Neurobiology of Aging, Vol. 10, p. 415. ~ Pergamon Press plc, 1989. Printed in the U.S.A. 0197-4580/89 $3.00 + .00

Designer Genes: Current Fad or Lasting Fashion?

THE study of the role of genetics in Alzheimer's disease (AD) has enjoyed a predictably rapid growth in the past several years. At the time the previous 1986 Neurobiology of Aging issue on AD was published, the notion that a genetic component contributed to at least a subset of AD was gaining support, while optimism that molecular genetics may help elucidate the relationship was grow- ing rapidly. Since that time, the likelihood of an inherited form of AD has gained even more widespread support as investigators from different genetic subspecialities continued to investigate the potential role of genetics in AD by identifying and studying greater numbers of pedigree families exhibiting a pattern of autosomal dominant inheritance. During this same period, a study by Hyslop and colleagues, applying the methods of molecular genetics, implicated a gene located on chromosome 21 as contributing to Familial Alzheimer's disease (FAD). Under any circumstances, identifying a gene that might be responsible for the inheritance of AD would have been cause for excitement. However, when the linked gene was found to reside on chromosome 21, in close proximity to the beta-amyloid peptide (BAP) precursor gene, the pace and pulse of research in the field quickened to that of a heated foot race.

However, it was not long before the excitement and expecta- tions were replaced with some degree of disappointment and controversy. The disappointment resulted from studies which clearly showed that although the FAD gene locus was physically close to the BAP gene, they were not linked. Moreover, the BAP gene was, at best, only loosely linked to AD. Controversy expanded because certain laboratories were unable to demonstrate linkage of FAD to a locus on chromosome 21 (although still others have subsequently reported confirmation of the linkage).

The initial optimism and unbridled enthusiasm was soon followed by confusion, disagreement and methodological debates, producing several different schools of thought. Some continue to support the likelihood of a chromosome 21 locus for FAD, while others conclude that no gene locus for FAD has yet been demonstrated on any chromosome. An emerging camp in the middle road maintains that a strong case for genetic heterogeneity has been made and that multiple gene loci must be responsible for AD. Finally, there also exists a number of investigators who feel that too much emphasis has been directed toward the genetic role of AD, especially in view of the admittedly simplistic single gene hypothesis that has primarily prevailed.

In the next review of this issue, Dr. Hyslop provides a comprehensive overview of this complicated and controversial field, offering an excellent look at the current thinking and

research on the genetics of AD. His valuable review of the field is nicely organized into several major sections including those on Population and Epidemiologic Studies, Molecular Genetic Studies and Future Directions. In each case, he provides a scholarly description of the various approaches and opportunities for ad- dressing current questions, including a discussion of the major assumptions and limitations of each. Within each section also occurs a reasonably balanced review of the literature which employs those approaches and a discussion of some of the current problems. The commentators provide an unusually broad range of perspectives and comments. In terms of the variety of their remarks, thus what may seem lean in terms of any consensus is quite rich. The dialogue contained in these pages reveals the study of the genetics of Alzheimer's will continue to be intense, controversial and exciting for some time.

The commentaries that follow Dr. Hyslop's review provide an interesting representation of the diversity of thinking and the areas of disagreement that seems to have recently emerged in this field. Some of these investigators are attempting to develop more innovative strategies to help break the empirical/intellectual log- jam and reestablish the momentum toward greater insight that seemed so strong just two years ago. Many continue to search the genome for more conclusive evidence of genetic linkage. Most seem to agree that many of the current impediments to progress should decline with time, especially as the genome becomes better characterized, greater numbers of twins, pedigree families and other resources become more widely available, more conclusive methods of diagnosing and defining heterogeneous subgroups are developed, and finally when the environmental variables and other major risk factors are more conclusively defined.

Nonetheless, the optimism that recently existed seems to have been replaced by a more cautious and respectful appreciation for the apparent complexity of the disease and the enormity of the current problems that limit current progress. Although one senses from the following review and commentaries that few doubt that the underlying genetic and environmental variables responsible for AD will be eventually elucidated, it is becoming increasingly clear that the relationships are not likely to be simple. Hopefully, the dialogue contained in these pages will help focus and stimulate attention so that our common search for answers will be facili- tated.

Raymond T. Bartus Guest Editor

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