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Current status on Alzheimer disease molecular genetics: from past, to present, to future.

Bettens K, Sleegers K, Van Broeckhoven C - Hum. Mol. Genet. (2010)

Bottom Line: Linkage studies, candidate gene and whole-genome association studies have resulted in a tremendous amount of putative risk genes for Alzheimer's disease (AD).Yet, besides the three causal genes-amyloid precursor protein and presenilin 1 and 2 genes-and one risk gene apolipoprotein E (APOE), no single functional risk variant was identified.Discussing the possible involvement of rare alleles and other types of genetic variants, this review summarizes the current knowledge on the genetic spectrum of AD and integrates different approaches and recent discoveries by genome-wide association studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.

ABSTRACT
Linkage studies, candidate gene and whole-genome association studies have resulted in a tremendous amount of putative risk genes for Alzheimer's disease (AD). Yet, besides the three causal genes-amyloid precursor protein and presenilin 1 and 2 genes-and one risk gene apolipoprotein E (APOE), no single functional risk variant was identified. Discussing the possible involvement of rare alleles and other types of genetic variants, this review summarizes the current knowledge on the genetic spectrum of AD and integrates different approaches and recent discoveries by genome-wide association studies.

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Related in: MedlinePlus

Overview of several disease pathways involved in AD pathogenesis. Causal AD genes and AD risk factors are marked in blue. APP is synthesized by the endoplasmatic reticulum (ER) and the Golgi apparatus (1). Following the amyloidogenic pathway in neurons, APP is cleaved by β-secretase (BACE1) and γ-secretase (PSEN) to generate Aβ peptides and the amyloid intracellular domain [AICD] (2), which influences the transcription of several genes (3). In the APP retromer recycling pathway (1), APP is redirected to endosomes by SORL1. PICALM has a presumed role in APP endocytotic recycling (1). Aβ monomers aggregate into Aβ fibrils, causing amyloid plaques in brain parenchyma and vasculature (4). Aβ activates microglia and astrocytes, inducing the complement system, local inflammatory responses and oxidative stress (5). CR1 is the receptor of the complement C3b protein and participates in the clearance of Aβ from circulation (6). Besides causing increased Aβ endocytosis into glial cells, CLU is involved in Aβ clearance at the blood–brain barrier (7). APOE enhances amyloid plaque formation by conformational changes of Aβ. Clusterin (APOJ) and APOE are the main escorting proteins of Aβ in brain (7). Both are also important in cholesterol metabolism at the neuronal membrane (8) and high intracellular cholesterol may enhance APP amyloidogenic processing (2), which in turn can lead to membrane damage (9). Moreover, impaired cholesterol metabolism may influence synaptic dysfunction (10). Both PICALM and DNMBP are related at the synapse (10). Interaction of Aβ oligomers at the membrane is further connected to the calcium hypothesis in AD (11). Polymorphisms in the Ca2+ channel CALHM1 impair Ca2+ permeability at the plasma membrane (11). In addition, PSENs function as ER Ca2+-leak channels and several early-onset mutations impair Ca2+-leak-channel function, resulting in an excessive Ca2+ accumulation in the cytosol. An excessive Ca2+ is taken up by mitochondria, further leading to oxidative stress and apoptosis (12).
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DDQ142F2: Overview of several disease pathways involved in AD pathogenesis. Causal AD genes and AD risk factors are marked in blue. APP is synthesized by the endoplasmatic reticulum (ER) and the Golgi apparatus (1). Following the amyloidogenic pathway in neurons, APP is cleaved by β-secretase (BACE1) and γ-secretase (PSEN) to generate Aβ peptides and the amyloid intracellular domain [AICD] (2), which influences the transcription of several genes (3). In the APP retromer recycling pathway (1), APP is redirected to endosomes by SORL1. PICALM has a presumed role in APP endocytotic recycling (1). Aβ monomers aggregate into Aβ fibrils, causing amyloid plaques in brain parenchyma and vasculature (4). Aβ activates microglia and astrocytes, inducing the complement system, local inflammatory responses and oxidative stress (5). CR1 is the receptor of the complement C3b protein and participates in the clearance of Aβ from circulation (6). Besides causing increased Aβ endocytosis into glial cells, CLU is involved in Aβ clearance at the blood–brain barrier (7). APOE enhances amyloid plaque formation by conformational changes of Aβ. Clusterin (APOJ) and APOE are the main escorting proteins of Aβ in brain (7). Both are also important in cholesterol metabolism at the neuronal membrane (8) and high intracellular cholesterol may enhance APP amyloidogenic processing (2), which in turn can lead to membrane damage (9). Moreover, impaired cholesterol metabolism may influence synaptic dysfunction (10). Both PICALM and DNMBP are related at the synapse (10). Interaction of Aβ oligomers at the membrane is further connected to the calcium hypothesis in AD (11). Polymorphisms in the Ca2+ channel CALHM1 impair Ca2+ permeability at the plasma membrane (11). In addition, PSENs function as ER Ca2+-leak channels and several early-onset mutations impair Ca2+-leak-channel function, resulting in an excessive Ca2+ accumulation in the cytosol. An excessive Ca2+ is taken up by mitochondria, further leading to oxidative stress and apoptosis (12).

