Linde Jacobs paced back and forth across her bedroom, eyeing the open laptop on the dresser and willing the doctor to appear. Her husband was dropping off their older daughter at school. Their younger daughter was downstairs, occupied by a screen. Linde wanted to be alone when she learned whether she carried the family curse.
Linde’s mother, Allison, had died just four weeks before, after a mutant gene gradually laid waste to her brain. In her 50s, Allison transformed from a joyful family ringleader into an impulsive, deceptive pariah. She drove like a maniac on cul-de-sacs. She pinched strangers, shoplifted craft supplies and stole money from her daughter.
Now, on this morning in September 2021, Linde would find out if she had inherited the same vile genetic mutation.
She had a bad feeling. She and her mother had been so alike. Allison had been a physical therapist and Linde was a nurse. They were both doers — taking charge, mending wounds, planning theme parties. They were both chipper and a bit unfiltered, easy to a smirk or a four-letter word.
She probably gave me this, too, Linde thought.
The doctor finally popped up on the computer. Wasting no time on pleasantries, she shared her screen and zoomed in on one line of laboratory paperwork: POSITIVE.
Linde was 33. Within about two decades, in all likelihood, her daughters would watch her become selfish, manipulative, reckless — the opposite of everything she’d taught them to be. Just like Allison, Linde would turn into someone hard to tolerate, let alone love.
And more insidious: Her girls and her two sisters each had a 50-50 chance of carrying the mutation. There was no cure for this disease, called frontotemporal dementia, nor even any treatments.
Soon, Linde’s husband, Taylor, pulled into the garage and opened the car door. He could hear her sobbing.
They loaded the 3-year-old into the car and went for a long drive around their Minneapolis suburb.
Linde looked at Taylor. “I don’t want you to feel stuck with me,” she said.
Leaving had never crossed his mind. Allison’s miserable experience, he told Linde, did not have to be hers. “You have all this time,” he said. “Do something about it.”
Even as they spoke, scientists were working on projects that might one day help her. Some had discovered how to cure grave conditions with gene editing. Others were tinkering with patients’ skin cells to test experimental drugs. And pharmaceutical companies were developing new Alzheimer’s therapies, one of which happened to target the rare defect in Linde’s brain.
Linde didn’t know any of that yet. But she decided to take Taylor’s advice. She would use the time she had, somehow, to find influential scientists and make them care about what was happening to her — and what might happen to her girls.
‘Happy to help if I can’
Linde and Taylor scoured the internet for any scrap of hope about treating frontotemporal dementia, or FTD. There was little to read.
Taylor remembered a Netflix documentary about a new way to edit genes. The method, called CRISPR, had cured some children with sickle cell disease. He searched “FTD treatment CRISPR” and found the website of Dr. Claire Clelland, a neurologist at the University of California, San Francisco. She had collected skin cells from patients with FTD, reprogrammed them into neurons and tried to edit the faulty genetic code within.
The website listed a phone number. Taylor called and left a message — a Hail Mary, he figured.
Within a day, Dr. Clelland responded by email. “Happy to help if I can,” she wrote.
Taylor and Linde were floored. While Allison was alive, doctor after doctor had dismissed the family’s concerns about her behavior. Now a big shot was readily offering her expertise. Where have you been the last 12 years, Linde thought.
Taylor wrote back, passing on what doctors had told them — that Linde carried a mutation in a gene called MAPT. Their aim, he wrote, was “to hopefully find a therapy/cure someday.” He attached a photo of himself seated next to Linde, beaming under the sun with a little girl snuggled on each of their laps.
Dr. Clelland was moved by the picture. She had two daughters, too, around the same ages. What would I do in her situation? she wondered.
Her small lab, she wrote, was building a program to repair the handful of genes that caused FTD. She wasn’t working on the MAPT gene yet, but she planned to.
The scientist promised to keep Linde in the loop about clinical trials. “It would be incredibly motivating and inspiring to hear how you have come to know FTD through your mother,” she wrote.
Linde, in quiet disbelief that anyone would care, shook off her nerves and told this new confidante about her ravaged family tree.
An unacknowledged family history
When Linde was growing up in a leafy neighborhood in Eagan, a Minneapolis suburb, her mother burst with creativity. Allison wallpapered, tiled floors and built a koi pond with a waterfall in the backyard.
But life inside that well-tended house was not so serene. Linde and her two sisters sometimes huddled in a bedroom, crying over their parents’ screaming matches.
