To prevent Alzheimer's disease, environment and lifestyle are more important than genetics! Professor Ji Sihan of Tsinghua University interprets 3 important research results

▎Alzheimer's disease (AD), edited by WuXi AppTec's content team, is the most common type of dementia.
As a degenerative disease of the nervous system, its pathogenesis is complex and currently cannot be cured.
It has become a threat to the health of the elderly.
One of the important chronic diseases
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At present, the total number of elderly people aged 60 and over in China has reached 264 million.
With the aging of the population entering the fast lane, Alzheimer's disease has also become a public health and social issue worthy of attention
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Recently, Professor John S.
Ji (Ji Sihan) of Vanke School of Public Health and Health, Tsinghua University, and his research team published important results in the journals Frontiers in Aging Neuroscience, Science of the Total Environment, and PLOS Medicine.
These series of studies are centered on Altz The development of apolipoprotein E (APOE) gene, a genetic risk factor related to Hemer's disease, is aimed at exploring the interaction between APOE gene and metabolic indicators, as well as the value of residential environment intervention and life>The results of these three studies show that APOEε2 has a protective effect on cognitive function, while the APOEε4 genotype only has a harmful effect on the cognitive function of people with low levels of LDL-C
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In addition to genetic risk factors, for people with a low genetic risk score for Alzheimer's disease, a higher level of residential greening may help reduce the risk of Alzheimer's disease
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And a healthier life>
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If these research results can be confirmed in a larger population cohort, then we will need to develop personalized prevention and intervention strategies for the above genetic risks, environmental exposures and other factors in the future.

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WuXi AppTec's content team specially invited Professor Ji Sihan to interpret the innovative findings of these three studies
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Associate Professor John S.
Ji, Ph.
D.
Supervisor, Vanke School of Public Health and Health, Tsinghua University Research Fields: Environmental Epidemiology, Climate Change, Healthy Cities, Healthy Longevity Education Experience: Johns Hopkins University, Bachelor of Neuroscience, Harvard Interpretation by Professor Ji Sihan, PhD in Environmental Epidemiology, School of Public Health of the University (Swipe left and right to view the Chinese/English version) Q1: APOE gene is the most important genetic risk factor for cognitive impairment and AD recognized so far.
What are the current three studies? New discovery? Professor John S.
Ji: My research is based on the long-term research of past scientists
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In the mid-1970s, researchers discovered that APOE protein is involved in removing cholesterol from the blood
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In the 1990s, Allen Roses, a neuroscientist at Duke University, discovered that APOE protein is associated with the deposition of sticky plaques in the brains of patients with Alzheimer's disease
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Now that the APOE gene has been confirmed as a genetic risk factor for Alzheimer’s disease, Nature magazine lists it as the fifth most studied gene in history, but at the same time, how exactly this gene works still remains Many places worth exploring
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APOE has different alleles
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Among them, APOEε3 is the most common and is considered to be unrelated to the risk of Alzheimer's disease
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APOEε2 is relatively rare and helps prevent the occurrence of Alzheimer's disease
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APOEε4 is not only one of the most important genetic factors that increase the risk of Alzheimer's disease, but also increases the risk of cardiovascular disease, stroke, and other neurodegenerative diseases
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It should be emphasized that carrying the APOEε4 allele does not mean that a person will definitely suffer from this disease
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The risk of genetic diseases in different environments may not be the same, so we designed these "gene-environment interaction" studies
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In one of the studies, we aimed to explore whether blood glucose or lipoprotein imbalance is a precursor of dementia and an intermediary factor of gene action, and found that blood lipid levels have an important impact
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In our study population, higher levels of total cholesterol (TC), triglycerides, and HDL-C (high-density lipoprotein cholesterol) are all associated with the risk of cognitive dysfunction
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APOE can work by changing lipid levels
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Interestingly, part of the protective effect of APOEε2 on cognitive function can be negatively mediated by TC and LDL-C, and its direct protective effect is roughly equivalent to reducing the cognitive decline caused by 3 years of age
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Secondly, through new remote sensing technology, we explored the correlation between cognitive function and the level of residential green space
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More and more research evidences around the world show that air pollution is one of the causes of cognitive decline and dementia, but there is still little evidence on the role of the built environment such as residential greening
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We found that among people with low genetic risk, a high level of greenery is associated with a lower risk of dementia
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This result has brought about a paradigm shift in thinking that urban planning can have an impact on dementia like a doctor
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Such evidence is particularly important for preventing dementia.
Even if it produces only a small effect, it can still prevent millions of diseases from occurring
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Q2: How to prevent or delay the occurrence of AD through living environment or life>What other work do you and your team plan to do in the future? Professor John S.
Ji: 1.
Regardless of genetic risk factors, controlling smoking, drinking, weight, eating patterns and exercise levels, and adopting a healthy life>
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2.
Living environment can change the risk of dementia
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A more green living environment helps prevent dementia and other chronic diseases
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3.
