Supplementary Material for: Cognitive Activities, Lifestyle Factors and Risk of Cognitive Impairment, With an Analysis of the Apolipoprotein Epsilon 4 Genotype

Introduction: Cognitive stimulating activities and a healthy lifestyle are associated with less cognitive impairment. However, whether the association is varied by Apolipoprotein epsilon 4 (APOE ε4) allele carrier status remains inconclusive. We aimed to investigate whether the association of cognitively stimulating activities and a healthy lifestyle with the risk of cognitive impairment varied by APOE ε4 allele carrier status. Methods: A case-control study was conducted for adults aged 60 years and above. Six province administrative units (Beijing, Shanghai, Hubei, Sichuan, Guangxi, and Yunnan) were included using stratified multi-stage cluster sampling. A total of 1300 individuals were identified with cognitive impairment (cases) at enrollment and were matched 1:2 on sex, age (±2 years), and residential district with controls who were cognitively normal at the time of the evaluation. We used a standardized questionnaire to collect information on cognitive stimulating activities, lifestyle factors, demographics, and comorbidity. Cognitive stimulating activities included reading books or newspapers, playing cards or mahjong, using the Internet, socializing with neighbors, and community activities. Lifestyle factors included smoking, alcohol drinking, daily tea drinking, and regular exercise. We used logistic regression to assess the interaction between cognitive stimulating activities, lifestyle factors, and APOE ε4 allele carrier status (yes/no) on the risk of cognitive impairment. We tested for additive interaction by estimating relative excess risk (RERI) due to interaction and multiplicative interaction employing the P value of the interaction term of each lifestyle factor and APOE ε4 into the model. Results: Four cognitive stimulating activities were associated with less cognitive impairment regardless of APOE ε4 status. Using the Internet (odds ratio [OR] 0.53, 95% confidence interval [CI], 0.30-0.95), daily tea drinking (OR 0.79; 95% CI, 0.63-0.98), and regular exercise (OR 0.78; 95% CI, 0.65-0.94) were associated with less cognitive impairment only in non-carriers. Multiplicative and additive interactions were found between community activities and APOE ε4 carrier status (Multiplicative P value=.03; RERI 0.738, 95% CI, 0.201-1.275). Conclusion: The associations between cognitive activities and cognitive impairment were robust regardless of the APOE ε4 carrier status, while the associations between lifestyle factors and cognitive impairment varied by APOE ε4 carrier status.

引言：认知刺激活动与健康生活方式与较低的认知障碍发生风险相关。然而，该关联是否因载脂蛋白ε4（Apolipoprotein epsilon 4, APOE ε4）等位基因携带状态不同而存在差异，目前尚无定论。本研究旨在探讨认知刺激活动、健康生活方式与认知障碍发生风险之间的关联是否随APOE ε4等位基因携带状态而异。

方法：本研究针对60岁及以上成年人开展病例对照研究。采用分层多阶段整群抽样方法，纳入北京、上海、湖北、四川、广西、云南6个省级行政单位的受试者。共纳入1300例基线确诊为认知障碍的个体作为病例组，并按照性别、年龄（±2岁）及居住街区以1:2的比例匹配同期评估认知功能正常的对照个体。采用标准化问卷收集认知刺激活动、生活方式因素、人口学特征及共病情况相关信息。认知刺激活动涵盖阅读书籍或报纸、打牌或麻将、使用互联网、与邻里社交及参与社区活动。生活方式因素包括吸烟、饮酒、每日饮茶及规律运动。采用logistic回归模型评估认知刺激活动、生活方式因素与APOE ε4等位基因携带状态（是/否）对认知障碍发生风险的交互作用。通过计算交互作用所致相对超额风险（relative excess risk, RERI）检验相加交互作用，并通过将各生活方式因素与APOE ε4的交互项纳入模型后的P值检验相乘交互作用。

结果：无论APOE ε4携带状态如何，4项认知刺激活动均与较低的认知障碍发生风险相关。使用互联网（比值比[odds ratio, OR]=0.53，95%置信区间[confidence interval, CI]=0.30~0.95）、每日饮茶（OR=0.79；95%CI=0.63~0.98）及规律运动（OR=0.78；95%CI=0.65~0.94）仅在非携带者中与较低的认知障碍发生风险相关。社区活动与APOE ε4携带者状态之间存在相乘和相加交互作用（相乘交互P值=0.03；RERI=0.738，95%CI=0.201~1.275）。

结论：认知活动与认知障碍之间的关联不受APOE ε4携带状态的影响，而生活方式因素与认知障碍之间的关联则随APOE ε4携带状态不同而存在差异。