I decided to participate in a genome study that was to determine if people would make lifestyle changes if they knew they had an increased genetic risk for certain diseases. Some of the diseases that were included in this study were obesity, type 2 diabetes, macular degeneration, MS and AD. So sure, why not participate? Wouldn't this be fun, enlightening, and empowering! I mean, isn't knowledge power? And, even though I had a strong family history of AD, I was in "healthy denial" about it, and being my age, I wasn't a bit concerned about AD anyway. Besides, I wanted answers about my risk of MS due to episodes of ataxia. AD was furthest from my mind.

So, I bought the ticket for the ride! This will be fun! Besides, how fast or dangerous can the ride be? Then, the e-mail I had been waiting for popped into my mailbox informing me that the results were in. How exciting! I couldn't log on fast enough to see the results! I now will be able to take control of my medical destiny and make better lifestyle choices and...  Read more

I decided to participate in a genome study that was to determine if people would make lifestyle changes if they knew they had an increased genetic risk for certain diseases. Some of the diseases that were included in this study were obesity, type 2 diabetes, macular degeneration, MS and AD. So sure, why not participate? Wouldn't this be fun, enlightening, and empowering! I mean, isn't knowledge power? And, even though I had a strong family history of AD, I was in "healthy denial" about it, and being my age, I wasn't a bit concerned about AD anyway. Besides, I wanted answers about my risk of MS due to episodes of ataxia. AD was furthest from my mind.

So, I bought the ticket for the ride! This will be fun! Besides, how fast or dangerous can the ride be? Then, the e-mail I had been waiting for popped into my mailbox informing me that the results were in. How exciting! I couldn't log on fast enough to see the results! I now will be able to take control of my medical destiny and make better lifestyle choices and prevent disease. Then, there it was, looking me in the face....

I am the lucky owner of two copies of the ApoE4 allele. Huh? Wait, wait, slow the ride down a bit; what does this mean? It means the ride just became a rollercoaster. The information that was given to me was basically "common knowledge" in nature (i.e., keep your mind active, maintain a healthy diet, and exercise regularly). Okay, shouldn't everyone be practicing this healthy lifestyle? How is this going to change my odds of getting AD as I'm watching my father decline and my maternal grandmother experience a horrible death? What can I do to really prevent this disease? What evidence-based studies are there to prove it to me? How do these lifestyle changes truly affect the odds of preventing AD?

The bottom line is there are no factual answers to these questions, but suggestions based in theory gleaned from epidemiological data. Furthermore, the statistical odds of having AD based on genetic data are confusing at best. For example, the company that did the testing put my risk at 69 percent for Alzheimer disease, whereas past research from Duke University put it at 91 percent (NIA, 1993).

Now that the ride has slowed down a bit and I've caught my breath, I'm hoping that by sharing my experience it will help others in their decision-making process. This is not something that should be taken lightly, and I would strongly recommend that one-on-one genetic counseling be sought before making this decision. Had I had an interactive genetic counseling session, my motivation for participation in this study could have been vetted, my strong family history would have been highlighted, and I would have made a better informed decision. Would I have chosen not to be tested? I'm not sure, but if I had to make an assumption, I probably would have not. The lifestyle changes I can make should be changes we all should be making. And sadly, there are no evidence-based studies to prove that doing so will prevent AD (unlike other diseases where lifestyle changes can indeed prevent onset).

I would just like to suggest one question that might be of help in making your decision to test or not to test. That is to ask yourself, "Do I really need to know this information and will it make me make changes that I already should be doing anyway?"

Whew, what a ride!

References:
National Institute of Aging. (1993, November 7). Possible Targets for Treatment of Alzheimer’s Disease Advanced by Recent Gene Breakthroughs (U.S. National Institutes of Health, Nov. 7, 1993). Retrieved March 10, 2009, from The National Institute on Aging.

View all comments by A. Anonymous

“A funny thing happened on the way to the genome lottery!”

People must realize the profound implications of “knowing your lottery ticket”—a fact genetic counselors know all too well.

View all comments by Fred Van Leuven

All of the attempted estimates being marketed on the Web are for a lifetime risk of AD, and ApoE4 and ApoE3 polymorphisms are not included on the genomewide SNP platforms—for this very reason. This type of testing has variable meaning depending on your age at the time of testing—and now we have strong evidence that ApoE4 is just reflecting the polyT length polymorphism distribution at rs10524523 [523] in TOMM40 [1]. While this test is still unvalidated prospectively—and should not yet be used clinically—it provides relevant information for both ApoE4 and ApoE3 DNA strands, and is useful for predicting risk of onset for the next five to seven years, depending on age and 523 type. The clinical parameters of the test and accuracy of prediction will be measured in a five-year diagnostic clinical validation and a simultaneous delay of onset [preventive] clinical trial. Studies performed with DNA for ApoE4 in proper research tests might be enhanced by re-studying with the correct AD-related genetic polymorphism (see   Read more