Mentions: The design of hypothesis-driven association studies has gradually shifted from studies in which only a few SNPs per gene were investigated to studies employing a more extensive linkage disequilibrium (LD)-based approach covering the complete genetic variation in a gene or a gene region, including, for example, regulatory regions. Besides the amyloid hypothesis, numerous candidate genes fitting one or another AD-related hypothesis on neurodegenerative pathways were analyzed, such as APP cleavage and trafficking, cholesterol metabolism, calcium dysregulation and so on (Fig. 2). As such, an endless record of candidate-gene-based studies was publicized. Nevertheless, none of the associated candidate genes attained an effect size similar to APOE ε4 and along with positive associations, negative replications for the same gene were described (their number will probably be higher since publication in the field is biased toward positive finding; http://www.alzgene.org/). Reasons for lack of reproducibility may include: insufficient study power to detect variants with minor contributions, biological, genetic and allelic heterogeneity, differences in study design and the presence of population substructure.


Current status on Alzheimer disease molecular genetics: from past, to present, to future.

Bettens K, Sleegers K, Van Broeckhoven C - Hum. Mol. Genet. (2010)

Overview of several disease pathways involved in AD pathogenesis. Causal AD genes and AD risk factors are marked in blue. APP is synthesized by the endoplasmatic reticulum (ER) and the Golgi apparatus (1). Following the amyloidogenic pathway in neurons, APP is cleaved by β-secretase (BACE1) and γ-secretase (PSEN) to generate Aβ peptides and the amyloid intracellular domain [AICD] (2), which influences the transcription of several genes (3). In the APP retromer recycling pathway (1), APP is redirected to endosomes by SORL1. PICALM has a presumed role in APP endocytotic recycling (1). Aβ monomers aggregate into Aβ fibrils, causing amyloid plaques in brain parenchyma and vasculature (4). Aβ activates microglia and astrocytes, inducing the complement system, local inflammatory responses and oxidative stress (5). CR1 is the receptor of the complement C3b protein and participates in the clearance of Aβ from circulation (6). Besides causing increased Aβ endocytosis into glial cells, CLU is involved in Aβ clearance at the blood–brain barrier (7). APOE enhances amyloid plaque formation by conformational changes of Aβ. Clusterin (APOJ) and APOE are the main escorting proteins of Aβ in brain (7). Both are also important in cholesterol metabolism at the neuronal membrane (8) and high intracellular cholesterol may enhance APP amyloidogenic processing (2), which in turn can lead to membrane damage (9). Moreover, impaired cholesterol metabolism may influence synaptic dysfunction (10). Both PICALM and DNMBP are related at the synapse (10). Interaction of Aβ oligomers at the membrane is further connected to the calcium hypothesis in AD (11). Polymorphisms in the Ca2+ channel CALHM1 impair Ca2+ permeability at the plasma membrane (11). In addition, PSENs function as ER Ca2+-leak channels and several early-onset mutations impair Ca2+-leak-channel function, resulting in an excessive Ca2+ accumulation in the cytosol. An excessive Ca2+ is taken up by mitochondria, further leading to oxidative stress and apoptosis (12).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2875058&req=5

