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Brain Imaging, Cognitive Evaluation Link TOMM40 Alterations to Alzheimer's Risk in Healthy Patients

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By Turna Ray 

Researchers have combined genotyping with brain imaging and cognitive assessment to determine that the TOMM40 genetic marker may predict which healthy adults with a family history of Alzheimer's have a high risk of developing the disease.

Several studies presented this week at the International Conference on Alzheimer's Disease in Honolulu, Hawaii, indicated that the TOMM40 rs10524523 poly-T polymorphism, which in linkage disequilibrium with APOE alleles, is associated with physical characteristics of Alzheimer's in pre-symptomatic subjects.

In one study, researchers used brain imaging to determine that patients homozygous for very long TOMM40 poly-T lengths had less gray matter volume in a region of the brain associated with the disease, while another study used a learning test to show that TOMM40 poly-T sequence was linked to cognitive decline.

“To our knowledge, this is the first study to associate TOMM40 523 genotypes to brain imaging,” researchers led by University of Wisconsin-Madison's Sterling Johnson stated in their ICAD abstract. In the study, researchers hypothesized that changes in the brain that manifest earlier in patients at high risk for late-onset Alzheimer's disease (LOAD), may be associated with TOMM40 polymorphisms.

Johnson's study expands on earlier research by Allen Roses, which found that long, repeated sequences of the polymorphism at rs10524523 – located within intron 6 of the TOMM40 gene and linked to APOE3 and APOE4 polymorphisms – can predict whether a person over 60 years old will develop Alzheimer's disease within a five- to seven-year window (PGx Reporter 01/06/10).

Roses' research shows that patients with a short version of TOMM40 and APOE3 will not get Alzheimer's until after age 80. However, the long version of TOMM40 occurring with either APOE3 or APOE4 means the person will likely get Alzheimer's before the age of 80. Further honing in on age of onset through TOMM40 genotyping, Roses and a team of researchers published a paper in the Dec. 22 issue of The Pharmacogenomics Journal reporting that for APOE ε3/4 patients who developed LOAD after 60 years of age, those harboring long poly-T repeats linked to APOE ε3 develop LOAD an average of seven years earlier than individuals with shorter poly-T repeats linked to APOE ε3.

According to Roses, Johnson's study – involving hundreds of healthy children of Alzheimer's patients in the Wisconsin Registry for Alzheimer’s Prevention – further validates the use of TOMM40 polymorphisms as a biomarker for age of onset since study participants with long poly-T lengths had lower gray matter density, an early sign of Alzheimer's.

Roses, director of Duke University's Deane Drug Discovery Institute and a co-author in the Johnson study and several others presented at ICAD, also told Pharmacogenomics Reporter that his company Zinfandel Pharmaceuticals is close to netting a contract with a major drug company for the development of a preventative Alzheimer's drug. Roses has already designed a study for the development of a drug that will prevent or delay Alzheimer's along with a pharmacogenetic test that identifies which patients are at high risk for developing the disease.

Roses has previously described this predictive and prognostic test as being able to determine which patients are at high risk of getting Alzheimer's disease based on whether they are over 60, their TOMM40 poly-T repeat status, and their APOE genotype. Those identified to be at high risk for developing Alzheimer's by this test would then be candidates for receiving the preventative drug. Roses has indicated in the past that this test would likely involve analysis by PCR and next-generation sequencing.

Gray Matter and TOMM40

In the study presented at ICAD, Johnson and colleagues confirmed their hypothesis that diminishing gray matter volume and longer TOMM40 523 lengths are connected in predicting the early development of Alzheimer's in high-risk patients.

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Specifically, researchers reported that healthy APOE3 homozygous adults with a mean age of 57 years, who were also homozygous for long TOMM40 poly-T lengths, “had significantly less gray matter volume in the ventral posterior cingulate and precuneus, a region of the brain affected early in LOAD.”

This finding led them to conclude that this subset of patients “with very long TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes” — a sign that they are developing Alzheimer's earlier.

The researchers are planning to follow the participants in this study to determine genetic and other factors that predict cognitive decline and dementia.

In this study, the researchers were able to “differentiate, preclinically, before the onset of Alzheimer's disease, those genotypes that negatively affected the MRI in certain areas and those that didn't,” Roses said.

Johnson told Pharmacogenomics Reporter that further validation of this finding is definitely necessary and researchers plan to follow this cohort for some time.

“Our current findings only suggest that there may be risk-associated signal,” Johnson said. “The finding is in the right area of the brain and the memory findings line up with it, but this is a group effect and not yet useful to predict disease in individual subjects.”

