Genetic Factors in Alzheimer's Disease
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《新英格兰医药杂志》
Nearly 100 years ago, Alois Alzheimer described the clinical and pathological characteristics of a 50-year-old woman with the dementing illness that now bears his name.1 She had no family history of dementia. It soon became established dogma that Alzheimer's disease was a rare, noninherited cause of presenile dementia.
The past 25 years have seen an astounding confluence of seven new observations that have resulted in fundamental changes in our understanding of this important disease. First, Alzheimer's disease is by far the most common cause of dementia. Second, the major pathological component of the disease is the accumulation of a form of amyloid termed A peptide. Third, this peptide is cleaved from a larger protein, the amyloid precursor protein, the gene for which resides on chromosome 21. Fourth, the pathological changes of Alzheimer's disease are found in the brains of adults with trisomy 21 (Down's syndrome). Fifth, many families have an abundance of members with Alzheimer's disease, suggesting autosomal dominant inheritance. Sixth, mutations in any of three genes are sufficient to cause the disease in certain of these families. And finally, the 4 allele of apolipoprotein E is a risk factor for the most common type of Alzheimer's disease in the general population. The dogma has now been reversed: Alzheimer's disease is a common disease with important genetic components.
Initially, the genetic discovery with the greatest importance was that point mutations in any of three genes could cause autosomal dominant inherited forms of Alzheimer's disease that were clinically and pathologically identical to nongenetic forms of the disease except that the age at onset was younger.2 The first mutations were found in the APP gene on chromosome 21. These mutations tend to cluster near sites where the A peptide is cleaved from amyloid precursor protein (- and -secretase sites) or where the A peptide itself is cleaved (the -secretase site). The next group of mutations was found in the genes encoding two proteins called presenilin 1 and 2. Subsequently, it was discovered that these two proteins play a role in the -secretase cleavage of A from amyloid precursor protein. Thus, it became clear that the primary consequence of these mutations was an increase in the deposition of the pathogenic form of A, A(1– 42), in the brain. These findings, combined with the understanding that Alzheimer's disease in patients with trisomy 21 probably resulted from a lifelong, mild but consistent excess of A, provided the most important evidence supporting the amyloid-cascade hypothesis for the pathogenesis of the disease.
This hypothesis emphasizes the critical role of A deposition in the flow of events that lead to plaque formation, synaptic loss, neuronal dysfunction, neuronal death, and clinical dementia. The hypothesis is important in that it has led to prominent strategies for possible treatment of the disease, including vaccination with A peptide (or administration of antibodies to A) and attempts to inhibit -secretase activity. In addition, the role of neurofibrillary tangles in the pathogenesis of Alzheimer's disease requires further elucidation.
Mutations in the genes encoding amyloid precursor protein and presenilin 1 and 2 (APP, PS1, and PS2) cause familial early-onset Alzheimer's disease. The age at onset in these families is typically in the 40s or 50s and, astonishingly, sometimes as early as the 20s. The onset is almost never after 65 years of age — in contrast to the typical age at the onset of Alzheimer's disease in the general population, in which the frequency increases with every decade after 70 years of age. Although mutations in the APP, PS1, and PS2 genes cause less than 2 percent of cases of Alzheimer's disease, 25 percent of persons with late-onset forms of the disease have had a close relative with dementia. In fact, there are many families that have a heavy load of late-onset Alzheimer's disease but do not have mutations in APP, PS1, or PS2. The hunt is on to identify additional genetic factors in the more common late-onset form of the disease.
One factor is the gene (APOE) encoding apolipoprotein E, a plasma-membrane protein involved in lipid transport. The gene's 4 allele is associated with a shift to an earlier age at onset. For example, a person of European descent who is homozygous for the 4 allele (as about 2 percent of the population is) has a lifetime risk of Alzheimer's disease that is three to four times as great as that for someone of European descent who does not have an 4 allele. Moreover, the age at onset is likely to be about 10 to 15 years earlier than that in the general population.
However, the APOE 4 genotype is neither necessary nor sufficient for the occurrence of Alzheimer's disease. It is estimated that there are at least two or three (and possibly five or six) additional genes influencing the age at onset and the risk of the disease.3 Genetic linkage analysis and similar studies involving hundreds of families have produced evidence for a number of chromosomal regions suspected of harboring genes related to Alzheimer's disease. These include regions on chromosomes 6, 9, 10, 12, and 19.4 So far, careful scrutiny of these regions has not resulted in the identification of an unequivocal "Alzheimer's disease gene." More than 100 genes have been implicated through genetic-association studies, but none of these findings have been fully replicated.5 The hunt continues, driven by the need to better understand the pathogenesis of the disease and improve diagnosis, treatment, and prevention.
