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Genetics of Alzheimer's disease: recent advances.

Avramopoulos D - Genome Med (2009)

Bottom Line: Alzheimer's genetics research in the 1990s was successful in identifying three genes accounting for most cases of early-onset disease with autosomal dominant inheritance, and one gene involved in the more common late-onset disease, which shows complex inheritance patterns.Despite the presence of significant remaining genetic contribution to the risk, the identification of genes since then has been elusive, reminiscent of most other complex disorders.As sample sizes grow through new collections and collaborative efforts, and as new technologies make it possible to test alternative hypotheses, it is expected that new genes involved in the disease will soon be identified and confirmed.

View Article: PubMed Central - HTML - PubMed

Affiliation: McKusick Nathans Institute of Genetic Medicine and Department of Psychiatry, Johns Hopkins University School of Medicine, Broadway Research Building Room 509, 733 N Broadway, Baltimore, MD 21205, USA.

ABSTRACT
Alzheimer's disease is a progressive neurodegenerative disorder with high prevalence in old age. It is the most common cause of dementia, with a risk reaching 50% after the age of 85 years, and with the increasing age of the population it is one of the biggest healthcare challenges of the 21st century. Genetic variation is an important contributor to the risk for this disease, underlying an estimated heritability of about 70%. Alzheimer's genetics research in the 1990s was successful in identifying three genes accounting for most cases of early-onset disease with autosomal dominant inheritance, and one gene involved in the more common late-onset disease, which shows complex inheritance patterns. Despite the presence of significant remaining genetic contribution to the risk, the identification of genes since then has been elusive, reminiscent of most other complex disorders. In the past decade there have been significant efforts towards a systematic evaluation of the multiple genetic association studies for Alzheimer's disease, while the first genome-wide association studies are now being reported with promising results. As sample sizes grow through new collections and collaborative efforts, and as new technologies make it possible to test alternative hypotheses, it is expected that new genes involved in the disease will soon be identified and confirmed. The gene discoveries of the 1990s have taught us a lot about Alzheimer's disease pathogenesis, providing many therapeutic targets that are currently at various stages of testing for future clinical use. As new genes become known and the biological pathways leading to disease are further explored, the possibility of prevention and successful personalized treatment is becoming tangible, providing hope for the millions of patients with Alzheimer's disease and their caregivers.

No MeSH data available.


Related in: MedlinePlus

The amyloidogenic and non-amyloidogenic cleavage pathway of APP. Mutations in APP, PSEN1 or PSEN2 cause early-onset AD. PSEN1 and 2 are components of γ-secretase. The amyloidogenic peptide Aβ is shown in orange. reliable associations from GWAS, the best targets and strategies to intervene will become clearer.
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Figure 1: The amyloidogenic and non-amyloidogenic cleavage pathway of APP. Mutations in APP, PSEN1 or PSEN2 cause early-onset AD. PSEN1 and 2 are components of γ-secretase. The amyloidogenic peptide Aβ is shown in orange. reliable associations from GWAS, the best targets and strategies to intervene will become clearer.

Mentions: It is now more than 15 years since the discovery of the first genes involved in AD, and while we are still on a quest for additional genes, we have learned a lot about the disease. The processing of APP through cleavage by γ-secretase, an enzymatic complex whose catalytic subunit is formed by the presenilins [38], is considered by many as a key in the disease process. It leads to generation of the amyloidogenic peptide Aβ (Figure 1) and its aggregation into fibrils and toxic oligomeric forms, the earliest effectors of synaptic compromise [39], followed by neurodegeneration. The direct involvement of the products of at least three out of the four known genes in this hypothesis is no coincidence and significantly strengthens the confidence that this is a promising target for treatment. These genes have greatly enhanced our knowledge of the pathway leading to the production of amyloid (Figure 1), which has in turn provided targets for intervention.


Genetics of Alzheimer's disease: recent advances.

Avramopoulos D - Genome Med (2009)

The amyloidogenic and non-amyloidogenic cleavage pathway of APP. Mutations in APP, PSEN1 or PSEN2 cause early-onset AD. PSEN1 and 2 are components of γ-secretase. The amyloidogenic peptide Aβ is shown in orange. reliable associations from GWAS, the best targets and strategies to intervene will become clearer.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2664945&req=5

Figure 1: The amyloidogenic and non-amyloidogenic cleavage pathway of APP. Mutations in APP, PSEN1 or PSEN2 cause early-onset AD. PSEN1 and 2 are components of γ-secretase. The amyloidogenic peptide Aβ is shown in orange. reliable associations from GWAS, the best targets and strategies to intervene will become clearer.
Mentions: It is now more than 15 years since the discovery of the first genes involved in AD, and while we are still on a quest for additional genes, we have learned a lot about the disease. The processing of APP through cleavage by γ-secretase, an enzymatic complex whose catalytic subunit is formed by the presenilins [38], is considered by many as a key in the disease process. It leads to generation of the amyloidogenic peptide Aβ (Figure 1) and its aggregation into fibrils and toxic oligomeric forms, the earliest effectors of synaptic compromise [39], followed by neurodegeneration. The direct involvement of the products of at least three out of the four known genes in this hypothesis is no coincidence and significantly strengthens the confidence that this is a promising target for treatment. These genes have greatly enhanced our knowledge of the pathway leading to the production of amyloid (Figure 1), which has in turn provided targets for intervention.

Bottom Line: Alzheimer's genetics research in the 1990s was successful in identifying three genes accounting for most cases of early-onset disease with autosomal dominant inheritance, and one gene involved in the more common late-onset disease, which shows complex inheritance patterns.Despite the presence of significant remaining genetic contribution to the risk, the identification of genes since then has been elusive, reminiscent of most other complex disorders.As sample sizes grow through new collections and collaborative efforts, and as new technologies make it possible to test alternative hypotheses, it is expected that new genes involved in the disease will soon be identified and confirmed.

View Article: PubMed Central - HTML - PubMed

Affiliation: McKusick Nathans Institute of Genetic Medicine and Department of Psychiatry, Johns Hopkins University School of Medicine, Broadway Research Building Room 509, 733 N Broadway, Baltimore, MD 21205, USA.

ABSTRACT
Alzheimer's disease is a progressive neurodegenerative disorder with high prevalence in old age. It is the most common cause of dementia, with a risk reaching 50% after the age of 85 years, and with the increasing age of the population it is one of the biggest healthcare challenges of the 21st century. Genetic variation is an important contributor to the risk for this disease, underlying an estimated heritability of about 70%. Alzheimer's genetics research in the 1990s was successful in identifying three genes accounting for most cases of early-onset disease with autosomal dominant inheritance, and one gene involved in the more common late-onset disease, which shows complex inheritance patterns. Despite the presence of significant remaining genetic contribution to the risk, the identification of genes since then has been elusive, reminiscent of most other complex disorders. In the past decade there have been significant efforts towards a systematic evaluation of the multiple genetic association studies for Alzheimer's disease, while the first genome-wide association studies are now being reported with promising results. As sample sizes grow through new collections and collaborative efforts, and as new technologies make it possible to test alternative hypotheses, it is expected that new genes involved in the disease will soon be identified and confirmed. The gene discoveries of the 1990s have taught us a lot about Alzheimer's disease pathogenesis, providing many therapeutic targets that are currently at various stages of testing for future clinical use. As new genes become known and the biological pathways leading to disease are further explored, the possibility of prevention and successful personalized treatment is becoming tangible, providing hope for the millions of patients with Alzheimer's disease and their caregivers.

No MeSH data available.


Related in: MedlinePlus