Kentucky scientists have successfully edited genes in living mice, switching a gene associated with high risk of Alzheimer’s disease to its counterpart, a protective gene.
This new research, which came out of a 22-person team from the University of Kentucky and beyond, has the potential to someday prevent millions of cases of Alzheimer’s in humans, said Lance Johnson, an associate professor in the UK College of Medicine’s Department of Physiology.
The study, published this month in Nature Neuroscience, found that editing a specific gene known to increase risk of Alzheimer’s with its counterpart, a gene associated with lower risk, in mice resulted in “fewer Alzheimer’s-related brain changes such as amyloid plaque buildup and inflammation, and stronger performance on memory tests.”
Lesley Golden, the lead author, said in a statement that “this model allows us to test what happens when we go from risk to resilience. Remarkably, even switching the gene later in life improved multiple aspects of Alzheimer’s pathology at once.”
Everyone has the apolipoprotein E, or APOE gene, Johnson explained, though some people have variants — “the same gene that just differs by only one or two base pairs” — APO E2, E3 and E4. Most people inherited E3 from both parents, Johnson said. Some will inherit a mixture of variants.
People who got an E4 variant from both parents — about a quarter of the population, Johnson said — are about 15 times more likely to develop Alzheimer’s disease.
“The good news there is: Some people, I like to say, have won the genetic lottery in that they’ve inherited the E2 variant of the gene,” Johnson said. “And so those that have inherited E2 are equally as protected as the people who inherited E4 are at risk. So it’s an incredibly protective variant of this gene.”
He and his team wanted to answer this question: “Why don’t we just change the gene itself? if you got an E4 from mom and dad, and you’re facing an almost certain chance of getting this disease at some point, if it was possible, wouldn’t you want to have the E2 variant?”
Researchers gave living mice the risk variant “designed a mouse’s DNA so that it had the (protective gene) behind” the risk variant. Then, researchers injected a drug into the mice that directed the DNA to change from making the risk gene to making the protective gene.
The change took a few days in mice, but would likely take longer in a human body. (Mice have a lifespan of around 1.5 years). Mice also do not get Alzheimer’s disease, Johnson said, meaning the team had to “use a genetic model that makes lots of the amyloid plaque that features that disease.”
At best, making an effective gene switch in humans is years away, and there are many hurdles to clear before efficient and specific editing is an available treatment. But the research offers some hope to many Kentuckians who live with Alzheimer’s and the loved ones who take care of them.
The 2025 Alzheimer’s Disease Facts and Figures Report, released by the Alzheimer’s Association in May, reported that 80,000 Kentuckians aged 65 and older are living with an Alzheimer’s diagnosis. Additionally, around 160,000 Kentucky residents provide unpaid care for a loved one with Alzheimer’s, an incurable but treatable disorder characterized by memory loss.
“To us, it was an exciting proof-of-concept study to show that, okay, perhaps one day this would work in a human if we can figure out a safe way to deliver gene editing technology; if we can figure out a way to do that with the correct timing,” Johnson said.
Johnson hopes to continue his research in the coming years, “assuming we can continue to get (National Institutes of Health) funding for this.”
This research is not an end-all, fix-all to effectively treating Alzheimer’s. The gene that is protective against Alzheimer’s can raise a person’s risk of other conditions, Johnson explained, including age related macular degeneration and cardiovascular disease.
“It would be too good to be true if inheriting E2 was good for everything,” Johnson said. “The last thing you’d want to do is protect someone from Alzheimer’s disease, but put them at a higher risk for cardiovascular disease, right?”
The scientists studying this gene will need to keep that front of mind, Johnson said, and ensure that any treatments don’t put patients at risk of other diseases. He believes this will happen and is “as hopeful as I have been for this field and for tackling this disease.”
“My hope and my belief is that one day — and hopefully it’s sooner rather than later — we’re at a point where we have tools that can edit DNA efficiently and safely, and we could target something like APOE,” Johnson said. “In theory, we could prevent millions of Alzheimer’s disease cases from ever happening in the first place.”