老年人基因多型性、生活型態與認知功能障礙之關聯性研究

Abstract

前言: 失智症末期會讓人嚴重失能，對老年化的社會帶來巨大的健康及經濟負擔。目前眾所皆知的失智症危險因子包括高齡、女性、低社經地位、心血管疾病、憂鬱、apolipoprotein (APOE) ε4對偶基因狀況，以及不健康的生活型態。然而，過去的遺傳關聯研究常忽略基因-基因、基因-環境的交互作用，可能會因此導致重要的遺傳因子未被發現。另外，很少研究探討華人族群的各種生活型態，對於各面項的認知能力改變之綜合影響。此外，目前尚無研究探討生活型態對於認知變化的影響是否會因不同社經地位有所改變。本論文涵蓋兩部分，分別探討基因及生活型態這兩種失智症的重要預測因子。

第一部分: CHRNA7基因多型性與失智症之風險: 與Apolipoprotein ε4基因及吸菸之交互作用 前言: α7尼古丁乙醯膽鹼受體(α7 nAChR，由CHRNA7基因轉錄)，透過影響膽鹼性神經傳導、神經保護、以及與乙型類澱粉蛋白(amyloid β)之交互作用等機轉，在失智症的致病機轉中扮演重要角色。吸菸會使血管硬化增加失智症風險，但尼古丁也經由α7 nAChR產生神經保護的效果。目前尚無研究探討CHRNA7、APOE ε4（轉錄amyloid β）基因多型性、與吸菸對失智症的基因-基因, 基因-環境交互作用。 研究方法: 本研究是病例對照研究，於2007-2010年在三家教學醫院的神經科門診招募254位晚發型阿茲海默失智症、115位小血管性失智症患者，與435位來自健檢及志工的對照組，病人和對照組均 ≥65歲，選擇具代表性的九個CHRNA7標籤單核苷酸多型性[haplotype tagging single nucleotide polymorphism (htSNP) ]作基因分型。 結果: 在未帶APOE ε4對偶基因的人，CHRNA7 rs7179008的變異顯著降低晚發型阿茲海默症的風險，經多重校正後仍顯著(GG+AG vs. AA: 變項調整後的勝算比= 0.29，95%信賴區間 = 0.13-0.64, P = 0.002)。CHRNA7 第四單倍型區塊(haplotype block)的GT單倍型變異亦發現可降低晚發型阿茲海默症的風險。CHRNA7 rs7179008變異、CHRNA7 第四單倍型區塊的GT單倍型變異與APOE ε4帶原狀態對於晚發型阿茲海默症有顯著的交互作用。CHRNA7 rs7179008變異也可以減少吸菸對晚發型阿茲海默症的危害風險。CHRNA7基因與小血管性失智症未發現關聯。 結論: 在未帶APOE ε4對偶基因的長者，CHRNA7 rs7179008變異顯著降低晚發型阿茲海默症的風險。APOE ε4對偶基因與吸菸的狀態會改變CHRNA7基因多型性對於晚發型阿茲海默症的風險影響。

第二部分: 不同社經背景下生活型態對老年認知功能變化之影響 前言：本研究目的在找出可能會影響認知功能變化的生活型態，並探討這些生活型態在不同社經背景下是否對認知功能有不同的影響。 研究方法：本研究於2011年至2013年基線招募參與台大醫院老人健檢 ≥ 65歲的長者，在收案基線時(N = 603)及收案兩年後(N = 509)進行認知功能測驗，包含整體認知功能、邏輯記憶、執行能力、語文流暢度、以及專注力的評估。經過文獻回顧後選取九個生活型態因子及三個社經地位指標，探討這些因子對於兩年後認知變化的影響。使用線性迴歸分析，調整年齡、性別、教育、APOE ε4對偶基因狀態、以及基線時的認知功能。 結果：本研究發現，在調整年齡、性別、教育程度、APOE ε4對偶基因狀態、基線時的認知功能後，五種生活型態（較多的蔬菜攝取、較多的魚類攝取、規律運動、不抽菸、少至中量的飲酒）以及三種社經指標[較高收入（家庭年收入 ＞33,333 美元）、較高的工作複雜度、以及較高的教育程度( >12年)]可降低認知功能退化 (在任一個認知功能面項的P < 0.1，ß值介於0.06到0.38之間)。進一步的校正上述所有的生活型態及社經指標後，只有較多的魚類攝取、較高收入、較高的工作複雜度仍顯著的降低認知功能退化。健康的生活型態模式(定義為擁有 ≥ 3種健康的生活型態）與家庭年收入對於認知變化的影響有顯著交互作用（整體認知功能:Pinteraction = 0.02; 邏輯記憶:Pinteraction = 0.04）。健康的生活型態模式只有在較低收入的族群才對認知有保護效果（整體認知功能: ß = 0.17，95%信賴區間= 0.07-0.26;邏輯記憶:ß = 0.30，95% 信賴區間= 0.14-0.46）。 結論：據我們所知，本研究為首篇探討生活型態與社經背景對於認知功能變化的交互作用，研究結果可以協助發展失智症的預防計畫及改善健康不平等的狀況。