Cognitive Function and TOMM40

Another abstract presented at ICAD further supports the TOMM40 523 polymorphism's ability to gauge whether healthy people with a hereditary risk for Alzheimer's are likely to develop the disease.

Mark Sager and colleagues, including Roses, tested more than 700 patients in the same Wisconsin registry with a mean age of 54 and a family history of Alzheimer's to determine if those who were homozygous for TOMM40 short poly-T sequences, and therefore at low risk for early manifestation of LOAD, would perform better on measures of learning and memory than those homozygous for long poly-T lengths.

The investigation revealed that “the high and low risk TOMM40 groups differed significantly in total words learned on the Rey Auditory Verbal Learning Test, with the high-risk TOMM40 group remembering fewer words.”

Additionally, researchers reported that 19 percent of the low-risk short poly-T group had an APOE ε4 genotype compared with 55 percent of the high-risk long poly-T group. When researchers computed the study results taking into consideration carrier and non-carrier APOE ε4 status, TOMM40 lengths remained significant.

In this study, Sager and colleagues concluded that the changes in learning and memory of study participants suggest that “TOMM40 genotyping may prove useful in stratifying persons at different levels of Alzheimer's disease risk in studies of pre-symptomatic disease.”

However, the study authors noted that “the role that TOMM40 plays in Alzheimer's pathogenesis and its relationship to APOE genotypes as a genetic risk factor for AD are yet to be determined.”

Roses lauded the effort to link TOMM40 genotypes to neuropsychological differences in presymptomatic Alzheimer's patients. “Nobody has seen anything like this before,” he said.

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Two additional studies on the TOMM40 genotype were presented at ICAD. One, by researchers at Duke, the Mayo Clinic, the Translational Genomics Research Institute, and the Banner Alzheimer Institute, further showed that patients homozygous for long TOMM40 poly-T lengths had a significantly earlier age of clinical onset of Alzheimer's disease than patients with short or long heterozygous variants. Researchers in this study, in which Roses was a co-author, also observed that the age of onset in patients with homozygous long lengths of the 523 variant with either an APOE 3/4 or 3/3 genotype was younger than those with heterozygous variants.

Another study, led by Roses, looked at variations in the frequency of TOMM40 523 polymorphisms in different ethnic groups. In this study, the researchers concluded that “the distributions of inherited 523 poly-T lengths varies in populations with different evolutionary histories, and the relatively shorter allele lengths appear to be consistent with the older age of AD onset in Far Eastern populations compared to Caucasians.”

Furthermore, distributions of the polymorphism in West Africans are also different from Caucasian and Far Eastern groups. “These data may contribute to our knowledge of age-dependent disease risk in different world populations,” Roses et al. reported.

According to Roses, the Alzheimer's Disease Neuroimaging Initiative is also interested in examining the prognostic capabilities of the TOMM40 523 genotype. Further validation of the marker is being conducted in different cohorts through ADNI, which is currently studying mild cognitive impairment in Alzheimer's patients and controls.

Preventative and Pharmacogenetic

According to Roses, the findings provide further support of the development of a preventative drug and pharmacogenetic test for the identification and early treatment of people who are at high risk for developing Alzheimer's but don't show any signs of the disease.

For the past year, Roses has been in discussions with the US Food and Drug Administration's Voluntary Exploratory Data Submissions group regarding the submission strategy for such a drug/diagnostic combination product. The trial, called Opportunity for the Prevention of Alzheimer's, or OPAL, will enroll patients between the ages of 60 and 87 and test them neuropsychologically. If they pass the tests as normal, they will be enrolled into OPAL and genotyped for APOE status and TOMM40 '523 polymorphisms. Then, based on their age and TOMM40 status, they will either fall into the high-risk or low-risk category for developing Alzheimer's in the next five years.

At this point, the high-risk group will then be randomized to an investigational drug or to placebo. A portion of the low-risk group will be able to participate in the trial, but most of them will be placed in the placebo arm.

“At the end of the five-year trial, we would then expect to see the validation of the test prospectively because we would be able to get a positive and negative predictive value for the test,” Roses told PGx Reporter. “In the treated and untreated group we could determine whether or not there was a statistically significant difference in the rate of onset of Alzheimer's."

Currently, Roses' company Zinfandel Pharmaceuticals is in the process of finalizing negotiations with a major drug company for an investigational agent that would be studied in OPAL. With negotiations slated for completion in the fall, OPAL is expected to begin in 2011.

Since Zinfandel has signed confidentiality agreements with the unnamed drug company regarding the investigational drug candidate under negotiation, Roses could provide no further details regarding this agent.

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