All of the attempted estimates being marketed on the Web are for a lifetime risk of AD, and ApoE4 and ApoE3 polymorphisms are not included on the genomewide SNP platforms—for this very reason. This type of testing has variable meaning depending on your age at the time of testing—and now we have strong evidence that ApoE4 is just reflecting the polyT length polymorphism distribution at rs10524523 [523] in TOMM40 [1]. While this test is still unvalidated prospectively—and should not yet be used clinically—it provides relevant information for both ApoE4 and ApoE3 DNA strands, and is useful for predicting risk of onset for the next five to seven years, depending on age and 523 type. The clinical parameters of the test and accuracy of prediction will be measured in a five-year diagnostic clinical validation and a simultaneous delay of onset [preventive] clinical trial. Studies performed with DNA for ApoE4 in proper research tests might be enhanced by re-studying with the correct AD-related genetic polymorphism (see ARF related news story).

The following is a clinical comment which summarizes the data and provides insight to the availability of the assay as a research tool.

On the use of a new polymorphism for prediction of Alzheimer disease risk and clinical trial stratification:

We have recently published a research paper demonstrating that a variable-length, polyT polymorphism in the TOMM40 (Translocase of the Outer Mitochondrial Membrane) gene accounts for the age of onset of late-onset Alzheimer disease (LOAD), a complex disease [1]. These new data will add resolution to the age of onset distributions for patients with the ApoE3/4 and ApoE3/3 genotypes.

There are two distinct ranges of polyT lengths at the rs10524523 (“523”) locus in TOMM40. Longer polyT repeats (19-39 nucleotides) are associated with earlier age of onset than shorter polyT alleles (11-18 nucleotides). This locus distinguishes two forms of ApoE3 chromosomes and provides an alternative or extended explanation for the earlier disease onset for ApoE4 homozygotes, since ApoE4 is always in linkage with long polyT alleles. The polyT length alleles appear to be autosomal co-dominant with variable penetrance. Additional research will determine whether all alleles above a certain length are pathogenic or if the relationship between repeat length and pathogenicity is linear.

The phylogenetic experiments leading to the discovery of the polymorphism at the 523 locus in TOMM40 are detailed elsewhere [1]. Two points are noteworthy, however. First, TOMM40, and the 523 allele, is next to and in strong linkage disequilibrium with ApoE. Second, the 523 allele, although a repeated sequence motif, appears to be stably inherited through human evolution rather than representing a sporadic, recurrent, contemporary mutational event. This polymorphism is unlike the triplet repeat diseases with variable penetrance such as myotonic dystrophy, where the number of repeats is unstable through successive generations.

The 523 locus can, therefore, be used for disease risk prediction: Based on the age of an individual (between the ages of 60-87) and 523 genotype, we propose that a risk estimate [high or low] can be assigned for the onset of mild cognitive impairment [MCI] symptoms and conversion to AD over the next five to seven years; that is, this is not a lifetime risk prediction.

Three aspects of this discovery deserve consideration by the clinical community: 1) The implications of this data for prediction and prevention of LOAD; 2) The utility of the polymorphism for the design of delay of onset or intervention clinical studies; and 3) The relevance of the phylogenetic approach and structural polymorphisms to discovering genetic risk markers for other “complex diseases.”

Replication and validation of the 523 locus must be undertaken before the marker is used in clinical practice. For that reason, we have designed a prospective clinical validation study of the genetic marker combined with a delay of onset clinical trial using a safe and promising therapeutic. A number of considerations regarding this clinical study have been discussed with the U.S. FDA via the Voluntary Exploratory Data Submission mechanism. Discussions with pharmaceutical companies have been initiated by Zinfandel Pharmaceuticals, Inc., a “virtual” drug development company. During the course of this prospective study, a qualified assay will be developed as a test to accurately measure polyT variation at this locus. Even with accurate estimation of age of onset risk for enrichment of low and high risk study arms, a study of this nature will take 5+ years to complete. These genetic findings may be used for patient stratification of planned and ongoing clinical trials of AD interventions or preventatives.

While we have chosen not to commercialize this test for clinical use until validation, patent applications claiming use of this marker are filed. The intent is that the test will be available for sponsored academic research at low cost (perhaps supported by funding agencies via fee for service contracts), and also for commercial drug trials (by license agreements). At this time, the data is specific to Caucasians, but the frequencies of the 523 alleles will be measured for other ethnic groups. The 523 data will be transferable to other ethnicities, but the estimated risk prediction algorithms may change.

We anticipate—especially based on our early 1990s experience with the spirited debate around the diagnostic use of ApoE genotyping in AD—that there will be differences of opinion on the ethical, legal, or social issues (ELSI) for use of a test that predicts AD risk. We have, therefore, spent eight months in prospective consultation with a panel of external ELSI experts who helped us develop the plans for use of the test outlined above.

This work demonstrates the complexity of the genotype-phenotype relationship, and a reminder that we are just beginning our journey toward understanding the human genome and complex diseases.

References:
[1] Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, Sundseth SS, Huentelman MJ, Welsh-Bohmer KA, Reiman EM. (2009) A TOMM40 variable length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. In press.

View all comments by Allen Roses