A Molecular Epidemiology Study on Environmental and Genetic Risk Factors for Dementia
Date Issued
2007
Date
2007
Author(s)
DOI
en-US
Abstract
This thesis comprises two component studies to evaluate the associations between midlife and genetic risk factors and subtypes of dementia.
PART 1: Midlife Risk Study Objective: To identify the midlife risk factors for subtypes of dementia newly developed later in life. Methods: A nested case-control study was conducted on 157 demented cases and 628 comparison cases selected from 40,636 men and women who were enrolled from 1982 to 1992. Four comparison cases were frequency-matched on age, time at enrollment (within six months), gender, and residential township. Midlife risk factors included vascular risk factors (body mass index (BMI), total cholesterol, total triglycerides, blood sugar, cerebrovascular accident (CVA) history, diabetes mellitus history and hypertension history), cigarette smoking and alcohol consumption. Dementia assessments were ascertained through the computerized data linkage from National Health Insurance Database from 2000 to 2002 and clinically confirmed by neurologists or psychiatrists. Conditional logistic regression analysis was used to estimate the matched odds ratio (OR) and its 95 percent confidence intervals (95% CI) for each risk factor. Results: A J-shaped relationship was observed between BMI (kg/m2) and dementia. The multivariate-adjusted OR (95% CI) of developing dementia was 1.84 (1.02-3.33), 1.87 (1.08-3.23) and 2.44 (1.39-4.28), respectively, for a BMI of <20.5, 23.0-25.4, >25.5 compared with a BMI of 20.5-22.9 as the referent group (OR=1.0). Similar findings were observed for Alzheimer’s disease (AD) and vascular dementia (VaD). The association between obesity (BMI >25.5) and both AD and VaD was statistically significant among cigarette smokers but not among non-smokers. Additionally, history of CVA was a significant risk factor for VaD, but not for AD. Conclusions: Under- and overweight and cerebrovascular accident in midlife may increase the risk of dementia in late life. (This part has been accepted for publication in American Journal of Geriatric Psychiatry) PART 2: Genetic Risk Study Objective: To evaluate the associations of eighteen polymorphisms of thirteen candidate genes including leptin and its receptor genes with Alzheimer’s disease (AD) or vascular dementia (VaD) in Taiwan. Methods: A nested case-control study was conducted within a large population-based cohort, which had buffy coat samples. A total of 28 AD and 34 VaD patients and 298 comparison cases matched with cases on age, gender, entry date and residential area were included in this study. Polymorphisms of APOE ε2/ε3/ε4, A2M Ile1000Val, LRP C766T, VLDLR 5’UTR CGG-repeat, IDE 5’UTR G/T, TNF T-1031C, BACE C786G, ACE ins/del, MTHFR C677T, PON Arg192Gln, COMT Val158Met, LEP 5’UTR G/T, LEPR Arg109Lys, Arg223Gln Ser343Ser, Lys656Asn, intron 14 A/C and Pro1019Pro were examined by real time quantitative PCR, microsatellite or PCR-restriction fragment length polymorphism (RFLP) method. Unconditional logistic regression model was used to estimate multivariate-adjusted odds ratio (ORa) with its 95% confidence interval (CI) of developing AD or VaD for various genotypes after adjustment for age, gender, entry date, residential area and other confounding factors. Haplotype analysis was performed for the leptin receptor gene cluster. Moreover, gene-gene interaction and gene dosage effect were also evaluated. Results: An increased risk of AD was significantly associated with genotypes of APOE ε4 (ORa 3.21; 95% CI 1.09-9.53), PON Gln/Gln (ORa 6.66; 95% CI 1.98-22.4) and LEPR GCC haplotype of Lys656Asn, intron 14 and Pro1019Pro (ORa 6.45; 95% CI 2.07-20.1). The higher the number of putative high-risk genoypes of APOE, PON and LEPR was, the higher the risk of AD was. However, no significant associations were observed between VaD and these gene polymorphisms. Conclusions: This preliminary study confirmed the association between AD and APOE ε4 and found a significant association between AD and polymorphisms of LEPR and PON genes.
