Meta-analysis of genetic variability in the β-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 β‐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, α1‐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) ε4 carriers [odds ratio (OR) = 0.57; 95% confidence interval (CI): 0.38–0.88], and as a risk factor in ApoE ε4 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 Aβ production, aggregation and degradation mediators might help in determining the risk profile for AD.