Research on one of the most famous families in neurology has shed new light on the interplay between Alzheimer’s disease and a rare gene that protects against it, as well as how that learning might one day turn into a drug.
In the Colombian family, with more than 6,000 members, nearly one in five carry a genetic mutation that causes amyloid protein to build up in their brains at a young age, causing cognitive impairments in their 40s, dementia in their 50s and death in their 60s.
Earlier research had identified a woman who carried two copies of a protective mutation, dubbed Christchurch, and whose disease was delayed by decades. But a small number of the family members also carry a single copy of the mutation, the researchers found, which delays the first signs of cognitive impairment by about five years.
“This is the nastiest and most aggressive form of Alzheimer’s, so the protection is substantial,” Joseph Arboleda-Velasquez, a medical researcher who led the study at Mass Eye and Ear in Boston, told Endpoints News in an interview. The study was published this week in the New England Journal of Medicine.
Until the discovery, researchers had worried that mimicking the effects of two copies of the gene would be difficult to do with a drug. And they didn’t know if a single copy of the gene would still be protective.
“A 100% effect is very hard to reproduce with any drug, but a 50% effect is something that drugs can do,” Arboleda-Velasquez said. His team found 27 members of the family who carried a single copy of the variant, and that it delayed the median age of disease onset from 47 to 52 years. “That got us very encouraged that the effects of this mutation can be reproduced with drugs that we can make.”
The Christchurch mutation lies in a well-known gene called APOE. One version of the gene, called APOE4, strongly increases the odds of developing Alzheimer’s, while another called APOE2 lowers the risk. The protective Christchurch mutation is an incredibly rare form of APOE3 — the standard version of the gene that most people have.
Curiously, brain scans of people with the Christchurch mutation show that they still have heads full of amyloid plaques, the protein many scientists have long held is responsible for Alzheimer’s. But they had very little buildup of a second protein called tau, which often accumulates after amyloid and actively damages brain cells.
“It’s good news, because it’s again confirming that reducing tau pathology is worthwhile,” Jacob Raber, a neuroscientist at Oregon Health and Science University who wasn’t involved in the study, told Endpoints. (The debate about whether Alzheimer’s therapies should go after amyloid, tau or both has echoed through drug development for decades.)
Small startup targets new drugs
Arboleda-Velasquez and some of his colleagues have already formed a small company called Epoch Biotech to translate the Christchurch mutation and other genetic clues into new drugs, with an initial focus on an antibody licensed from his lab that mimics the effect of the mutation.
Michael Aceti, the startup’s managing director and president, told Endpoints in an email that the company has raised about $1 million and that its work is “advancing significantly,” but that it’s still in the very early stages of preclinical research. “We continue to attract the attention of both financial and strategic potential investors and are in advanced discussions with multiple parties,” Aceti said.
The group also found that the Christchurch mutation hinders the natural ability of APOE from binding to proteins that are crucial for ferrying tau into cells. By restricting their interaction with APOE, more of them are free to help microglia chew up and destroy tau.
Arboleda-Velasquez’s team has already designed an antibody that blocks APOE, mimicking the effects of the Christchurch mutation. The antibody, which they tested in the retina of mice in a study published in October, has been licensed to Epoch.
It’s not necessarily an easy target, said Jason Ulrich, a neurologist at the Washington University School of Medicine in St. Louis who has studied the Christchurch mutation in mice.
Ulrich said the antibody inhibitor idea was “interesting,” but he cautioned that “there’s a lot of APOE in the brain, so there’s a lot of target you’d have to neutralize.” And since APOE is found throughout the body, bypassing those proteins and getting the drug directly into the brain could be another challenge, he said.
“But either way, it’s great biology to understand to try and get at this question of how to avoid tau,” Ulrich said.
Some scientists are already thinking about using gene editing tools like CRISPR to turn common versions of APOE into a protective variant. “The question is how much genetic editing do we need to do?,” Raber said, noting the difficulty of getting genetic medicines distributed widely through the brain.
Raber also noted that so far, the most promising evidence for the Christchurch mutation all comes from the Colombian family. “We don’t know what it will look like in another cohort,” he said. It’s possible that protective effects are restricted to people with the same rare mutations that cause early-onset Alzheimer’s in the Colombian family, or that the protection could vary by ethnicity. And there have been cases where patients with regular forms of Alzheimer’s disease who carried the Christchurch mutation developed dementia anyways.
But for Arboleda-Velasquez, his studies show that more work needs to be done on understanding people who are protected from Alzheimer’s.
“The field hasn’t paid enough attention to APOE. That’s the bottom line,” Arboleda-Velasquez said. “Everyone just focuses on amyloid. And even within APOE, there’s been too much focus on high-risk variants compared to protective variants. If we change the paradigm and focus on the genetics of health, we can probably develop really exciting new therapies.”