Linkage Disequilibrium Analysis Of The Candidate Genes For Alzheimer's Disease

Alzheimer disease (AD) is characterized by progressive and insidiousneurodegeneration of the central nervous system leading to a gradual decline ofcognitive function and memory. The key neuropathological features of AD includeextracellular β-amyloid (Aβ) deposited in the form of senile plaques, abundantamounts of intracellular neurofibrillary tangles, reduced numbers of synapses andloss of neurons. With the increasing logevity of our population, AD will become oneof the severest diseases that threaten our health in the 21st century. While our understanding of the disease etiology still remains fragmentary, it isnow widely accepted that genes play an essential role in predisposing to onset and inmodifying the progression of AD. The genetics of AD is heterogenous and complex.To date, three major genes (APP, PSEN-1 and PSEN-2) have been implicated in theearly-onset familial form of AD, while the APOE ε4 is the only identified geneticrisk factor for the late-onset sporadic AD. However, APOE ε4 accounts for onlyabout 50% of the genetic variation in late-onset AD, and it is neither necessary norsufficient to cause AD. On this basis, identification of other risk factors is thereforeof great importance in the elucidation of AD etiology. Based on the positional information on chromosomes and the possiblebiological function in AD pathological pathways, our case-control studiesinvestigated four groups of genes: the IDE gene on Chromosome 10, which maydegrade Aβ directly;the LRP1 and A2M genes on Chromosome 12, which maymediate the clearence of Aβ;the BDNF gene on Chromosome 11, which canpromote the growth, development, differentiation, maintenance and regeneration ofvarious types of neurons;the CYP46A1 gene on Chromosome 14 and the LIPA geneon Chromosome 10, which are involved in the maintenance of the cholesterolhomeostasis. In addition, we have performed the first Meta-analysis for BDNF gene.In view of the muti-genetic nature of AD, mutiple logistic regression analysis wasperformed to assess any possible synergism between these genes.Our case-control results showed: the rs4646953 C allele of IDE gene wasassociated with the increased AD risk (P=0.005), which depended on the existenceof APOE ε4 (P=0.003);the CTCG haplotype of LRP1 gene was associated with thereduced AD risk (P=0.002), which was independent of APOE ε4 (P=0.003). Mutiplelogistic regression analysis showed that a significant syngism existed between thers2146238 and rs3752958 in CYP46A1 gene (P=0.03). Further, we found thecoexistence of TT genotype at rs2146238 and AC genotype at rs3752958 showed anegative association with AD (P=0.02, OR=0.15, 95%CI=0.03-0.76). However, thisnegative association should be treated cautiously, because the number of individualscarrying both of the two genotypes was very small (only 2 patients and 10 normalcontrols). Conversely, we failed to find any possible association between other SNPsand AD.Our studies suggest that the IDE gene may interact with APOE ε4 to increasethe AD risk, while the LRP1 gene and the CYP46A1 gene may be protective factorsfor AD. Of course, our results should be confirmed with larger sample size indifferent populations.