Evidence for the latest candidate gene (UBQLN1, encoding ubiquilin 1) is presented by Bertram and colleagues in this issue of the Journal (pages 884–894). UBQLN1 is intriguing as a candidate gene because of its potential role in the proteasome degradation of proteins and its interaction with PS1 and PS2. As always, this new association requires replication and confirmation in additional populations of patients with Alzheimer's disease.
The role of environment cannot be ignored. The days of debating nature versus nurture are long past: it is clear that most disease is caused by a combination of genetic and environmental factors (see the diagram). The key issues in complex conditions such as Alzheimer's disease are identifying those specific genetic and environmental factors, determining their relative importance, understanding their interactions, and capitalizing on this knowledge in order to treat and prevent the disease. These remain the goals of the many scientists who are doggedly pursuing the puzzle of Alzheimer's disease.
Adding up to Alzheimer's Disease.
The known genetic causes of Alzheimer's disease (left side) are responsible for only a small number of the total cases. The possible environmental factors (right side) are largely speculative; none are proven causes. The most likely pathway resulting in Alzheimer's disease in the general population (bottom) involves predisposing genetic factors (such as the 4 variant of the APOE gene) combined with a variety of environmental factors and interacting with physiological aging processes in the brain.
Dr. Bird reports having served on the speakers bureau for Athena Diagnostics.
Source Information
Dr. Bird is a professor of neurology, medicine, and psychiatry at the University of Washington and a research neurologist at the Veterans Affairs Medical Center in Seattle.
References
Maurer K, Volk S, Gerbaldo H. Auguste D and Alzheimer's disease. Lancet 1997;349:1546-1549.
Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med 2003;348:1356-1364.
Daw WE, Payami H, Nemens EJ, et al. The number of trait loci in late-onset Alzheimer disease. Am J Hum Genet 2000;66:196-204.
Kamboh MI. Molecular genetics of late-onset Alzheimer's disease. Ann Hum Genet 2004;68:381-404.
Bertram L, Tanzi RE. Alzheimer's disease: one disorder, too many genes? Hum Mol Genet 2004;13 Special No. 1:R135-R141.(Thomas D. Bird, M.D.)
The past 25 years have seen an astounding confluence of seven new observations that have resulted in fundamental changes in our understanding of this important disease. First, Alzheimer's disease is by far the most common cause of dementia. Second, the major pathological component of the disease is the accumulation of a form of amyloid termed A peptide. Third, this peptide is cleaved from a larger protein, the amyloid precursor protein, the gene for which resides on chromosome 21. Fourth, the pathological changes of Alzheimer's disease are found in the brains of adults with trisomy 21 (Down's syndrome). Fifth, many families have an abundance of members with Alzheimer's disease, suggesting autosomal dominant inheritance. Sixth, mutations in any of three genes are sufficient to cause the disease in certain of these families. And finally, the 4 allele of apolipoprotein E is a risk factor for the most common type of Alzheimer's disease in the general population. The dogma has now been reversed: Alzheimer's disease is a common disease with important genetic components.
Initially, the genetic discovery with the greatest importance was that point mutations in any of three genes could cause autosomal dominant inherited forms of Alzheimer's disease that were clinically and pathologically identical to nongenetic forms of the disease except that the age at onset was younger.2 The first mutations were found in the APP gene on chromosome 21. These mutations tend to cluster near sites where the A peptide is cleaved from amyloid precursor protein (- and -secretase sites) or where the A peptide itself is cleaved (the -secretase site). The next group of mutations was found in the genes encoding two proteins called presenilin 1 and 2. Subsequently, it was discovered that these two proteins play a role in the -secretase cleavage of A from amyloid precursor protein. Thus, it became clear that the primary consequence of these mutations was an increase in the deposition of the pathogenic form of A, A(1– 42), in the brain. These findings, combined with the understanding that Alzheimer's disease in patients with trisomy 21 probably resulted from a lifelong, mild but consistent excess of A, provided the most important evidence supporting the amyloid-cascade hypothesis for the pathogenesis of the disease.