Introduction: Advanced dementia is a debilitating disease that caused tremendous health economic burden in the aging society. The well-recognized risk factors for dementia include older age, female gender, lower socioeconomic status (SES), cardiovascular diseases, depression, APOE ε4 status, and unhealthful lifestyles. However, important genetic variant might be missed in previous genetic association studies neglecting gene-gene, gene-environment interactions. Besides, few studies evaluated the effect of combined lifestyle factors on cognitive change in different cognitive domains in Chinese population. It is also currently unknown that whether the effect of lifestyles differs under different SES. This dissertation is composed of two parts focusing on the genetic and lifestyle factors.

Part 1. CHRNA7 polymorphisms and dementia Risk: interactions with apolipoprotein ε4 and cigarette smoking Background: α7 nicotinic acetylcholine receptor (α7nAChR, encoded by CHRNA7) is involved in dementia pathogenesis through cholinergic neurotransmission, neuroprotection and interactions with amyloid-β. Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via α7nAChR in preclinical studies. No studies explored the gene-gene, gene-environment interactions between CHRNA7 polymorphism, APOE ε4 status and smoking on dementia risk. Methods: This case-control study recruited 254 late-onset Alzheimer’s disease (LOAD) and 115 vascular dementia (VaD) cases (age ≥ 65) from the neurology clinics of three teaching hospitals in Taiwan during 2007-2010. Controls (N = 435) were recruited from health checkup programs and volunteers during the same period. Nine CHRNA7 haplotype-tagging single nucleotide polymorphisms representative for Taiwanese were genotyped. Results: Among APOE ε4 non-carriers, CHRNA7 rs7179008 variant carriers had significantly decreased LOAD risk after correction for multiple tests (GG + AG vs. AA: adjusted odds ratio = 0.29, 95% confidence interval = 0.13-0.64, P = 0.002). Similar findings were observed for carriers of GT haplotype in CHRNA7 block4. A significant interaction was found between rs7179008, GT haplotype in block4 and APOE ε4 status on LOAD risk. rs7179008 variant also reduced the detrimental effect of smoking on LOAD risk. No significant association was found between CHRNA7 and VaD. Conclusion: CHRNA7 rs7179008 is associated with decreased LOAD risk in APOE ε4 non-carriers. APOE ε4 and smoking status substantially modified the effect of CHRNA7 polymorphisms on dementia risk.

Part 2. The effect of lifestyle on late-life cognitive change under different socioeconomic status Background: This study aimed to identify lifestyle factors associated with cognitive change and to explore whether the effect of lifestyle varies by socioeconomic status (SES). Methods: Participants aged 65 years and older were recruited from elderly health checkup programs from 2011 to 2013 in Taiwan. Neuropsychological tests, including tests of global cognition, logical memory, executive function, verbal fluency and attention, were administered at baseline (N = 603) and 2 years later (N = 509). After literature review, 9 lifestyle factors and 3 SES indicators were chosen and their effects on cognitive change were evaluated using linear regression adjusting for age, sex, education, APOE ε4 status, and baseline cognitive score. Results: After adjusting for age, sex, years of education, APOE ε4 status, and baseline cognitive domain score, five lifestyle factors (high vegetable and fish intake, regular exercise, not smoking, and light to moderate alcohol consumption) and 3 SES indicators [annual household income [> US dollar (USD) 33,333 vs. less], occupational complexity (high vs. low mental demanding job), and years of education (> 12 years vs. less)] were found to be protective against cognitive decline (P < 0.1 in any cognitive domains, ß ranging from 0.06 to 0.38). After further adjusting for all the lifestyle and SES factors, fish intake, higher income and occupational complexity remained protective. Significant interactions were found between a healthful lifestyle (defined as having ≥ 3 healthful lifestyle factors) and income on changes of global cognition and verbal fluency (Pinteraction = 0.02 and 0.04). The protective effect of a healthful lifestyle was observed only among participants with lower income in global cognition and logical memory [ß = 0.17, 95% confidence interval (CI) = 0.07-0.26; ß = 0.30, 95% CI = 0.14-0.46]. Conclusion: To the best of our knowledge, this study for the first time explored how the interaction of lifestyle and SES affect cognitive change. Our findings will aid in developing dementia prevention programs and reduce health inequalities.