Skip to content
Join Life Time
illustration of brain with puzzle piece

I suppose you could call it ironic that researchers seem finally to be homing in on a potential cause of Alzheimer’s at a time when our chief regulatory agency is becoming more skeptical of potential remedies. Call it what you will, but I suspect recent developments on the dementia frontier will likely leave physicians and their cognitively challenged patients more vexed than hopeful.

Scientists in Spain last month released the results of a study suggesting that a certain gene long thought to be merely a risk factor for the disease may actually cause the illness. As Pam Belluck reports in the New York Times, the findings indicate that hundreds of thousands of Americans could be treated for Alzheimer’s well before showing any signs of cognitive dysfunction. Big Pharma, meanwhile, could respond by expanding its current scope of research, focusing more intently on gene therapy, for instance, rather than its current fixation on brain plaque.

“This reconceptualization that we’re proposing affects not a small minority of people,” lead study author Juan Fortea, PhD, tells Belluck. He estimates that about 15 to 20 percent of all Alzheimer’s cases “can be tracked back to a cause, and the cause is in the genes.”

People carrying two copies of the gene variant APOE-ε4 have generally been considered vastly more likely than those without the gene to develop Alzheimer’s, so Fortea, director of the Saint Pau Memory Unit in Barcelona, and his team analyzed data from more than 500 subjects fitting that profile and found almost all of them had developed a key biological marker of the disease — an accumulation of amyloid plaque on the brain — by the age of 55.

That means the disease could be well advanced by the time doctors are able to make a diagnosis and suggest treatment options, notes study coauthor Reisa Sperling, MD, a neurologist at Mass General Brigham Hospital in Boston. “The critical thing is that these individuals are often symptomatic 10 years” before they’re diagnosed with Alzheimer’s disease, she says.

These APOE-ε4 carriers are also more likely to suffer from brain swelling and bleeding when treated with the Alzheimer’s drug currently on the market, a fact that leads some experts to argue that Fortea’s study should inspire drug companies to include this cohort in trials focusing on safer, more effective medications. Some scientists are already searching for gene-editing options that would transform the more dangerous variant to its APOE-ε2 cousin, which has shown signs of protecting the brain against plaque accumulation, Belluck reports. Other researchers are exploring the potential of injecting APOE-ε2 into the brains of Alzheimer’s patients.

Whether such exotic remedies would pass muster at our suddenly scrupulous Food and Drug Administration (FDA), however, is another question altogether.

On Monday, a full 364 days after Eli Lilly submitted its application for approval of its Alzheimer’s drug donanemab, an FDA advisory panel convened to make its recommendation. And if preliminary reports are any indication, the Big Pharma giant is likely to face some tough questions.

The FDA back in March notified Lilly that it was delaying action on the drugmaker’s application as it sought to get more clarity on the drug’s safety and efficacy as well as its trial design. The move caught the company by surprise. “We were not expecting this,” Lilly executive vice president Anne White told the Times. It was unusual to make such a move “at the end of the review cycle and beyond the action date that the FDA had given us.”

But the agency was still reeling from its controversial accelerated approval in 2021 of Biogen’s initial entry into the Alzheimer’s sweepstake, aduhelm. The FDA’s ruling came despite almost unanimous disagreement from its advisory panel, and the well-documented controversy — along with the drug’s price and questions about its safety and efficacy — swiftly dampened demand. The company withdrew it from the market earlier this year.

In the months since the aduhelm controversy, the agency has approved one other Alzheimer’s drug, Leqembi, while managing to sidestep further turmoil, and the Lilly decision seems to reflect a more cautious approach. In documents released last week, agency scientists revealed various concerns, including whether donanemab treatments should be limited to patients whose brains have accumulated deposits of tau, a toxic protein. They also encouraged the panel to determine the risks of brain swelling and what criteria would be used to consider ending a patient’s treatment.

This level of oversight does not disqualify Lilly’s drug; the FDA panel on Tuesday determined that donanemab’s benefits outweighed its risks. It does, however, seem to indicate that it will be some time before we’ll be able to head to our local clinic for an APOE-ε2 brain injection when we’re feeling a little absent-minded. I suspect that won’t prevent the more curious among us from surveying their genetic makeup hoping to learn whether they’re carrying the APOE-ε4 variant, but Stanford University neurologist Michael Greicius, MD, MPH, counsels against such an exploration.

Fortea’s study, he argues, was limited by a lack of ethnic diversity among its participants, making it more difficult to generalize its results. “One important argument against their interpretations is that risk of Alzheimer’s disease in APOE-ε4 homozygotes varies substantially across different genetic ancestries,” he explains. “This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease, and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

Besides, with no reliable treatment options for those who have lost the genetic lottery, such knowledge offers few benefits. “My recommendation is if you don’t have symptoms, you should definitely not figure out your APOE status,” he says. “It will only cause grief at this point.”

Craig Cox
Craig Cox

Craig Cox is an Experience Life deputy editor who explores the joys and challenges of healthy aging.

Thoughts to share?


More Like This

a woman holds her hands over an elderly person's heart

How Super-Agers Avoid Dementia

By Craig Cox

Genes play a role, but so do lifestyle factors, according to a recent study of centenarians.

Back To Top