PART 1: Midlife Risk Study Objective: To identify the midlife risk factors for subtypes of dementia newly developed later in life. Methods: A nested case-control study was conducted on 157 demented cases and 628 comparison cases selected from 40,636 men and women who were enrolled from 1982 to 1992. Four comparison cases were frequency-matched on age, time at enrollment (within six months), gender, and residential township. Midlife risk factors included vascular risk factors (body mass index (BMI), total cholesterol, total triglycerides, blood sugar, cerebrovascular accident (CVA) history, diabetes mellitus history and hypertension history), cigarette smoking and alcohol consumption. Dementia assessments were ascertained through the computerized data linkage from National Health Insurance Database from 2000 to 2002 and clinically confirmed by neurologists or psychiatrists. Conditional logistic regression analysis was used to estimate the matched odds ratio (OR) and its 95 percent confidence intervals (95% CI) for each risk factor. Results: A J-shaped relationship was observed between BMI (kg/m2) and dementia. The multivariate-adjusted OR (95% CI) of developing dementia was 1.84 (1.02-3.33), 1.87 (1.08-3.23) and 2.44 (1.39-4.28), respectively, for a BMI of <20.5, 23.0-25.4, >25.5 compared with a BMI of 20.5-22.9 as the referent group (OR=1.0). Similar findings were observed for Alzheimer’s disease (AD) and vascular dementia (VaD). The association between obesity (BMI >25.5) and both AD and VaD was statistically significant among cigarette smokers but not among non-smokers. Additionally, history of CVA was a significant risk factor for VaD, but not for AD. Conclusions: Under- and overweight and cerebrovascular accident in midlife may increase the risk of dementia in late life. (This part has been accepted for publication in American Journal of Geriatric Psychiatry) PART 2: Genetic Risk Study Objective: To evaluate the associations of eighteen polymorphisms of thirteen candidate genes including leptin and its receptor genes with Alzheimer’s disease (AD) or vascular dementia (VaD) in Taiwan. Methods: A nested case-control study was conducted within a large population-based cohort, which had buffy coat samples. A total of 28 AD and 34 VaD patients and 298 comparison cases matched with cases on age, gender, entry date and residential area were included in this study. Polymorphisms of APOE ε2/ε3/ε4, A2M Ile1000Val, LRP C766T, VLDLR 5’UTR CGG-repeat, IDE 5’UTR G/T, TNF T-1031C, BACE C786G, ACE ins/del, MTHFR C677T, PON Arg192Gln, COMT Val158Met, LEP 5’UTR G/T, LEPR Arg109Lys, Arg223Gln Ser343Ser, Lys656Asn, intron 14 A/C and Pro1019Pro were examined by real time quantitative PCR, microsatellite or PCR-restriction fragment length polymorphism (RFLP) method. Unconditional logistic regression model was used to estimate multivariate-adjusted odds ratio (ORa) with its 95% confidence interval (CI) of developing AD or VaD for various genotypes after adjustment for age, gender, entry date, residential area and other confounding factors. Haplotype analysis was performed for the leptin receptor gene cluster. Moreover, gene-gene interaction and gene dosage effect were also evaluated. Results: An increased risk of AD was significantly associated with genotypes of APOE ε4 (ORa 3.21; 95% CI 1.09-9.53), PON Gln/Gln (ORa 6.66; 95% CI 1.98-22.4) and LEPR GCC haplotype of Lys656Asn, intron 14 and Pro1019Pro (ORa 6.45; 95% CI 2.07-20.1). The higher the number of putative high-risk genoypes of APOE, PON and LEPR was, the higher the risk of AD was. However, no significant associations were observed between VaD and these gene polymorphisms. Conclusions: This preliminary study confirmed the association between AD and APOE ε4 and found a significant association between AD and polymorphisms of LEPR and PON genes.
Subjects
阿滋海默症
血管性失智症
流行病學
身體質量指數
危險因子
基因多型性
瘦素受體基因
Paraoxonase基因
Vascular Dementia
Epidemiology
Body Mass Index
Risk Factors
Gene Polymorphisms
Leptin Receptor Gene
Paraoxonase Gene
SDGs
Type
thesis
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