Three siblings, one fatal gene: A family's fight against early-onset Alzheimer's

Mint

29-06-2025

Hannah Richardson is hopeful about her future and its endless possibilities. But the 24-year-old's plans are clouded by an unthinkable reality—there is a 50% chance she will develop Alzheimer's disease in her 30s.
Hannah's family has a history of a rare genetic mutation that, when inherited, virtually guarantees that the carrier will die of an aggressive form of Alzheimer's early in life. No drug has been found to stop it. But now researchers are exploring a new avenue: Could pre-emptive treatment slow or even halt the memory-robbing disease in people at high risk of developing it?
Hannah and her two siblings will help researchers test that theory. They are enrolling in a new clinical trial led by doctors at the Washington University School of Medicine. As part of the trial, the siblings will finally find out if they carry the fatal gene.
'I don't know if being in the trial is going to save me or my siblings. But in my head, it's the least I can do. Research is how cures are found," said Hannah, who dreams of becoming a physician assistant and is applying to graduate programs. Her brother Jacob, 22, and sister Rylee, 19, are both in college.
Unlike most cases of Alzheimer's, which are unpredictable, 'in this population we know who will develop the disease and when they will develop it," said Heather Snyder, senior vice president of medical and scientific operations at the Alzheimer's Association, a major funder of the trial.
Doctors have identified over 300 inheritable genetic mutations that cause early-onset Alzheimer's. These rare genes account for less than 1% of people with the condition, but researchers say that studying families like the Richardsons can offer insights into how to prevent and treat Alzheimer's in everyone.
Among the people in Hannah's family who carry a mutation in what is known as the presenilin-1, or PSEN1, gene, the average age when Alzheimer's symptoms start is 39, according to the family. The disease is aggressive once symptoms appear and the decline is swift, the family said.
'I call it the monster," said Mary Salter, Hannah's grandmother.
Hannah's grandfather and three of his four brothers died of Alzheimer's in their early 40s, soon after developing symptoms. Hannah's uncle died last year of the disease at the age of 44. And Hannah's mother, Carrie Richardson, started showing subtle signs of the disease in her early 40s. Now at age 44, Carrie has started to decline mentally.
Carrie's children remember vividly the day in 2012 when she learned she was a carrier of the PSEN1 mutation. Her eyes were red and puffy when she picked the kids up from school. Pressed by Hannah to tell them why, a sobbing Carrie told them the news in the car. The siblings, who were all under 12, remember crying, too, though not fully understanding why.
Today, Carrie has memory lapses and sometimes struggles to communicate, her children say. Her worsening symptoms forced her to quit her job as a preschool teacher and this month, she started the process of leaving her own home to move in with Mary.
Carrie and her brother enrolled in a clinical trial that began at WashU Medicine in 2012. That trial tested whether the early use of experimental drugs that target a sticky protein in the brain known as amyloid could slow the progression of Alzheimer's in people who carried PSEN1 mutations and other rare genes.
Hannah's uncle hadn't been able to join an extension of the trial because his symptoms became too pronounced, but her mom continues to be a participant and receives a bimonthly infusion of an antiamyloid drug.
In a paper published in Lancet Neurology in March that detailed interim results of the extended trial, WashU Medicine researchers said treating people like Hannah's mom with antiamyloid drugs before Alzheimer's symptoms began, delayed the onset of the disease—in some cases lowering participants' risk of developing symptoms by 50%.
The first antiamyloid drugs were approved by the Food and Drug Administration in 2021. These drugs clear accumulations, or plaques, of amyloid in the brain, which researchers once thought could be the root cause of Alzheimer's. But some doctors have since questioned this hypothesis, as well as whether the benefits of these treatments outweigh their risks.
The drugs don't stop Alzheimer's in its tracks and though they have shown to reduce cognitive decline in some large clinical trials, the slowing was modest at best, said Dr. Scott Small, a Columbia University neurologist.
Carrie Richardson prepares to blow out candles on her birthday cake surrounded by her children and mother.A sign honoring Bryan Salter hangs on Mary Salter's home.
'The science now predicts that amyloid plaques are not the root source of Alzheimer's," Small said.
Swelling and bleeding in the brain is a possible side effect of antiamyloid drugs. Rarely, people have died from this complication. In about half of all patients in the WashU Medicine study, some brain swelling and microbleeds were detectable in MRI scans, though researchers said about 95% of participants had no symptoms from the medications.
Antiamyloid drugs remain the only FDA-approved treatment available that can change the course of Alzheimer's. Dr. Randall Bateman, a neurologist who led the WashU Medicine study, said early use of the treatments could improve their efficacy and safety. He said he remains optimistic that removing—or even preventing altogether—the buildup of amyloid could slow or even halt the progression of the disease.
Hannah and her siblings believe that antiamyloid drugs have helped stall their mom's Alzheimer's. That belief spurred them to enroll in a similar WashU Medicine clinical trial—one that seeks to treat carriers of rare genes with a different experimental antiamyloid drug, called remternetug, many years before they develop symptoms and, in some cases, even before amyloid has built up in their brains.
Drugmaker Eli Lilly, which makes the drug, said it works similarly to earlier antiamyloid treatments but has the benefit of being administered as an injection rather than an intravenous infusion.
Rylee Richardson, a cheerleader and rising sophomore at Tulane University, said she and her siblings thought long and hard about participating in the trial. They ultimately decided that it was worth the potential risks.
'I will do anything that gives me and my siblings a better chance," she said.
Until now, Rylee and her siblings had decided not to find out if they carry the PSEN1 mutation out of fear that it could upend their lives. But if they want to participate in the extended phase of the trial, they will have to learn the truth. The initial phase will last for two years and focus on basic efficacy and safety questions, said Dr. Eric McDade, a colleague of Bateman's who is leading the trial.
Only people who test positive for a high-risk genetic mutation will be randomized to either receive a low dose of the active drug or placebo. For those who test negative, they can stay in the trial if they choose not to find out their genetic status and would be given a placebo.
Dr. Richard Isaacson, a neurologist at the Institute for Neurodegenerative Diseases who isn't involved in the trial, said he believes antiamyloid drugs could be helpful in slowing cognitive decline when used preventively in patients at risk of Alzheimer's.
He himself prescribes them to patients at his clinics in New York and Florida, but only in people who already have some amyloid buildup. He questioned whether it made sense to use these drugs in people who don't have amyloid at all.
'That is not something that sits well with me," said Isaacson.
WashU Medicine researchers said that in animal experiments, antiamyloid treatments were most effective when used before evidence of amyloid buildup. But such an experiment has yet to be conducted in people.
Alzheimer's has been a specter that has haunted the Richardson siblings since they were children. The three of them made a pact years ago to not have children if they learned that they carried the Alzheimer's gene.
'We decided that we would be the last three. No one has to suffer anymore from our family," Hannah said. 'We want to do everything we can to stop it for us and everybody else."