Alzheimer’s disease is the most common form of dementia with polygenic disposition occurring within various populations. A series of molecular studies indicated that there are number of genes linked to late onset Alzheimer’s disease (AD). In the current study, we examined the contribution of B2-AR (Gly16, Arg), TLR2 (-196TO-174del), PICALM (rs3851179) and BDNF (rs6265) alleles and genotypes, and their relevance in response to Rivastigmine in 150 Iranian AD patients and 150 controls. Genotyping was performed employing Tetra-primer ARMS–PCR and RFLP-PCR methods. Our statistical analysis suggests that A and G alleles of B2-AR show significantly negative (Pc=0.02, RR= 0.65, 95%Cl=0.30-0.94) and positive (Pc=0.02, RR=1.21, 95%Cl=1.06-3.29) associations with familial Alzheimer’s disease (FAD), respectively. Interestingly, after excluding APOE ε4 allele, our results indicated that B2-AR A allele confers more significant protection (Pc=0.006, RR=0.52, 95%Cl=0.33-0.83), while G allele (Pc=0.006, RR=1.90, 95%Cl=1.20- 3.00) and GG genotypes (Pc=0.008, RR= 2.25, 95%Cl=1.26-4.06) provide major susceptibility to AD. We also calculated the clinical relevance of the testing utilizing Prevalence-corrected Positive Predictive Value (PcPPV) formula. The PcPPV of B2-AR A and G alleles were 1.5% and 2.7% respectively in FAD patients. Moreover, the PcPPV for Apo E4 negative AD patients carrying B2-AR GG genotype was 3.5%, meaning that such patients have 3.5% absolute risk for developing AD. Pharmacogenetic analysis of AD patients in a two-year follow-up response to Rivastigmine was also performed. Analysis of Genotype-Related Drug Responses demonstrated that patients carrying B2-AR homozygous GG genotypes were the worst responders to Rivastigmine treatment when compared to total AD patients (baseline) (ΔCDR=0.54). Interestingly, patients with B2-AR homozygous AA genotype, had a best response to the Rivastigmine therapy and decreasing trend in the disease severity and symptoms (ΔCDR= -0.12). These findings suggest that B2-AR A allele acts as a recessive allele in positive response to Rivastigmine treatment. Furthermore, we examined the interactions of the genes related to this study with the genes studied previously in the same patients for response to Rivastigmine. The results indicated, patients, carrying B2-AR AX-A2M AX bigenic genotype show good response (ΔCDR= 0.18) and B2-AR GX- IL6 GX carriers were bad responder to Rivastigmine treatment (ΔCDR= 0.97).
Alzheimer, B2-AR, TLR2, PICALM, BDNF, Rivastigmine