This hypothesis emphasizes the critical role of A deposition in the flow of events that lead to plaque formation, synaptic loss, neuronal dysfunction, neuronal death, and clinical dementia. The hypothesis is important in that it has led to prominent strategies for possible treatment of the disease, including vaccination with A peptide (or administration of antibodies to A) and attempts to inhibit -secretase activity. In addition, the role of neurofibrillary tangles in the pathogenesis of Alzheimer's disease requires further elucidation.
Mutations in the genes encoding amyloid precursor protein and presenilin 1 and 2 (APP, PS1, and PS2) cause familial early-onset Alzheimer's disease. The age at onset in these families is typically in the 40s or 50s and, astonishingly, sometimes as early as the 20s. The onset is almost never after 65 years of age — in contrast to the typical age at the onset of Alzheimer's disease in the general population, in which the frequency increases with every decade after 70 years of age. Although mutations in the APP, PS1, and PS2 genes cause less than 2 percent of cases of Alzheimer's disease, 25 percent of persons with late-onset forms of the disease have had a close relative with dementia. In fact, there are many families that have a heavy load of late-onset Alzheimer's disease but do not have mutations in APP, PS1, or PS2. The hunt is on to identify additional genetic factors in the more common late-onset form of the disease.
One factor is the gene (APOE) encoding apolipoprotein E, a plasma-membrane protein involved in lipid transport. The gene's 4 allele is associated with a shift to an earlier age at onset. For example, a person of European descent who is homozygous for the 4 allele (as about 2 percent of the population is) has a lifetime risk of Alzheimer's disease that is three to four times as great as that for someone of European descent who does not have an 4 allele. Moreover, the age at onset is likely to be about 10 to 15 years earlier than that in the general population.
However, the APOE 4 genotype is neither necessary nor sufficient for the occurrence of Alzheimer's disease. It is estimated that there are at least two or three (and possibly five or six) additional genes influencing the age at onset and the risk of the disease.3 Genetic linkage analysis and similar studies involving hundreds of families have produced evidence for a number of chromosomal regions suspected of harboring genes related to Alzheimer's disease. These include regions on chromosomes 6, 9, 10, 12, and 19.4 So far, careful scrutiny of these regions has not resulted in the identification of an unequivocal "Alzheimer's disease gene." More than 100 genes have been implicated through genetic-association studies, but none of these findings have been fully replicated.5 The hunt continues, driven by the need to better understand the pathogenesis of the disease and improve diagnosis, treatment, and prevention.
Evidence for the latest candidate gene (UBQLN1, encoding ubiquilin 1) is presented by Bertram and colleagues in this issue of the Journal (pages 884–894). UBQLN1 is intriguing as a candidate gene because of its potential role in the proteasome degradation of proteins and its interaction with PS1 and PS2. As always, this new association requires replication and confirmation in additional populations of patients with Alzheimer's disease.
The role of environment cannot be ignored. The days of debating nature versus nurture are long past: it is clear that most disease is caused by a combination of genetic and environmental factors (see the diagram). The key issues in complex conditions such as Alzheimer's disease are identifying those specific genetic and environmental factors, determining their relative importance, understanding their interactions, and capitalizing on this knowledge in order to treat and prevent the disease. These remain the goals of the many scientists who are doggedly pursuing the puzzle of Alzheimer's disease.
Adding up to Alzheimer's Disease.
The known genetic causes of Alzheimer's disease (left side) are responsible for only a small number of the total cases. The possible environmental factors (right side) are largely speculative; none are proven causes. The most likely pathway resulting in Alzheimer's disease in the general population (bottom) involves predisposing genetic factors (such as the 4 variant of the APOE gene) combined with a variety of environmental factors and interacting with physiological aging processes in the brain.
Dr. Bird reports having served on the speakers bureau for Athena Diagnostics.
Source Information
Dr. Bird is a professor of neurology, medicine, and psychiatry at the University of Washington and a research neurologist at the Veterans Affairs Medical Center in Seattle.
References
Maurer K, Volk S, Gerbaldo H. Auguste D and Alzheimer's disease. Lancet 1997;349:1546-1549.
Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med 2003;348:1356-1364.
Daw WE, Payami H, Nemens EJ, et al. The number of trait loci in late-onset Alzheimer disease. Am J Hum Genet 2000;66:196-204.
Kamboh MI. Molecular genetics of late-onset Alzheimer's disease. Ann Hum Genet 2004;68:381-404.
Bertram L, Tanzi RE. Alzheimer's disease: one disorder, too many genes? Hum Mol Genet 2004;13 Special No. 1:R135-R141.(Thomas D. Bird, M.D.)