Meta-analysis of genetic variability in the beta-amyloid production, aggregation and degradation metabolic pathways and the risk of Alzheimer's disease.
BACKGROUND
Variants in genes encoding enzymes involved in production, aggregation or degradation of beta-amyloid are potential risk factors for sporadic Alzheimer's disease (AD).


METHODS
Meta-analyses on AD association with BACE1 exon 5, BACE1 intron 5, FE65 intron 13, CYP46 intron 2, alpha(1)-antichymotrypsine Ala17Thr, bleomycin hydrolase I443V, lectin-like oxidized low-density lipoprotein receptor (OLR1) 3'-UTR (+1071) and (+1073), and very-low-density lipoprotein receptor (VLDLR) 5'-UTR (CGG-repeat) polymorphisms.


RESULTS
In BACE1 exon 5, genotype CC+CT acts as a protective factor in Apolipoprotein E (ApoE) epsilon 4 carriers [odds ratio (OR) = 0.57; 95% confidence interval (CI): 0.38-0.88], and as a risk factor in ApoE epsilon 4 non-carriers (OR = 1.33; 95% CI: 1.00-1.78). OLR1 3'-UTR (+1073) allele C is associated with increased risk (OR = 1.23; 95% CI: 1.01-1.50). VLDLR 5'-UTR genotype 2 is associated with increased risk (OR = 1.70; 95% CI: 1.09-2.63) in the Asian population and is protective (OR = 0.48; 95% CI: 0.26-0.86) in the non-Asian population. Other studied polymorphisms are not associated with AD.


CONCLUSIONS
The overall impact on AD risk of the genes for which meta-analyses are now available is rather limited. Additional meta-analyses of other different genes encoding for A beta production, aggregation and degradation mediators might help in determining the risk profile for AD.
Llorca
J
J
Division of Epidemiology and Computational Biology, University of Cantabria School of Medicine, Santander, Spain. llorcaj@unican.es
Rodríguez-Rodríguez
E
E
Dierssen-Sotos
T
T
Delgado-Rodríguez
M
M
Berciano
J
J
Combarros
O
O
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000235:genetics
D016229:Amyloid beta-Peptides; C495137:OLR1 protein, human; D011973:Receptors, LDL; D051127:Scavenger Receptors, Class E; C036053:VLDL receptor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human