When it comes to treating Alzheimer’s disease, two primary targets for treatment have been beta-amyloid plaques and tau tangles.
These sticky buildups of proteins damage brain tissue. Beta-amyloid protein fragments accumulate in spaces between nerve cells, and the twisted forms of tau crowd inside brain cells. Studies have linked plaques and tangles to the memory loss, personality changes, and difficulties with normal day-to-day activities related to dementia.
Although several experimental drugs in development have targeted these proteins, few have produced any significant results. Because of trial failures, the Alzheimer’s Drug Discovery Foundation (ADDF) and other expert sources have been pushing for research looking into other factors that may contribute to the disease.
“We’re always going after the plaques and the tangles as the target for treatment and prevention of Alzheimer’s disease, but the fact is two-thirds of people in their eighties who have plaque don’t have Alzheimer's,” says Gayatri Devi, MD, attending neurologist at Lenox Hill Hospital and director of Park Avenue Neurology in New York City.
“I think of Alzheimer’s as a condition which is a confluence of multiple roads,” Dr. Devi says. “Everything has to be just right to create a perfect storm of Alzheimer’s, and plaque perhaps is just one of the components for creating this clinical storm.”
Epigenetics: The Potential of Modifying Genes
One of the newest and most promising roads to treatment that scientists are exploring is an area of study called epigenetics. Epigenetics involves the biological mechanisms that turn genes on or off in cells.
Researchers have been exploring epigenetic drugs that make chemical changes in cells, activating or inactivating genes to improve Alzheimer’s symptoms.
Howard Fillit, MD, a specialist in geriatric medicine at The Mount Sinai Hospital in New York City and founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation, explains that epigenetic treatments harness our body’s ability to change gene expression for the better.
Investigators presented results from several epigenetics studies at the 12th Annual Clinical Trials on Alzheimer’s Disease (CTAD) meeting in San Diego in December 2019.
One of the CTAD presenters, Oryzon Genomics, based in Barcelona, Spain, began work on epigenetic drugs for cancer in 2008. With funding from the ADDF, the biopharmaceutical company has been working on an epigenetic Alzheimer’s treatment that inhibits the enzyme lysine-specific histone demethylase 1 (LSD1).
“By inhibiting this enzyme, the treatment, called vafidemstat (ORY-2001), promotes the survival of neurons and may restore memory deficits and cognitive function,” says Dr. Fillit.
The latest information put forth at CTAD shows that vafidemstat restores memory, decreases neuroinflammation, eliminates aggressiveness, and restores sociability in mice. An upcoming study will examine its effects on Alzheimer’s-related aggression in human participants.
Also at CTAD, the Canadian biotech firm Resverlogix offered a progress update on the oral epigenetic medication apabetalone (RVX-208), which inhibits bromodomain and extra-terminal domain (BET) proteins. In lab tests, the drug demonstrated potential to reduce brain inflammation and possibly reduce cognitive decline.
The Gut-Brain Connection and Other Therapeutic Pathways
Increasingly, evidence is showing that the gut microbiome (the trillions of bacteria, viruses, and microorganisms that live in the gut) plays a role in almost every aspect of our health.
Several CTAD investigations examined how irregularities in the gut microbiome could be linked to Alzheimer’s, and discussed possible therapies.
“My thinking is maybe because the gut biome is so intricately involved in inflammation, it may in some way change things in the brain enough so that clinical symptoms can be ameliorated,” says Devi.
Devi adds that infectious causes, such as bacteria in the mouth from gingivitis, have been linked to dementia, according to a study published January 2019 in Science Advances.
Other research out of Korea presented at CTAD demonstrated that antiviral treatment for herpes zoster may reduce the risk of dementia.
“All these studies show that it’s not just the presence of plaques and tangles,” says Devi. “It seems more likely that for clinical symptoms of dementia to develop, a person has to have plaque or tangles — plus something wrong with their immune system, or maybe some kind of prior exposure to infection — something that puts them at risk, in addition to the fact that they are aging.”
Amyloid Plaques and Tau Still Drug Targets
Beta amyloid and tau remain the most common drug targets in Alzheimer’s clinical trials, according to Fillit, and while few related studies have produced significant positive results, there is still potential in medication directed at these proteins.
At CTAD, scientists with Biogen detailed new results from analysis of its drug aducanumab indicating that the drug, when given in high doses, may slow decline in cognition and function in those with mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease dementia.
In October 2019, the biotech company announced that it planned to seek approval for aducanumab from the U.S. Food and Drug Administration (FDA). The news came as a reversal after a Biogen report in the spring finding that the drug had failed to produce significant results.
“The drug ‘hit its target’ and was able to remove beta-amyloid from the brains of patients,” says Fillit. “It is encouraging the FDA has agreed to review the drug application for possible approval.”
He noted that if aducanumab is approved, it may be most effective given along with other therapies that are still in the research stages. The ADDF estimates that more than 100 potential treatments for Alzheimer's disease are currently in clinical development.
“As with cancer therapy, we expect patients with Alzheimer’s will be taking a combination of drugs to slow down the illness,” says Fillit.
“This is very exciting time,” he adds. “We’re starting to see some success in our clinical trials. There’s a lot of hope right now.”