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Epigenetics and Alzheimer’s: A Conversation with Raffaella Nativio

By | October 12th, 2020

Alzheimer’s main hallmarks — beta-amyloid plaques and tau tangles — have long been the focus of the quest to come up with an Alzheimer’s drug. However, clinical trials for drugs that focus on these hallmarks have largely failed. Increasingly, scientists are searching for promising new approaches. Dr. Raffaella Nativio, lecturer and group leader in dementia research at Imperial College London, discusses the new field of research that examines the link between a genetic discipline called epigenetics and Alzheimer’s.

  • Epigenetics involves changes in the structure of genes which do not change the gene’s DNA
  • The environment can influence how genes are turned on and off
  • Researchers hope to develop drugs targeting molecules that influence gene expression and behaves differently in Alzheimer’s

Being Patient: What is epigenetics? 

Dr. Raffaella Nativio: The word epigenetics means ‘on top of genetics.’ Epigenetics is a change in phenotype without a change in genotype. For example, all the cells in our body have exactly the same number of genes with the same genetic sequence. But why do the cells in our body look different? Why do cells from the skin look different from cells in the bones, lungs and eyes if we have exactly the same genetic code? 

The differences are dependent on the structure of the genes. Depending on how the genes are folded, the genes can be turned on or off. In different cell types, we have different sets of genes that are turned on or off. Through epigenetics, the environment can influence how these genes are turned on and off. That’s why skin cells look like skin cells and bone cells look like bone cells. 

Being Patient: How is epigenetics related to neurodegeneration? 

Dr. Raffaella Nativio: There are two forms of Alzheimer’s disease. One is the familial form of Alzheimer’s where mutations in genes which we inherited from our parents drive the disease. Genetic mutations are changes in the sequence of the gene, but not changes in the structures of the gene. Epigenetics is not involved in this form of Alzheimer’s disease. And this form of Alzheimer’s disease quite rare.  

The other type of Alzheimer’s is called late-onset Alzheimer’s disease. This type of Alzheimer’s comes with aging. Aging is the top risk factor for this type of Alzheimer’s, which is the most common type that comes with aging. Studies in the lab where I’m from, the laboratory of Shelley Burger who is my former supervisor, identify that epigenetics plays a role in aging in model organisms. 

For example, you can delay animals from aging by inducing epigenetic modifications. You can improve lifespan or make it worse depending on which direction you induced epigenetic changes. Based on our studies of aging in model organisms and how the environment affects epigenetics, we came up with the hypothesis that epigenetics might be involved in Alzheimer’s because of the connection with aging. 

Being Patient: What are the biological mechanisms involved with the changes in the structure of the genes?

Dr. Raffaella Nativio: There are epigenetic factors that induce these changes. For example, studies in fruit fly show that if we increase the expression of one of these epigenetic factors, we can delay aging in a fly. There are many epigenetic factors. Some improve aging, some make aging worse. That’s why studying model organisms can create the foundation to then study humans. 

We performed a study using post-mortem brain tissue from patients who very kindly donated their brains for research. We looked at epigenetics in brain tissue of patients with Alzheimer’s and compared it to post-mortem brain tissue of patients of similar age who did not have Alzheimer’s. In addition, we also performed a comparison with post-mortem brain tissue from healthy younger donors. We wanted to look at epigenetics of healthy aging versus diseased aging, which is neurodegeneration. 

By directly looking at epigenetics in post-mortem brain tissue, we made a few interesting observations. We found that there is an epigenetic factor that is increased with healthy aging, and it’s decreased in Alzheimer’s disease. At the same time, we found another epigenetic factor that’s actually not changing with healthy aging but it’s increased in Alzheimer’s. 

This tells us two things: Alzheimer’s is not the acceleration of healthy aging. On the other hand, epigenetics is changing in the brain affected with Alzheimer’s, and it’s different from healthy aging, and different epigenetic factors either promote neurodegeneration or delay neurodegeneration. 

Being Patient: How are lifestyle changes involved in epigenetics? 

Dr. Raffaella Nativio: Because we see epigenetic changes in Alzheimer’s and because epigenetic changes are driven by environmental factors, it’s very possible that changes in diet, air pollution and exercise can influence Alzheimer’s through modulation of epigenetics. 

For example, when you drink alcohol, the alcohol goes to the liver and gets broken down into different chemicals, one of which is called acetate. Acetate travels through the bloodstream, it gets to the brain and transforms into an epigenetic marker which is called acetylation. The acetylation gets added on top of the genes, and modulates them to be turned on or off. This is an example of how diet impacts epigenetics and epigenetic impacts gene expression changes. 

Being Patient: What are potential therapies in epigenetics for Alzheimer’s? 

Dr. Raffaella Nativio: Studies in mouse models of Alzheimer’s show that treatment of mice with Alzheimer’s with drugs that change epigenetics can ameliorate memory. Now, these drugs are not very specific and my study showed that some epigenetic factors promote Alzheimer’s while others are protective. An avenue to finding a treatment could be to find drugs that target specific epigenetic factors, to inhibit those that promote Alzheimer’s, and to improve or promote those that stop Alzheimer’s. 

The interview has been edited for length and clarity.

Contact Nicholas Chan at nicholas@beingpatient.com

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