Allison’s life began to crater when she was 47. Her husband moved out, Linde left for college and both of her parents died. Allison lived with her youngest daughter, Ashlyn, whose harsh teenage assessment was that stress had turned her mother “psycho.” Allison drank too much and wrote notes in capital letters. One Thanksgiving, she threatened to kill herself if the girls visited their dad.
Most embarrassing, she incessantly touched other people. During Ashlyn’s senior trip to Mexico, Allison picked and poked at the arm of another student’s father, who exploded, “Get your hands off me!”
Allison’s physician blamed menopause and the divorce and prescribed antidepressants. They didn’t help.
These unsettling changes reminded Linde of her grandmother, Bev. In her 50s, Bev had started hoarding, filling her house with newspapers, figurines and even roadkill. She grabbed others’ food and argued with strangers. She wound up in a nursing home, where she languished for a decade before her death at 72.
An autopsy found shrinkage throughout the front and sides of Bev’s brain, the hallmark of frontotemporal dementia. The report said the disease could be hereditary, but Allison didn’t reveal that to Linde, who was 18 at the time.
Years later, when Allison grew so mean, Linde couldn’t help but wonder if the problem was genetic. She left a phone message for Allison’s doctor. All these bizarre personality changes, she said. Are you sure my mom doesn’t have what my grandma had?
The doctor didn’t call her back. It was the first of many times that Linde would be let down by the people charged with caring for her mother.
Linde and her older sister, Jenica, eventually gave their mom an ultimatum: No babysitting our children until you see a neurologist. Allison acquiesced to brain scans and neurological tests. But this doctor, like the last one, said the problem was psychiatric, diagnosing stress and obsessive-compulsive disorder.
Linde felt gaslit. Was it possible she was projecting her grandmother’s dementia onto her mother?
Whatever the trouble was, it was accelerating. Allison stole $9,000 from Ashlyn’s student loan account. Minnesota suspended her physical therapy license for “boundaries issues”: She had shown up at the home of a client’s uncle, asking him to pay for a medical device.
Allison cheerfully rejected any notion that she had dementia. Without telling her daughters, she had another brain scan. She mailed Linde a copy of the results.
“There was some shrinkage of the cortex of the brain,” said the letter from the clinic, “but this is nothing to be concerned about as it is a normal process of aging.”
Diagnosed by an inmate
One evening, Linde’s husband, Taylor, a police officer, got a call in his squad car about a known shoplifter named Allison trespassing inside Hobby Lobby. A screen on his dashboard gave a description: White female. Brown hair. Black leather jacket. Silver Prius.
Definitely her, he thought. Another officer wrote her up for trespassing.
Linde was embarrassed and exasperated. But she didn’t have any legal power over her mother, a gregarious and active 59-year-old. Plus, Linde was already stretched thin, working full time as a nurse while raising two little ones.
Not long after the trespassing citation, Ashlyn got a startling text: Allison’s neighbors hadn’t seen her in a couple of weeks. Linde, acting on a gut feeling, searched the county jail’s website. There was Allison, frowning in a mug shot.
“Mom’s in jail,” Linde wrote her sisters. As it turned out, the previous year, Allison had fled after an officer tried to pull her over for rolling through a stop sign. Now she was in jail for missing a court date.
While waiting for Allison’s release, Linde visited her house for the first time in more than a year. She was taken aback. Dark sludge lined the toilet bowls. Pringles cans had been wedged into bedroom cabinets and scrapbooking paraphernalia filled three rooms.
Allison had always been horrified by the squalor in which Bev had lived. Now she was living in it.
A few days later, Jenica received a letter in the mail from Allison’s cellmate at the jail. The woman was worried; Allison was agitated and hadn’t showered.
“Your mother should not be in here with these animals,” she wrote in neat script. “I am assuming she has dementia.”
After Allison’s release, a specialist finally diagnosed her with frontotemporal dementia. By that time, in 2018, scientists estimated that roughly 40 percent of FTD cases were hereditary. A devastating pattern was now emerging in Linde’s family tree: Her aunt and two uncles — Allison’s siblings — were all showing signs of the disease.
Later, Allison was tested to see if she carried one of the handful of genes that had been linked to FTD. Sitting next to their mother in a sterile exam room, Linde and Jenica were shown cold proof of a biological culprit: a single aberrant letter of DNA code.
That rare mutation had caused a protein called tau to build up in Allison’s brain, gradually killing neurons. Linde’s vague sense that she and her sisters might be afflicted was now replaced with a precise numerical probability: There was a 50 percent chance that they had inherited the same defect.
