* Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease by Rudolph E. Tanzi and Ann B. Parson, Perseus Publishing, $26, 281 pages.



The News & Observer


June 3, 2001

Searching for the source of Alzheimer's


By Phillip Manning

Americans haven't attained Methuselah's life span yet, but we're getting there. In the past 100 years, life expectancy in the United States has increased 50 percent. A child born today will live, on average, more than 76 years -- slightly more for women, a little less for men. And if you are already 65 years old, you probably have another 15 or 20 years in front of you.

This remarkable increase in longevity is due largely to scientific advances made in the 20th century. Vaccines and antibiotics now prevent or cure infectious diseases that once killed millions, and improved prenatal and natal care has reduced infant mortality. But the longer we live, the more susceptible we become to genetic diseases, such as Huntington's and Parkinson's, which usually kick in later in life and rob people of their expected years and dignity. One of the most widespread of these genetic diseases is Alzheimer's. Today, almost 5 million Americans suffer from it, and that number is expected to triple in the next 50 years. Will science gallop to the rescue again?

In "Decoding Darkness," Rudolph E. Tanzi, a neurology professor at Harvard and head of a genetic research team at Massachusetts General Hospital, and science writer Ann B. Parson tell the story of how scientists are attacking this mind-stealing and deadly disease.

Many of us know the symptoms of Alzheimer's all too well from watching it waste friends and loved ones. At first, victims suffer short-term memory loss: They are forever unable to remember where they left their keys or glasses five minutes before. As the dementia grows, their judgment diminishes. Driving becomes a dangerous adventure. They become unable to spell the word "world" backward. Eventually, Alzheimer's ravages so much of the brain that sufferers can no longer speak rationally or recognize family members. Then, it kills them. What is this monster, this dark affliction?

The disease is named for Alois Alzheimer, a German physician who, in 1906, watched one of his patients enter into a deadly spiral of memory loss, disorientation and delirium. After her death, Dr. Alzheimer examined her brain. He spotted thousands of tiny clusters scattered across the cerebral cortex. He also found nerve cells choked by "dense bundles of fibrils."

The clusters proved to be waxy deposits known as amyloid plaques. Today, many scientists, including Tanzi, believe that these plaques cause Alzheimer's, although a smaller number suspect that the tangled fibrils are the problem. This book focuses on three questions about amyloid plaques: What are they? Where do they come from? And, finally, what can be done about them and the disease they likely cause?

The answers came slowly at first because few scientists wanted to work on the relatively rare disease. But as life spans increased, doctors began seeing more and more patients with Alzheimer's symptoms, and in 1976 one neurologist wrote that the disease was the "fourth or fifth most common cause of death in the United States." This statistic galvanized the scientific community.

The first breakthrough came in 1983, when George Glenner and Cai'ne Wong, working at the University of California-San Diego, identified the substance in the plaques. The raw material for their research came from two freezers full of frozen brains taken from the victims of Alzheimer's. After many late nights in the lab, they determined the chemical structure of the culprit. It turned out to be a peptide, a short chain of amino acids snipped out of a protein.

Now the hunt was on to find the aberrant gene or genes that released excessive amounts of the amyloid-forming peptide. As the authors describe the often tedious lab work undertaken by researchers during the 1980s, we see how the search was complicated because the disease comes in two forms. Early-onset Alzheimer's is a rare disorder that strikes people in their 40s or even earlier, while the more common late-onset form attacks those 60 or older. Further muddying the waters, most scientists believed that multiple genes were involved in both forms of Alzheimer's.

Today, researchers have identified three genes that account for 40 percent of early-onset Alzheimer's. The genes associated with the late-onset form have proved more difficult to track down. The first late-onset gene was reported in 1992 by Allen Roses at Duke University. Recent work by Tanzi's own team at Massachusetts General has uncovered another one. However, the correlation between gene and disease is less predictive than it is with the early-onset form. People with these genes don't necessarily contract late-onset Alzheimer's, but they are more likely to get it. The situation is similar to that of cancer, the authors write, where only 5 percent of cancers are "solely and directly caused by a single genetic defect at an early age." Tanzi and other researchers believe environmental factors also play a role.

Head trauma, for example, can cause not only dementia, such as that experienced by boxer Sugar Ray Robinson, but also the Parkinson's-type symptoms seen in Muhammad Ali. This leads to the big question: Aside from inheriting good genes and not getting knocked silly, can we do anything to hold off late-onset Alzheimer's?

Surprisingly enough, the answer appears to be yes. "The bottom line," write Tanzi and Parson, "is pretty irrefutable: What is good for the heart is good for the brain." Anti-inflammatories, such as aspirin and ibuprofen, antioxidants, exercise and wine all benefit the cardiovascular system and have been linked to a lower incidence of Alzheimer's. Highly educated people tend to resist dementia longer, too.

But don't let this list of Alzheimer's ameliorators fool you. Some Nobel-prize winners who take good care of themselves get Alzheimer's. We are a long way from being able to predict who will get the disease, much less cure it. Nevertheless, Tanzi and Parson are optimistic that science can overcome Alzheimer's. Drug companies are searching for medicines that will block the production of the plaque-forming peptide, and the recent deciphering of the human genome will speed up identification of the genes that make one susceptible to the disease.

"A futuristic vision for conquering Alzheimer's," they write, "wraps around the powerful combination of genetic screening ... and preventative drugs optimized for a person's genome." The year might be 2010 or later, they speculate, but the foundation to successfully treat Alzheimer's is being laid now.

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