Researchers “can either go out with the popular theory that you’re going to go after the things that you can see under a microscope, or you can go after it by learning the mechanism of disease,” said Dr. Roses. He described an experiment that illuminated the mechanism by which Alzheimer’s disease works.

Eric M. Reiman, MD, of the Department of Psychiatry at the University of Arizona, led a study in which a population of hundreds of nonpatient volunteers (ages 50 to 63 years) with a family history of probable Alzheimer’s disease underwent positron emission tomography (PET) scans and were genotyped. Two years later, the same data were taken from 10 persons who had the 4/4 genotype. At that time, clinical testing for Alzheimer’s disease or any detectable memory deficits was negative. Fifteen controls with the 3/3 or 2/3 genotype tested negative as well.

Glucose utilization in both groups was compared. PET scans from patients with Alzheimer’s disease revealed decreased sugar or glucose utilization in very specific parts of the brain. Those volunteers (nonpatients) with the 4/4 genotype showed the same metabolic abnormality as people with Alzheimer’s disease, yet they had no symptoms and were about 20 years before their expected average age of onset of disease.

“The mechanism may relate to the fact that there was decreased glucose metabolism, and wouldn’t that be an interesting place to look?” he asked. “The world is looking at amyloid, or the goo that’s laid down in the brain. If we could stop it here, then these people would never see Alzheimer’s disease. They may have the genetic propensity for it, but if you can intervene and correct the metabolism, then you wipe out the disease.”

In 1997, Dr. Roses’ research group went on to map across the region of the genome where APOE is coded using single-nucleotide polymorphisms (SNP)—APOE-like elements that may or may not be in genes but provide markers in a genome.

Whereas previously two million markers were identified, SNP mapping allowed the isolation of about 45,000 bases, which contained the coding regions of only two genes—APOC1 and APOE. “Had these methods been available in 1989 or 1990, we would have found it in a four-month period of time instead of a six-year period of time,” Dr. Roses said. And now “we could do this in a couple of weeks.”

BETTER, SAFER DRUGS

Just as there are susceptibility genes for Alzheimer’s disease, there may be susceptibility genes for drug reactions—and these inherited susceptibilities to drug reactions can also be detected with a series of markers across the genome. In the next year, Dr. Roses predicts, the first proof of principle study will be done to test for an adverse drug reaction. Accelerated recovery rates, increased efficacy rates, and fewer adverse events are anticipated when medications are prescribed via the analyzation of a patient’s individual genetic profile.

The impact of this personalized medicine will be so great that, according to Dr. Roses, “you can envision a world, in the next five or 10 years … in which the FDA [Food and Drug Administration] and other regulators are going to demand that this is done, so that we can pick out before you take your drug whether you’re one of the people who is going to get an adverse reaction.

“We all go to the doctor for the same reason. You want an accurate diagnosis; you want medicine that’s going to cure you, or certainly treat you properly; you want no adverse events; and you want it for free. You’re going to get three out of four, for a lot cheaper than what you’re paying for now,” Dr. Roses explained. In fact, pharmacogenetics may bring about decreases in health care costs realized on a small and large scale, as patients will not be paying for inefficacious medicine, side effects, and adverse events. Cost containment may also be achieved through a reduction in the number of failed drug trials, shortening the length of time needed for drug approval, and increases in the number of possible drug targets.

SMALL DISEASES AND BIG DRUGS

The same methodologies that are now employed to more accurately pursue therapies for complex disease such as Alzheimer’s disease, depression, and cancer will also make it affordable to go after single-gene, orphan diseases. “Why don’t we work on my disease first? Because it isn’t worth a lot commercially,” echoed Dr. Roses of what had been the prevailing sentiment. However, the recent advances now make pursuit of these conditions and their cures more plausible. “If we can target that orphan disease and make our trials smaller and less expensive, then this methodology will be a great equalizer among diseases. We can go in the natural order that a physician would love to, which is what we consider the worst diseases first, rather than the most profitable diseases only.”

Does the precision of genetics spell the death of the blockbuster drug? Drugs that are going to have a large effect on a symptom or a disease, that are fairly safe, will still be utilized. Pharmacogenetics can be used to put into place a reasonable, rational surveillance system for new drug entities, he maintains, and can be embedded in clinical trials as the “first entry into the efficacy market. If you can cut down your double-blind trials, the people you know will get a response. Then you’re taking a lot of the noise out of the system, [and] you can do them smaller and faster. In the business world, 60% to 70% of the costs of these huge research and development budgets in pharmaceutical companies is in the clinical regulatory arena; it’s not in what I do.”

NR