Decoding Darkness: The Search for the Genetic Causes of Alzheimer’s Disease

On November 5, 1994, former President Ronald Reagan made headlines when he delivered a handwritten message to the public stating that he had Alzheimer’s disease. His message heightened awareness of the ailment, which now claims 4 million victims in the United States.

Alzheimer’s has been the subject of a substantial amount of scientific research since the mid-1980s. In Decoding Darkness, scientist Rudolph Tanzi gives a behind-the-scenes look at the search for the molecular genetics of the disease.

Among brain disorders, Alzheimer’s disease is particularly tragic. “Few real nightmares on earth compare to the terror wrought by Alzheimer’s disease,” says Tanzi. Especially devastating for patients is the loss of memory, for without memory, everyday experience loses its context.

Tanzi begins his story with a scientific triumph. As a young research assistant at Massachusetts General Hospital in the early 1980s, he worked on the project that found the gene for Huntington’s disease, an inherited brain disorder. To locate the gene, Tanzi performed genetic linkage studies on blood samples obtained from afflicted families; the disease strikes in an autosomal dominant pattern. After the Huntington’s triumph, he decided to track down the gene for early-onset Alzheimer’s disease, a rare form of Alzheimer’s that attacks its victims in their thirties and forties. Like Huntington’s disease, early-onset Alzheimer’s has a clear-cut pattern of inheritance. Decoding Darkness details the arduous seven-year search to elucidate early-onset Alzheimer’s molecular genetics, which, it turned out, involved multiple genes.

Tanzi based his approach on the disease’s pathology, which is characterized by the death of up to 50% of nerve cells in some parts of the brain and by the presence of devilishly insoluble clumps of a peptide called amyloid beta, or A-beta. Like many scientists, Tanzi believed that A-beta was at least partly to blame for the neuronal destruction, so he sought to locate its gene. He fished for the gene by using oligonucleotide probes based on A-beta’s amino acid sequence.

more good reading

Alzheimer’s Disease: The Changing Scene By Robert Katzman and Katherine Bick Academic Press, 2000 Alzheimer Research Forum www.alzforum.org Between Two Worlds: Special Moments of Alzheimer’s & Dementia By Ellen P. Young Prometheus Books, 1999 Speaking Our Minds: Personal Reflections from Individuals with Alzheimer’s By Lisa Snyder W. H. Freeman, 2000

The worldwide search for the A-beta gene was ultimately successful, but the story behind it is one of hopes fulfilled and hopes dashed. The research community slowly learned that mutations in more than one chromosome led to the disease. Not until the early 1990s was the molecular genetics of early-onset Alzheimer’s disease fairly well understood.

Tanzi then turned his attention to finding the genes for late-onset Alzheimer’s, which comprises 99% of cases. The genetics of this disease was muddy, however. Late-onset Alzheimer’s is too erratic to affect many members in a family. In identical twins, it could emerge in one twin a decade or more after the other. Many scientists now believe that late-onset Alzheimer’s is caused by at least five or six genes. And to complicate matters, these genes are influenced by the environment.

With the molecular genetics of Alzheimer’s becoming clearer in the 1990s, Tanzi and other scientists collaborated with drug companies in a search for candidate molecules. A drug that delayed the onset of Alzheimer’s could garner an estimated $2–6 billion in revenues annually (by comparison, sales of Prozac are $3 billion a year). Because of the many steps in the biochemical pathways that lead to the disease, drug companies are working on many targets. A reported 60-plus new Alzheimer drugs are under development.

Decoding Darkness is a firsthand chronicle of the tremendous progress that Alzheimer’s research has made between 1980 and 2000. Drugs for treating this tragic condition are likely to emerge from the pipeline within 10 years. The authors conclude, “Not long ago, the idea of curbing cognitive loss seemed as futile as trying to stop a spring tide from going out. To be now at the point of testing drugs . . . seems nothing short of a miracle.”