The Association Study Of Apolipoprotein E Gene Polymorphism With Different Types Of Dementia In A Chinese Han Population

Background:Dementia is an acquired and gradually progressed syndrome charactered with cognitive impairment, and Alzheimer’s disease(AD) is the most common type of it. Vascular dementia (VaD)is the common form of dementia secondary to cerebral vascular disease, and frontotemporal lobe Degeneration(FTLD) and dementia with Lewy body(DLB) are also common forms of dementia which caused by neurodegenerative diseases. Up to now,apolipoprotein E(ApoE) ε4allele is the only and definite risk factor of sporadic or late onset of familial AD and has significant association with age at onset,clinical progression and therapeutic response of AD. It has been reported that there was great difference of ApoE alleles distribution between countries and continents.Objectives:To explore the distribution of ApoE alleles and genotypes in Chinese populations with different forms of dementia, make sure of difference of it between Chinese and other populations and then evaluate the role of ApoE gene polymorphorism in the pathogenesis of different dementia;to illustrate the correlation of ApoE ε4with age at onset and atrophy and asymmetry of hippocampals and then evaluate its role as an important marker of clinical course of AD.Methods:This study is a retrospective case-control study.All cases come from consrcutive patients of the Clinic of Memory and Cognitive Impairment of Peking Union Medical Collge Hospital(PUMCH) from1999to2010, and controls come from non-dementing individuals born in PUMCH from1921to1941and from1948to1954. All subjects need to meet the corresponding inclusion and exclusion criteria. Cinical evaluation, including demographic data, clinical history, physical examination, cognitive function tests and neuroimaging test had been completed in PUMCH. DNA was extracted and ApoE genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The linkage between ApoE alle or genotype and risk of different dementia and clinical character of AD were analyzed by single factor and multi-factors analysis with SAS software.Results:Univariate analysis:1. ApoE ε2and ε3alle frequency for AD patients were significantly lower than the control, while the e4frequency was significantly higher.2. ApoE ε3alle frequency for VaD patients was significantly lower than the control, whereas ε4frequency was significantly higher than control.3. ApoE ε2allele and genotype frequency among AD patients with family history was significant lower than those without family history; ApoE ε3/4freqency among female AD patiens was significantly higher than male AD while ε3/3frequency was lower than male.4. ApoE ε3frequency of both AD and the control in China was all significantly higher than that of both groups in western countries, while ApoE ε4freqency of the former was significantly lower than that of the latter.There was no statistical difference between Chinese and other Asians.5. ApoE alleles and genotypes were not associated with age at onset(AAO) of early onset AD.6. Among late onset AD patients, all ApoE genotypes were significantly associated with AAO and AAO reduced gradually in a way as follows: ε2/3> ε3/3> ε3/4> ε2/4> ε4/4. ApoE ε4carrier had lower AAO than non-carrier.7. Among late onset AD patients, ApoE ε4had no significant effect on AAO of those with vascular risks.8. There was no significant difference.in the volume and asymmetry index of hippocampals between ε4-/-、ε4+/-and ε4+/+carriers.Multivariate analysis:1. Logistic regression with ApoE ε2and APOE ε4allele as covariates showed no significant protective effect of ε2allele (OR=0.75,95%CI0.23-1.12) for developing AD,but showed significantly increased ORs for AD among all genotypes containing the ApoE ε4allele after all other varariates adjusted(OR=4.32,95%CI2.19-6.32for ε4+/-; OR=25.84,95%CI3.35-199.52for ε4+/+);2. Logistic regression with ApoE ε2and ApoE ε4allele as covariates showed significantly increased ORs for VaD among all genotypes containing the ApoE ε4allele after all other varariates adjusted(OR=2.88,95%CI1.57-5.29for ε4(+); OR=11.22);3. Analyse of covariance showed that there was no difference in asymmetry index of hippocampals between ε4-/-、ε4+/-and ε4+/+carriers after age,gender and degree of severity were adjusted.Conclusions:1. There was significant difference in ApoE gene distribution between Chinese Han population and western populations, while no significant difference between Asian populations.2. ApoE ε4allele is a strong risk factor for AD and VaD in Chinese Han population.3. Gender and family history of dementia had great effect on ApoE gene distribution among AD patients.4. ApoE ε4allele had possible association with some clinical characteristics of DLB and FTLD, and the research containing sufficient cases are expected to prove it. 5. ApoE genotypes perhaps have no association with the volume and asymmetry index of hippocampals of AD.6. ApoE genotypes containing at least one ε4allele can significantly lower AAO of late onset AD in a dose-dependent manner.7. Vascular risk factors possibly can reduce or diminish the effect of ApoE ε4(+) genotype on AAO of late onset AD.8. ApoE ε4allele may be a good biomarker of dementias in the clinical study.