A new review of Nat Rev Neurol: Emerging roles of gene-environment interactions-epigenetics in Alzheimer's disease

With the exception of a very small number of single-gene mutations in Alzheimer's disease (AD), the etiology of AD is complex, involving a variety of susceptibility genes and environmental factors
.
Although previous studies have confirmed that some environmental factors (diet, lifestyle, smoking, drinking, pollution) are risk factors for AD, it is only in recent years that the molecular mechanisms underlying gene-environment interactions have been gradually understood
.

Focusing on the relationship between environmental factors and epigenetic modifications of AD-related genes and pathways, Prof.
L Migliore and F Coppedè summarized more than 20 years of research and published the results "Gene–environment interactions in Alzheimer disease: the emerging role of epigenetics" in Nature in September 2022 Reviews Neurology
.
Related Reading:

1.
Complexity of the etiology of AD

In addition to APP, AD caused by rare gene mutations on PSEN1 and PSEN2, the vast majority of AD (99%) is caused
by the interaction of multiple genes and environmental factors.
Among them, APOE ε4 is the most important influencing factor of AD, and other genes found in genome-wide association analysis have a small
influence on AD.

The effects of environmental factors on AD tend to be contradictory in different studies, but in general, metals and metalloids (mercury, cadmium, arsenic, aluminum, etc.
), occupational exposure (neurotoxic pesticides, low-frequency electromagnetic fields, etc.
), air factors (PM2.
5, nitrogen oxides, CO, etc.
), lifestyle (high-fat diet, smoking, drinking, lack of exercise, etc.
), traumatic brain injury, and inflammation are all risk factors
for AD.

G x E interactions refer to the fact that the combination of a genotype at a particular site with endogenous or exogenous material exposure affects susceptibility to a disease
.
The G x E study mainly looked at how the APOE genotype affects AD or dementia in different environmental factors, although other genes, such as TERM2, were also studied, but relatively rarely
.
In these studies, there are a large number of epigenetic modifications caused by environmental factors and GxE-driven epigenetic alterations, which make them the focus
of research.

The receptor profile forms oscillatory neurodynamics

The authors found that overlapping spatial topography of multiple neurotransmitter systems may eventually manifest as coherent oscillation patterns (Figure 1a).

The authors found that the spatial distribution of MOR (opioid), H3 (histamine), and α4β2 contributed significantly to the fit between the receptor and the low-frequency (θ and α) and low-γ power bands compared to other receptors (Figure 1b).

Figure 1.
Receptor contour formation oscillatory neurodynamics

2.
The potential role of epigenetics in AD

Twin experiments are a common way to study environmental and genetic influence on complex traits and diseases, with identical twins thought to have the same genome and fraternal twins having half of the genetic variation identical
.

Previous studies have shown that the epigenetics of identical twins are consistent in the early stages, but after that, their total DNA as well as site-specific DNA methylation and histone acetylation differ markedly, most likely due to
environmental exposures and lifestyle differences.
In twin studies of AD, it was found that the twin with AD experienced a decrease in DNA methylation as well as hydroxymethylation (Table 1).

Table 1.
Epigenetic studies of twins with AD

Previous twin studies have led to more candidate gene methylation studies, and in the Global Epigenetic Genomics Study (EWAS) found that there are many AD-associated differentially expressed methylation sites (DMPs), histone tail modifications, and non-coding RNAs (ncRNAs).

Some of these are likely to serve as biomarkers for AD (Table 2).

DMPs are mainly ANK1, ARID5B, CDH23, CHRNB1, HOXA3, FBXL16, OXT, RHBDF2 and RPL13
.
AD-related histone tail modifications are mainly histone H3, lysine 9 (H3K9ac) and histone H3 lysine 27 (H3K27ac).

ncRNAs are mainly miR-181c-5p, miR-29c-3p, miR-125b-5p, miR-146a-5p and miR-223-3p
.

Table 2.
Possible AD epigenetic biomarkers

3.
Environmental exposure and epigenetics

The above shows that many environmental factors are risk factors for AD, and these environmental factors have been found to affect epigenetic expression in recent studies (Figure 2).

For example, rising aluminum levels in the body can lead to decreased levels of DNA methylation in the body, arsenic can lead to altered histone modifications and miRNA levels, lead exposure can lead to changes in specific DNA methylation sites, and early exposure can persist in adulthood
.

Pesticides, air pollution, neuroinflammation, folate deficiency, alcohol intake, smoking, and other risk factors for AD can all cause DNA methylation and hydroxymethylation changes, histone tail modifications, and ncRNA changes
like metals.
Figure 1.
Effects of environmental factors on the epigenome

4.
Antioxidants and epigenetic mechanisms

Oxidative stress is also an important factor in AD, and oxidative stress can cause many epigenetic changes
in addition to causing oxidative damage and promoting neuroinflammation.
In neuronal cells, oxidative stress leads to hypomethylation, while in the corresponding AD model, oxidative stress causes H3K9me3 levels to rise
.

Some foods in life have been studied to have antioxidant effects, and some of their extracts, such as resveratrol, have neuroprotective effects on AD and may exert neuroprotective effects by altering epigenetic changes to exert antioxidant stress (Figure 3).

Figure 3.
Dietary compounds with antioxidant and epigenetic properties

Conclusion

Epigenetics plays an important role in AD G x E interactions, and subsequent studies exploring the influence of the environment on AD should focus more on the role
of epigenetics.