DDQ142F2: Overview of several disease pathways involved in AD pathogenesis. Causal AD genes and AD risk factors are marked in blue. APP is synthesized by the endoplasmatic reticulum (ER) and the Golgi apparatus (1). Following the amyloidogenic pathway in neurons, APP is cleaved by β-secretase (BACE1) and γ-secretase (PSEN) to generate Aβ peptides and the amyloid intracellular domain [AICD] (2), which influences the transcription of several genes (3). In the APP retromer recycling pathway (1), APP is redirected to endosomes by SORL1. PICALM has a presumed role in APP endocytotic recycling (1). Aβ monomers aggregate into Aβ fibrils, causing amyloid plaques in brain parenchyma and vasculature (4). Aβ activates microglia and astrocytes, inducing the complement system, local inflammatory responses and oxidative stress (5). CR1 is the receptor of the complement C3b protein and participates in the clearance of Aβ from circulation (6). Besides causing increased Aβ endocytosis into glial cells, CLU is involved in Aβ clearance at the blood–brain barrier (7). APOE enhances amyloid plaque formation by conformational changes of Aβ. Clusterin (APOJ) and APOE are the main escorting proteins of Aβ in brain (7). Both are also important in cholesterol metabolism at the neuronal membrane (8) and high intracellular cholesterol may enhance APP amyloidogenic processing (2), which in turn can lead to membrane damage (9). Moreover, impaired cholesterol metabolism may influence synaptic dysfunction (10). Both PICALM and DNMBP are related at the synapse (10). Interaction of Aβ oligomers at the membrane is further connected to the calcium hypothesis in AD (11). Polymorphisms in the Ca2+ channel CALHM1 impair Ca2+ permeability at the plasma membrane (11). In addition, PSENs function as ER Ca2+-leak channels and several early-onset mutations impair Ca2+-leak-channel function, resulting in an excessive Ca2+ accumulation in the cytosol. An excessive Ca2+ is taken up by mitochondria, further leading to oxidative stress and apoptosis (12).
Mentions: The design of hypothesis-driven association studies has gradually shifted from studies in which only a few SNPs per gene were investigated to studies employing a more extensive linkage disequilibrium (LD)-based approach covering the complete genetic variation in a gene or a gene region, including, for example, regulatory regions. Besides the amyloid hypothesis, numerous candidate genes fitting one or another AD-related hypothesis on neurodegenerative pathways were analyzed, such as APP cleavage and trafficking, cholesterol metabolism, calcium dysregulation and so on (Fig. 2). As such, an endless record of candidate-gene-based studies was publicized. Nevertheless, none of the associated candidate genes attained an effect size similar to APOE ε4 and along with positive associations, negative replications for the same gene were described (their number will probably be higher since publication in the field is biased toward positive finding; http://www.alzgene.org/). Reasons for lack of reproducibility may include: insufficient study power to detect variants with minor contributions, biological, genetic and allelic heterogeneity, differences in study design and the presence of population substructure.

Bottom Line: Linkage studies, candidate gene and whole-genome association studies have resulted in a tremendous amount of putative risk genes for Alzheimer's disease (AD).Yet, besides the three causal genes-amyloid precursor protein and presenilin 1 and 2 genes-and one risk gene apolipoprotein E (APOE), no single functional risk variant was identified.Discussing the possible involvement of rare alleles and other types of genetic variants, this review summarizes the current knowledge on the genetic spectrum of AD and integrates different approaches and recent discoveries by genome-wide association studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.

ABSTRACT
Linkage studies, candidate gene and whole-genome association studies have resulted in a tremendous amount of putative risk genes for Alzheimer's disease (AD). Yet, besides the three causal genes-amyloid precursor protein and presenilin 1 and 2 genes-and one risk gene apolipoprotein E (APOE), no single functional risk variant was identified. Discussing the possible involvement of rare alleles and other types of genetic variants, this review summarizes the current knowledge on the genetic spectrum of AD and integrates different approaches and recent discoveries by genome-wide association studies.

Show MeSH
Related in: MedlinePlus