By Caroline Seydel
November 10, 2020
Last Friday, an FDA advisory panel voted unanimously against recommending the Alzheimer’s drug aducanumab. Based on evidence from two clinical trials, they found that the data did not show that the drug effectively treats Alzheimer’s disease. Remarkably, however, the panel agreed that the drug does appear to reduce the brain protein thought to cause the disease. What’s going on?
Despite hundreds of clinical trials conducted, no new Alzheimer’s drugs have been approved in almost two decades. Many of these attempts have centered on reducing two Alzheimer’s-associated proteins in the brain, called beta amyloid plaques and tau tangles.
Maybe these drugs aren’t working because something else causes the disease, besides beta amyloid and tau. Some researchers are working a different angle, called epigenetics, to try to find a way to stop the disease.
Genetics considers a person’s DNA sequence, and epigenetics looks at how the cell turns genes on and off. By comparing the genes that are activated in healthy people versus those with Alzheimer’s, researchers hope to understand how healthy aging changes the brain — and how certain changes open the door to disease. Research teams around the world have identified significant epigenetic changes associated with Alzheimer’s disease, and these changes may be modifiable with medications.
Epigenetics changes with age
Shelley Berger is the founding director of the Epigenetics Institute at University of Pennsylvania. She’s studying how genes are turned on and off in the brain, and how different patterns of gene activation could be related to Alzheimer’s disease.
Every single cell in your body has the same set of genes. For instance, the gene responsible for producing insulin is present in all your cells, but it’s only active in certain cells in the pancreas. That’s because cells have chemical signposts that they plant in the DNA, to mark which genes should be switched on. Epigenetics is the study of how cells use these chemical signposts.
All sorts of things can change your epigenetic profile, including environmental exposures and aging. There’s a concept called an “epigenetic clock”: you can pretty closely guess a person’s age by looking at the epigenetic changes in their DNA.
Berger and her team compared the epigenetics of brain cells from three populations: older people with Alzheimer’s disease, older people without Alzheimer’s disease, and healthy people younger than 65.
“Most people in the field of Alzheimer’s disease compare cognitively normal, age-matched samples to Alzheimer’s disease samples,” she said. “That’s interesting, that tells you what kind of changes happen in disease.” By also looking at gene expression in young brains, Berger and her colleagues singled out changes that happen naturally with healthy aging.
“We find that there are some changes that happen in the cognitively normal aged brain that are protective, that actually help to maintain healthy aging,” Berger said. The study also discovered that those protective changes do not occur in people with Alzheimer’s disease.
How the signposts work
If the cell’s DNA was laid out full-length, it would stretch from your head to your toes. To cram all that into the cell, and keep it organized, the DNA is tightly wrapped around proteins called histones. Adding molecules called acetyl groups to the histones can loosen up the package, allowing the cell’s DNA-reading tools to get in there and activate the gene.
By looking at where these acetyl group signposts were added at different stages, Berger found clues to how genes are activated differently in Alzheimer’s disease than in healthy aging. She found acetyl groups improperly placed at two very interesting spots: they were directing the cell to make more of a molecule, called an enzyme, that adds the acetyl groups to the histones.
“There are different enzymes that put the acetyl group on the packing material,” said Berger. In this case, she said, “It’s kind of a feed-forward mechanism, where the enzyme is leading to more activation of its own gene.”
It may be possible to develop drugs to stop that self-activating pathway, as there are compounds known to inhibit the enzyme doing the work. But that would be a long way down the road, Berger said.
Two paths to the same endpoint
New findings in epigenetics will more than likely tie into what’s already been learned about the disease genetics. Jonathan Mill, an epigeneticist at the University of Exeter, UK, led a similar study, looking for epigenetic signals in Alzheimer’s patients.
Researchers know Alzheimer’s disease has a genetic component, but it’s still not well understood. People who inherit certain genetic mutations, such as in the ApoE gene, develop Alzheimer’s at a young age. This is called familial or early-onset Alzheimer’s, and it’s fairly rare. Far more often, the genetic cause of the disease is more subtle and distributed among many genes that each exert a tiny effect. This is called sporadic Alzheimer’s, and it usually comes on a little later, with symptoms arising after age 65 or so.
