American Scientist

Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease. Rudolph E. Tanzi and Ann B. Parson. xviii + 281 pp. Perseus Publishing, 2000. $26.

The stakes are high in the search for an effective therapy for Alzheimer's disease: In the United States, about 10 percent of people over 65 years of age are affected, and the prevalence roughly doubles every five years beyond age 65; health care costs are estimated to be about $100 billion per year. The number of Americans with the disease (4 million) is expected to triple (to 14 million) by 2050. To find a cure, researchers are investigating the causes.

Decoding Darkness—written jointly by Rudolph E. Tanzi, director of the Genetics and Aging Unit at Harvard's Massachusetts General Hospital, and Ann B. Parson, a science journalist—recounts key events in the fiercely competitive race to uncover the genetic basis of Alzheimer's disease. Written from Tanzi's perspective as a participant in that race, the account is autobiographical and highly personal. Conversational in tone, the book contains enough basic information to be accessible to nonscientists.

The pathological hallmarks—and suspected, although not established, causes—of Alzheimer's disease include extracellular neuritic plaques and intracellular neurofibrillary tangles. These plaques contain amyloid-β peptide, which varies in length because it has from 39 to 43 amino acids. Amyloid-β peptides, especially those with 42 amino acids, are thought to form fibrils by self-aggregation and then clump into plaques in the brain. Neurofibrillary tangles are made up of a highly phosphorylated protein called tau. The normal function of tau is to bind and stabilize the microtubule assembly in the cytoplasm. However, in the brain of a patient with Alzheimer's disease, hyperphosphorylated tau clumps into tangles and causes microtubules to destabilize and eventually collapse.

Whether plaques or tangles are the primary lesion in Alzheimer's disease is still a matter of debate, but most researchers believe that amyloid-β peptide is the primary culprit (many think it is toxic to neurons) and that other events are a consequence of amyloid deposition. Tanzi himself is in the amyloid camp, and the main focus of the book is to review evidence that establishes a direct link between genetic mutations and amyloid or delineates the role of amyloid load in the development of Alzheimer's disease.

The book starts out by describing Tanzi's early training in James Gusella's laboratory at Massachusetts General Hospital, where he learned novel molecular and genetic techniques for finding disease genes—techniques that he subsequently applied to his Alzheimer's research. Then the narrative backtracks to provide a summary of historical events from the first description of the disease by Alois Alzheimer in 1906 up through the landmark work of George Glenner and Cai'ne Wong in isolating amyloid-b peptide in 1984.

In 70 percent to 90 percent of cases, Alzheimer's disease is sporadic, meaning that no obvious family history is present; the remainder of cases are familial. Early-onset Alzheimer's disease (occurring in patients younger than age 65) is usually familial, following an autosomal dominant inheritance pattern; a mutation in a single gene can cause the disease. The heart of Decoding Darkness (chapters 3 through 10) deals with a race among researchers that resulted in the discovery of three genes for early-onset disease—the amyloid-β precursor protein gene (APP) on chromosome 21 and the presenilin genes (PS1 on chromosome 14 and PS2 on chromosome 1). Efforts to discover the effects of mutations in these genes on the accumulation of amyloid-β peptide are also described. It should be noted that mutations in APP, PS1 and PS2, although they account for about 40 percent of early-onset disease (with the main contribution being from the PS1 gene), explain less than 2 percent of all cases of Alzheimer's disease.

The book is particularly illuminating in its depiction of the human dimension of this research—the day-to-day lives of dedicated scientists, their perseverance, the satisfaction and joy they experience when they are the first to make a discovery and the agony they go through when they are defeated by their competitors. It is made clear that competition, although it can contribute to rapid progress in science, can backfire, as when scientists, in a game of "King of the Hill," deliberately delay the publications of their competitors or steal ideas and rush to publish them.

Chapter 11 briefly summarizes advances in the genetics of late-onset Alzheimer's disease, for which only one established susceptibility gene—the apolipoprotein E gene (APOE) on chromosome 19—has so far been identified, although linkage studies indicate the presence of additional genes. The APOE gene explains about 50 percent of the genetic risk for late-onset Alzheimer's. Late-onset disease is complex and involves several genetic and environmental factors; it does not show a clear mode of inheritance. Thus the authors correctly point out that genetic predictive tests for it may not be as straightforward as those for early-onset disease.

The last chapter is devoted to the efforts of pharmaceutical companies to design drugs that could halt Alzheimer's disease. The current focus, based on the hypothesis that the loss of neurons is primarily attributable to amyloid-b peptide, is on drugs that could block the production of the peptide, restrict its accumulation or accelerate its breakdown in the brain. Ongoing clinical trials of these drugs will provide the real test of this hypothesis. The authors are cautious not to give false hope to patients and families, since the exact mechanism of Alzheimer's disease is still uncertain. We have come a long way in uncovering its genetic basis, but before we can conquer this devastating disease, a great deal needs to be learned about its metabolic pathway.

I commend the authors for putting in perspective the scientific advancements of the last two decades. I learned many things from this book and recommend it for anyone interested in the disease, from researchers to families of patients.