The impact of environment and life>
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Our future plan is to study the relationship between climate change and the brain in more depth
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"Carbon neutral" policies and changing environmental risk factors will change our living communities and disease characteristics
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Our research results not only help to improve the level of individual health protection, but also provide ideas for health considerations in policy formulation
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Research paper introduction Research 1: APOEε2 has a protective effect on cognition, but it is not always beneficial! APOE gene is considered to be an important susceptibility gene in the occurrence and development of late-onset Alzheimer's disease
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In recent years, studies have shown that APOE gene can cause neurodegenerative diseases through various ways such as affecting axon remodeling, glutamate receptor function, synaptic plasticity regulation, and cholesterol redistribution
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APOE has 3 common alleles (ε2, ε3, and ε4), and 6 genotypes are derived from it
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In the first study, Professor Ji Sihan’s team analyzed the interaction and regulation of APOE genes, cholesterol, and blood sugar levels through data from a large cohort of Chinese elderly patients, as well as the impact of these relationships on cognition
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▲ Hypothesis of the relationship between APOE gene, lipid/blood sugar and cognitive function (picture source: Reference [1]) Research found: The relationship between APOE gene and cognitive function: Compared with the most common genotype APOEε3ε3 genotype , APOEε2 carriers have higher cognitive scores, and show lower levels of TC (total cholesterol), LDL-C (low-density lipoprotein cholesterol), etc.
, and higher levels of HDL-C (high-density lipoprotein cholesterol); and this At the same time, APOEε4 carriers did not show significantly lower cognitive scores, but showed the opposite characteristics, that is, compared with APOEε3ε3, the level of TC, LDL-C, etc.
is higher, and the level of HDL-C is lower
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The relationship between lipid/blood sugar levels and cognitive function: higher levels of triglycerides, HDL-C, and glycosylated hemoglobin are associated with higher cognitive scores
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There is no significant difference in cognitive function between people with normal fasting blood glucose and high fasting blood glucose (≥ 6.
1 mmol/L)
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In addition, fasting blood glucose, BMI, and hypertension are not significantly related to APOE gene
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Further analysis showed that APOE gene can affect cognitive function by changing cholesterol levels: APOEε2 has a protective effect on cognitive function, but APOEε2 can cause a decrease in total cholesterol and LDL-C levels, which may lead to later cognition Increased risk of dysfunction; APOEε4 only appears to have harmful effects on cognitive function in people with low levels of LDL-C, which suggests that the protective effect of higher levels of LDL-C in the elderly may offset the harmful effects of APOEε4
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▲ The correlation between gender, age, APOE gene, lipid/glycemia and cognitive function score (picture source: reference [1]) Study 2: What is the impact of living environment on Alzheimer's disease? APOE gene is the most significant genetic risk factor for cognitive impairment and Alzheimer's disease, so can we adjust the risk factors, such as changing the living environment, to reduce the possible genetic impact? Previous studies have shown that more exposure to the natural environment is beneficial to mental health, nervous system and cognitive function
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Based on this, current research explores the impact of residential greening levels on the susceptibility to Alzheimer's disease
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This study included genetic analysis data from a subgroup study of the Chinese Elderly Health Influencing Factors Follow-up Survey (CLHLS) (involving a total of 1199 elderly people aged 90 and over)
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By analyzing the interaction between the polygenic risk score and residential greening, the study found that the level of residential greening and the genetic risk of Alzheimer's disease are all related to cognitive impairment
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 ▲The protective effect of greening level on cognitive function is more significant in people with low genetic risk (picture source: reference [2]) Compared with people with low genetic risk of Alzheimer's disease, Alzheimer's disease has a high genetic risk The incidence of cognitive impairment in the population of the population is 44% higher; compared with those living in areas with low green levels, the incidence of cognitive impairment in people living in areas with high green levels is 33% lower
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It is worth noting that for people with a low genetic risk score for Alzheimer’s disease, a higher level of residential greening can help reduce the risk of cognitive impairment, and at the same time, for people with a higher genetic risk of Alzheimer’s disease In other words, the study did not observe a significant correlation between the level of residential greening and cognitive impairment
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In other words, the protective effect of greening on cognitive function may be more significant in people with low genetic risk! Study 3: How does life>In addition to the living environment, how will life>The researchers also used the genetic analysis data of the Central Asian Group of the Chinese Elderly Health Follow-up Survey (CLHLS) (involving a total of 6160 elderly people aged 80 and over)
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By comprehensively scoring the subjects' smoking, drinking, eating habits, exercise, and weight, the researchers divided the subjects' life>
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▲The relationship between different life>
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(Image source: Reference [3]) The current study found that there is a significant association between APOEε4 genotype and cognitive impairment
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However, regardless of whether the APOEε4 allele is a high-risk genetic factor, a healthier life>
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Specifically, compared with APOEε4 carriers, non-carriers have a 17% lower risk of cognitive impairment; compared to individuals with unhealthy life>At the same time, people with healthier life>
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References [1] Liu L, Li H, Iyer H, Liu AJ, Zeng Y, Ji JS.
Apolipoprotein E Induced Cognitive Dysfunction :Mediation Analysis of Lipids and Glucose Biomarkers in an Elderly Cohort Study.
Frontiers in Aging Neuroscience 2021;13: 1–11.
[2] Jin X,Shu C, Zeng Y, Liang L, Ji JS.
Interaction of greenness and polygenic risk score of Alzheimer's disease on risk of cognitive impairment.
Science of the Total Environment 2021;796:148767.
[3 ] Jin X, He W, Zhang Y,Gong E, Niu Z, Ji JS, Li Y, Zeng Y, Yan LL.
Association of APOE ε4 genotype andlife>
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