Genetics and Molecular Biology of Alzheimer’s Disease and Frontotemporal Lobar Degeneration
21, in which β-APP resides, is triplicated in Down’s syndrome and most cases also manifest AD by 50 years of age. Post mortem analyses of Down’s patients who die young show diffuse intraneuronal deposits of Aβ, suggesting that its deposition is an early event in cognitive decline. The discovery of an extra copy of the β-APP gene in familial AD9
production can cause the disease.
The other two genes causing familial AD are presenilin 1 (PSEN1) (14q24.3) and PSEN2 (1q31-q42).10,11
Presenilins represent a central
component of γ-secretase, the enzyme responsible for originating Aβ from the C-terminal fragment of the APP protein. Mutations in presenilins also alter APP cleavage, leading to an increased
production of Aβ42. So far, 178 mutations in PSEN1 have been identified and 14 additional mutations have been found in the homologous gene PSEN2 (
www.molgen.ua.ac.be/).
Most variants in PSEN1 are missense mutations resulting in single- amino-acid substitutions. Some are more complex, for example small deletions or splice mutations. The most severe mutation in PSEN1 is a donor–acceptor splice mutation that causes a two-amino- acid substitution and an in-frame deletion of exon 9. However, the biochemical consequences of these mutations for γ-secretase assembly seem to be limited.12,13
All of these clinical mutations are likely to cause a specific gain of toxic function for PSEN1, determined
by an increase of the ratio between Aβ42 and Aβ40 amyloid peptides, thus indicating that presenilins might modify the way in which γ-secretase cuts APP.
Mutations in presenilins occur in the catalytic subunit of the protease responsible for determining the length of Aβ peptides, thereby generating toxic Aβ fragments. However, presenilins also have non-proteolytic functions,14,15
contribute to familial AD pathogenesis.
Despite several carriers developing the disease early (at 40–50 years of age) with a typical AD phenotype, in some cases patients carrying the same mutation develop signs and symptoms resembling FTD instead of AD.16
In addition, other mutations are associated with myoclonus, seizures, bilateral spasticity, parkinsonian features or ataxia.17
Sporadic Alzheimer’s Disease
Risk genes are likely to be numerous, displaying intricate patterns of interaction with each other as well as with non-genetic variables, and – unlike classical Mendelian (‘simplex’) disorders – exhibit no simple mode of inheritance. Mainly due to this reason, the genetics of sporadic AD has been labelled ‘complex’.18
the sporadic forms of AD is apolipoprotein E (APOE),19
The gene mainly related to which is located
at chromosome 19q13.32 and was initially identified by linkage analysis.20
The relationship between APOE and AD has been confirmed in more than 100 studies conducted in different populations. The gene has three different alleles, APOE*2, APOE*3 and APOE*4. The APOE*4 allele is the variant associated with AD. Longitudinal studies in Caucasian populations have shown that carriers for one APOE*4 allele have a two-fold increase in the risk of AD.21
The risk increases in those
homozygous for the APOE*4 allele, and this allelic variant is also associated with an earlier onset of the disease.
Several linkage studies have been performed, giving rise to additional candidate susceptibility loci at chromosomes 1, 4, 6, 9, 10, 12 and 19.
EUROPEAN NEUROLOGICAL REVIEW
In particular, promising loci have been found at chromosomes 9 and 10.22,23
Recently, a wide genome analysis identified variants at CLU (which encodes clusterin or ApoJ) on chromosome 8 and phosphatidylinositol binding clathrin assembly protein (PICALM) on chromosome 11 associated with AD.24
Data on CLU were contemporarily provides further support that increased Aβ
replicated in an independent study that, in addition, demonstrated that CR1, encoding the complement component (3b/4b) receptor 1 and located on chromosome 1, is associated with AD.25
Also, a large number of candidate gene studies have been performed in order to search for a robust risk factor for the sporadic form of the disease. Several studies mainly focused on genes clearly involved in the pathogenesis of AD, such as genes encoding for inflammatory molecules or involved in the oxidative stress cascade.
Polymorphisms in the interleukin-1 (IL-1) complex, which includes IL-1α, IL-1β, and IL-1 receptor antagonist protein (IL-1Rα), are associated with AD in different populations.26–28
Several polymorphisms
in IL-6, which is a potent inflammatory cytokine but has also regulatory functions, have been investigated as well. The IL-6 gene is located at chromosome 7p21 and polymorphisms exist in the -174 promoter region and in the region of a variable number of tandem repeats (VNTR), which is located in the 3’ untranslated region. Both of them have been found to be associated with AD in case–control studies.29,30 Investigation of tumour necrosis factor-α (TNF-α) polymorphisms was initiated because genome screening suggested a putative association of AD with a region on chromosome 6p21.3, which lies within 20 centimorgans of the TNF-αgene. Furthermore, other polymorphisms located in the promoter region of TNF-α have been associated with autoimmune and inflammatory diseases.31
the disruption of which might also
Polymorphisms in chemokines have been investigated with regard to susceptibility to AD. In particular, monocyte chemoattractant protein- 1 (MCP-1) and regulated on activation, normal T-cell expressed and secreted (RANTES) genes have been widely screened in different neurodegenerative diseases.32
The distribution of the A-2518G variant
was determined in different AD populations with concordant results showing no evidence for association of this variant in AD compared with controls.33,34
RANTES promoter polymorphism -403 A/G, found to be associated with several autoimmune diseases, was examined in an AD population, failing to exhibit significant differences between patients and controls.32
The chemokine receptor 2 ( CCR2) and CCR5 genes, encoding for the receptors of MCP-1 and RANTES, respectively, have also been screened for association with AD. The most promising variants involve a conservative change of a valine with an isoleucine at codon 64 of CCR2 (CCR2-64I) and a 32bp deletion in the coding region of CCR5 (CCR5∆32) that leads to the expression of a non-functional receptor. A decreased frequency and an absence of homozygotes for the polymorphism CCR2-64I were found in AD, suggesting a protective effect of the polymorphic allele on the occurrence of the disease;65
conversely, no different distribution of the CCR5∆32 deletion in patients compared with controls was shown.35,36
Another chemokine recently tested for susceptibility with AD is IP-10. A mutation scanning of the gene coding region has been performed in AD patients searching for new variants. The analysis demonstrated the
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