In patients with sporadic Alzheimer’s, Mill detected a curious pattern. Comparing the differences in the acetyl groups in the DNA from healthy and Alzheimer’s brains, he found the changes were congregating around genes that are known to be damaged in early-onset familial Alzheimer’s.
“The endpoint is similar, and there’s many ways you can get there,” he explained. Mutations in the gene itself can cause it to no longer function: that’s what happens in early-onset cases. “The other way is altering the way the genes are expressed,” Mill said. “That’s probably by disruptions in the epigenetic signatures.”
Unlike genetic mutations, changes in the epigenetic signature can come and go over the course of a lifetime. Just as healthy aging causes natural epigenetic changes, environmental factors can alter epigenetic signals.
“It’s really clear that lots of things in the environment probably have effects on gene expression via epigenetic changes,” Mill said. One major contributor? Smoking. “It’s pretty amazing—I could pretty accurately work out who was a smoker and who wasn’t, based on their epigenetic profile.”
This fluidity is good, because it means we could potentially change our epigenetics with medication. And indeed, drugs already exist that can rearrange the epigenetic signposts in our genome. Whether this can effectively treat disease, however, depends on whether the epigenetic changes are causing the disease — or are a result of it.
"What we don’t know is whether the signature that we’re seeing is something to do with the onset, or a consequence of the pathology,” as Mill puts it.
Tau protein influences epigenetics
One distinctive feature of Alzheimer’s disease is long strings of protein, called tau tangles, that gather like dust bunnies inside neurons. Brain cells do normally contain tau, but in Alzheimer’s disease, it stops doing its job and instead forms tangled masses that eventually kill the cell.
It turns out that tau tangles can alter the epigenome. Philip De Jager, a neurologist at Columbia University in New York, investigated what epigenetic changes occurred in the presence of tau tangles.
De Jager and his team found that the tau tangles cause the tightly packed DNA to become disorganized — in a predictable, reproducible way. The researchers were able to induce the epigenetic changes in lab-grown neurons by adding tau tangles to the cells.
“By increasing expression of tau, we were able to generate some of the same changes in the epigenome in the lab that we saw in the actual brain,” De Jager said.
What’s exciting is that De Jager and his team were also able to stop tau from effecting these changes, using a drug candidate that inhibits a protein called Hsp90. Hsp90 may play a role in helping tau form those long tangles that build up in the cell, so blocking it with a drug could prevent tangle formation and thus stave off the epigenetic changes.
Tau may influence epigenetics, but epigenetics may also contribute to tau buildup. In a preprint earlier this year, De Jager’s group proposed another way that epigenetic changes could influence brain health: via the immune system. Immune cells called microglia help support neurons, cleaning up cellular debris, helping the brain recover after a stroke, and stopping beta amyloid plaques from forming. “In Alzheimer’s disease, with relation to amyloid, they seem to not be working quite as well as they should,” said De Jager. “Later, when tau begins to accumulate, it appears that the problem is that they’re overactive.” At that stage, the microglia begin releasing chemicals that may accelerate the buildup of tau.
Remember the genetic mutation in the ApoE gene, the one that causes early-onset, familial Alzheimer’s disease? It turns out that not everyone with that mutation ends up getting the disease. De Jager’s group tested people who had two damaged copies of ApoE but remained dementia-free in their 80s. Those people carried epigenetic factors that somehow make up for that mutation, reducing the risk of the disease. These factors influenced the activation of genes in the microglia, suggesting that they may restrain the microglia from promoting tau accumulation.
Because the brain is uniquely difficult to study, advances in Alzheimer’s disease have been a long time coming. With the power of modern genetic and epigenetic technology, some of the mysteries surrounding this devastating disease are beginning to open up. New understanding of how the complex tapestry of epigenetic changes impacts brain health will, hopefully, bring new insights into ways to slow or stop the disease.