John S. Ji教授：我的研究工作建立在既往科學家長期研究的基礎(chǔ)之上。在1970年中期,，研究人員發(fā)現(xiàn)APOE蛋白參與清除血液中的膽固醇,。90年代，杜克大學的神經(jīng)科學家Allen Roses發(fā)現(xiàn)APOE蛋白與阿爾茨海默病患者腦部粘性斑塊沉積有關(guān),。如今APOE基因已被確認為阿爾茨海默病的遺傳風險因素,，《自然》雜志將其列為有史以來被研究得最多的基因第五位，但與此同時,，該基因究竟如何發(fā)揮作用仍有許多值得探索的地方,。

APOE存在不同的等位基因。其中APOEε3最為常見,，被認為與阿爾茨海默病發(fā)病風險無關(guān),。APOEε2相對較為罕見，且有利于預(yù)防阿爾茨海默病的發(fā)生,。APOEε4不僅是增加阿爾茨海默病風險最重要的遺傳因素之一,，同時也會增加心血管疾病、卒中以及其他神經(jīng)退行性疾病的風險,。需要強調(diào)的是,，攜帶APOEε4等位基因并不意味著一個人一定會患上這種疾病。不同環(huán)境下的基因疾病風險可能并不相同,，因此我們設(shè)計了這些“基因-環(huán)境交互作用”的研究,。

在其中一項研究中我們旨在探索血糖或脂蛋白失調(diào)是否為癡呆癥的前兆及基因作用的中介因子，結(jié)果發(fā)現(xiàn)血脂水平具有重要影響,。在我們的研究人群中,，較高水平的總膽固醇（TC）、甘油三酯及HDL-C（高密度脂蛋白膽固醇）均與認知功能障礙風險相關(guān),。APOE可通過改變脂質(zhì)水平發(fā)揮作用,。有趣的是，APOEε2對認知功能的一部分保護作用可被TC和LDL-C負向介導(dǎo),，其直接保護效應(yīng)大致相當于減少了3年年齡增長帶來的認知能力下降,。

其次，通過新型遙感技術(shù),，我們探索了認知功能與住宅綠地水平的相關(guān)性,。全球越來越多的研究證據(jù)表明，空氣污染是導(dǎo)致認知能力下降和癡呆癥的原因之一,，但關(guān)于建筑環(huán)境如住宅綠化的作用證據(jù)仍較少,。我們發(fā)現(xiàn)在低遺傳風險人群中，高綠化水平與較低的癡呆癥風險有關(guān),。這項結(jié)果帶來了思維范式的轉(zhuǎn)變,，即城市規(guī)劃可以像醫(yī)生一樣對癡呆癥產(chǎn)生影響,。這樣的證據(jù)對于預(yù)防癡呆癥尤為重要，即使只產(chǎn)生了很小的效果,，仍可以預(yù)防數(shù)以百萬計的疾病發(fā)生,。（左滑查看英文回答）

John S. Ji: I want to start off by saying that my research is incrementally building off scientific work that spans a long time. In the mid-1970, APOE protein was found to involved in clearing cholesterol from the blood. Then in the 1990s, neuroscientist Allen Roses at Duke University found the APOE protein to appear along with sticky brain plaques of people with Alzheimer's disease. Although APOE is well studied and became an established a genetic risk for Alzheimer's disease, we still have a lot of work in understanding how exactly it works.

We know APOE gene also comes in several different forms, or alleles. APOE3 is the most common and not believed to affect Alzheimer's risk. APOE2 is relatively rare and may provide protection against Alzheimer's disease. APOE4 is one of the most significant genetic risk factors of AD.

We notice while APOE4 is the strongest risk factor gene for Alzheimer's disease, inheriting APOE4 does not mean a person will develop the disease. At the same time, APOE4 allele also affects risk for cardiovascular disease, stroke, and other neurodegenerative disorders.

We designed studies called gene-environment interaction studies, under the premise that a different effect of a genotype on disease risk in persons with different environmental exposures. We wanted to explore whether dysregulation of serum glucose metabolism or lipoprotein linked to vascular disease can be a precursor to dementia. We found that lipids levels are important, where higher TC, TG, HDL-C, and LDL-C were all associated with risks of cognitive dysfunction among all participants. APOE is acting through modification of lipid levels. Interestingly, APOE ε2 protective effect on cognitive function was mediated by TC and LDL-C. The advantage of people carrying the APOE ε2 is roughly equivalent magnitude of about 3-year reduction in age with respect to cognitive decline.

Second, we looked at residential green space levels in relation to cognitive function, by using novel remote sensing technology. Mounting research evidences globally point to air pollution as a causal agent of cognitive decline and dementia. We found that greenspace was associated with lower dementia among those with lower genetic risk. It led to a paradigm shift in thinking, that city planners can have as much of an impact on dementia as medical doctors. Evidences like this are especially important to prevention of dementia, even if the effect size is small, it would still prevent millions of disease incidences.

John S. Ji教授：

1. 無論遺傳風險因素如何,，控制吸煙,、飲酒、體重,、飲食模式以及鍛煉程度,，采取健康生活方式可以預(yù)防癡呆癥和阿爾茨海默病。

2. 居住環(huán)境可以改變癡呆癥風險,。綠化程度更高的居住環(huán)境有助于預(yù)防癡呆癥及其他慢性疾病,。

3. 環(huán)境和生活方式對癡呆癥的影響比遺傳風險大許多倍。

我們未來的計劃是更深入地研究氣候變化和大腦之間的關(guān)系,?！疤贾泻汀闭咭约安粩嘧兓沫h(huán)境風險因素將改變我們的生活社區(qū)和疾病特征。我們的研究結(jié)果不僅有助于提高個體的健康保護水平,，還可為政策制定中健康方面的考量提供思路,。（左滑查看英文回答）

John S. Ji: 

1. Regardless of genetic risk factors, a healthy lifestyle controlling smoking, alcohol consumption, body weight, dietary pattern, and physical activity can prevent against dementia and AD.

2. Where people live can change dementia risks. Having more green space can prevent against dementia, along with other chronic diseases.

3. The role of the environment and lifestyle have effects that are many times larger than the genetic risk on dementia.

Our plan in the future is take a deeper look at climate change and the brain. Carbon neutrality policies, along with changing environmental risk factors are going to alter our physical communities and disease profiles. Thus, perhaps our findings can be used by policy makers to integrate health into their decision making, as well as by individuals to protect their own health.