gene.”

Ronald C. Petersen, MD, PhD, professor of neurology, Cora Kanow Professor of Alzheimer's Disease Research, and director of the Alzheimer's Disease Research Center at the Mayo Clinic College of Medicine in Rochester, MN, said that if validated, “the findings could be important because they speak to APOEe3 carriers, who are the most common.

“In general, when we talk about allele frequencies, APOEe2 is inherited by about 8 percent of the population, APOEe4 by 15 percent, and APOEe3 by everyone else,” said Dr. Petersen, who is also chief of the Medical & Scientific Advisory Council of the Alzheimer's Association.

However, the researchers studied a relatively small number of subjects, “so we need replication in larger numbers,” Dr. Petersen said.

Identifying genes that are associated with an increased risk of AD is important from a scientific viewpoint, said William H. Thies, PhD, chief medical & scientific officer at the Alzheimer's Association in Chicago.



“But clinically now, without a treatment to offer, it doesn't do the clinician much good to know who is at increased risk. Once disease-modifying agents are developed, however, testing could be used to identify patients early and treat them before symptoms develop,” he said.

For now, testing is most useful for pharmaceutical companies who want to enroll high-risk persons in clinical trials, he said.

Ralph A. Nixon, MD, PhD, professor of psychiatry and cell biology at New York University School of Medicine and vice chair of the Medical & Scientific Advisory Council of the Alzheimer's Association, said that if confirmed, “this would be a real advance.

“Since TOMM40 is involved in the delivery of cholesterol to the mitochondria, this identifies a potential target for treatment that has a scientific basis.”

Dr. Nixon said that most research is “now concentrated in amyloid, but mitochondria may also prove a significant target.”

That said, “You can get a lot of hits with genetic studies that cannot be confirmed,” he said.

©2009 American Academy of Neurology