Unravelling a tangled mind

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

Perseus: 2000. 320 pp. $26, £15.95

Few human conditions cause the kind of suffering associated with Alzheimer's disease, because it robs people of their humanity. Despite substantial progress in Alzheimer's research over the past 15 years, the cause of the disease has yet to be definitively established, and there is still little that can be done to halt the inexorable march of cognitive decline. Decoding Darkness provides an autobiographical perspective on the discovery of the genes that cause familial Alzheimer's disease, and the evolution of the major pathogenetic hypotheses, by one of the leading researchers in the field.

A substantial portion of the book is devoted to the experiences of Rudolph Tanzi, a scientist who has made important contributions to the genetics of Alzheimer's disease. These personal adventures add entertainment value to the story. The book's coverage ranges from details of the positional cloning of genes that are associated with Alzheimer's disease to the Calistoga mud baths. It is written in a conversational style, with a minimum of technical jargon, and is an easy read even for non-scientists.

Although the book is highly personal, journalist Ann Parson made extensive efforts to interview many scientists in the field repeatedly, to get their stories right. The end result is a book that portrays many different viewpoints. Although the underlying theme is that amyloid protein is probably the cause of the disease, most of the major areas of investigation and points of view are represented.

Tanzi and Parson begin by describing some of the first attempts at the positional cloning of a disease gene in James Gusella's lab at the Massachusetts General Hospital in the early 1980s. The technique of linking benign genetic variations with a disease locus was a major advance in genetics that initially led to the mapping of genes for Huntington's disease and Duchenne muscular dystrophy. These initial forays gave rise to the search for genes that might cause Alzheimer's disease.

The modern era of Alzheimer's research began with George Glenner's discovery in 1984 that the protein deposits in the brains of patients with the disease are composed of amyloid-β protein. Glenner demonstrated that this same peptide accumulated in the brains of individuals with Down's syndrome, many of whom became demented as they reached late middle age.

With subsequent cloning of the gene for the amyloid precursor protein (APP) and its localization to chromosome 21, the Down's syndrome connection acquired new significance, because it was suspected that mutations in this gene might be the cause of familial cases of Alzheimer's. This idea was supported by a report in the late 1980s demonstrating genetic linkage of several Alzheimer's disease families to chromosome 21. Ironically, this paper turned out to be incorrect; the genetic defect in these families proved to be linked to chromosome 14, and the causative genetic mutations were in the presenilin genes rather than in the genes encoding APP.

Tanzi and Parson describe how a period of uncertainty followed these initial studies, while investigators looked elsewhere for the genes and proteins behind Alzheimer's disease. Enthusiasm for amyloid-β protein as a causal element in the disease was revived in the early 1990s with the discovery that the protein has neurotoxic properties. In 1992, John Hardy and colleagues described the first APP mutation in Alzheimer's disease families, and the description of other APP mutations soon followed. These findings provided indisputable evidence that the disease could start with a defect in APP. The power of genetics to provide instant proof of the relevance of a protein to the disease became all too clear.

But the mechanism by which genetic mutations result in Alzheimer's disease was not as clear as for some of the other inherited degenerative conditions, such as Huntington's disease and Duchenne muscular dystrophy. An important insight came from the observation by Steven Younkin and colleagues that APP mutations resulted in a subtle, yet important change in the production of amyloid-β protein. The resulting protein was longer than normal and had a high propensity to aggregate and form plaques in the brain. This peptide was presumed to be more neurotoxic and a key factor in the disease process. In 1995, scientists at Athena Neurosciences and Exemplar Corporation showed that expression of an APP mutation in transgenic mice resulted in amyloid plaque formation in the brain. This model solidified the connection between the molecular genetics and the pathology of the disease, and provided an animal model that could be used for drug testing.

A new gene family associated with early-onset Alzheimer's disease, the presenilins, was discovered by Peter St George-Hyslop and colleagues, signalling a second major chapter in the neurogenetics of Alzheimer's disease. The book gives a detailed account of the intense race between several groups to find the gene. Tanzi's own group had been working on chromosome 14, which contains the presenilin-1 gene, and had come very close.

Disease-causing presenilin mutations were found to increase the production of the longer, more pathogenic form of amyloid, similar to the effects of disease-causing mutations in APP. In addition, the presenilins turned out to be associated with interesting biology, playing a pivotal role in brain development and potentially affecting signalling pathways involving cell death. Furthermore, recent findings raise the intriguing possibility that presenilin may be one of the two enzymes that mediate the generation of amyloid-β protein. Thus, altered amyloid metabolism is currently the most straightforward explanation for the pathogenic effects of presenilin mutations, although whether this is the sole or predominant mechanism is not known.

Despite their conceptual importance, mutations in the presenilins and APP account for a relatively small proportion of cases of Alzheimer's disease. The major known genetic risk factor is the ɛ4 variant of the plasma protein apolipoprotein E (apoE), discovered by Allen Roses and colleagues. Unlike the mutations in APP and the presenilins, which almost guarantee that a person will develop Alzheimer's disease, the apoE ɛ4 variant is a susceptibility gene that increases the risk of Alzheimer's disease after the age of 60. But the mechanism by which apoE causes Alzheimer's is not known. The discovery of the role of apoE was followed by reports of several other potential susceptibility genes, one of the most hotly debated being α2-macroglobulin, a protein that may be involved in the metabolism of amyloid-β protein.

The convergence of genetics and cell biology gave rise to the amyloid hypothesis, which posits that the abnormal generation, localization or aggregation of this peptide is toxic to neurons and leads to dementia. However, many believe that other factors, such as disruption of the cell infrastructure by neurofibrillary tangles, are more likely to be directly related to dementia. This idea has recently received support from the identification of mutations in the tau protein — the major component of neurofibrillary tangles — in a group of dementing diseases known as frontotemporal dementias. Genetic abnormalities in tau can therefore lead to neuronal degeneration, raising the possibility that abnormalities of tau in Alzheimer's disease may have similar effects.

If the amyloid hypothesis is correct, we may be on the verge of finding drugs that alter the course of the disease. The enzyme responsible for one of the two cleavages that generate amyloid-β from APP has recently been identified, making it a matter of time before effective inhibitors of the process become available.

Another novel approach has been to use immunization with the amyloid peptide. This dramatically reduces subsequent plaque formation in mouse models of the disease. And the amyloid vaccine has now entered phase I clinical trials. Additionally, therapeutic agents designed to prevent amyloid aggregation and toxicity are being developed. The hope is that these approaches will result in drugs that affect the cause of the disease rather than just the symptoms, a limitation of currently available drugs.

Decoding Darkness will appeal to those who want to know about the human dimension behind this exciting science. It is recommended reading for anyone interested in Alzheimer's disease and neurogenetics.

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