Linde fixed her eyes on the doctor, trying to take in every word while her sister ugly-cried and their mother flailed around, laughing. “I’m fine!” Allison squealed. “I pay my bills!”
Linde and her sisters decided not to get tested right away. Insurance wouldn’t cover the $5,000 expense because they weren’t showing any symptoms of a disease. Even if they paid out of pocket, some doctors might require a psychiatrist’s sign-off. It all seemed like too much to deal with, on top of keeping their mother under close watch.
Linde figured she would get tested eventually. She didn’t feel any urgency — in her mind, a 50 percent chance might as well have been 100.
‘Why are you so mean to Gaga?’
Shortly before the Covid pandemic, Jenica and her family of five moved into Allison’s house. It was stressful, not least because Allison, who had no concept of social distancing, roamed around the neighborhood knocking on doors.
Allison called or texted Linde every day: Bring the kids over! Don’t forget to pick up my creamy ranch dressing! When they were together, Allison barked her demands a few inches from Linde’s face. Or she roughhoused on the floor with her young grandchildren, not realizing her own strength.
Linde often stormed out cursing and crying, then regretted it. The guilt kept her up at night, and deepened when her children asked, “Why are you so mean to Gaga?”
One afternoon, Allison fell in a Walgreens and fractured her skull. After weeks in and out of the hospital, she came home under her daughters’ care.
The sisters took shifts nursing, bathing and cradling their mother. One day in August 2021, Linde asked her how she was doing. Allison, snuggled in bed, smiled wide. “Happy and good,” she said, her last words.
By then, Linde had been offered free genetic testing as part of a large study of families with frontotemporal dementia. Two days after her mother died, she brushed the inside of her cheek with a cotton swab and mailed it to the lab. She was already grieving. What did she have to lose?
After hearing she carried the mutant gene, Linde collapsed into tears. Her young adulthood had been hijacked by her mother’s disease. To know that she would put her daughters through the same hell was too much to bear.
But she knew she didn’t have time to wallow; gene or no gene, her children would still be waking her up at 6:30 every morning. She had to show them resilience, so that later, when they would need the same strength, they might remember hers.
Putting a face to the cells
In the spring of 2022, six months after connecting with Dr. Clelland, the neuroscientist in San Francisco, Linde sent her a sobering update. Jenica, 36, had tested positive for the mutation. Dr. Clelland replied with condolences, and a bit of hope: She had hired someone to lead the study of the MAPT gene that affected Linde’s family.
Dr. Clelland asked Linde to join a Zoom call with the scientists in her lab. Linde fretted over what to say and how to say it. She had never used PowerPoint before, had never talked to strangers about her family’s hardships.
The day before the presentation, as Linde was gathering old photos and documents to use in her slides, she learned that Ashlyn, at 28, also carried the mutation.
The next afternoon, in her matter-of-fact, Midwestern lilt, Linde told her story to Dr. Clelland and about a dozen researchers. She clicked through 14 slides, each with a single family photo, creating a timeline of how one mutation had changed Allison, all three of Allison’s siblings, and now, all three of Allison’s daughters. Linde said she wanted the photos to “put a face to the cell.”
And she shared how the knowledge of her genetic fate had changed her. She had stopped drinking and cut down on red meat. She was spending $70 a month on a vitamin for brain health. She was trying to focus on what she could do now rather than dwell on the heavy reality of what lay ahead.
“Could I ask a question?” one young scientist said. How much risk, she wondered, was Linde comfortable taking on an experimental treatment? Editing genes with CRISPR was new, after all, and could come with serious side effects.
“Sign me up, patient zero, sounds good,” Linde said.
“What choice do I have,” she added, “if I don’t want the same future for myself as my mom had, and her mom?”
The Michael Jordans of tau science
When she wasn’t working or coaching her daughter’s soccer team, Linde threw herself into the scientific research on MAPT — a niche but growing subfield. The gene provides the instructions for cells to make tau, a protein in the brain.
One day she came across news of a project investigating how tau can go awry. She wrote to the scientist leading the work, Dr. Kenneth Kosik of the University of California, Santa Barbara, describing her family and asking to talk.
Dr. Kosik was sitting in his home office when her note landed in his inbox. “It was the second time in my life that I realized, I’ve got to get back to this person in, like, a nanosecond,” he recalled.
He was one of the world’s foremost experts on tau. In the 1980s, he and others found that the protein accumulated inside neurons in Alzheimer’s disease, forming spindly tangles.
And in 2019, Dr. Kosik and his colleagues made headlines for an unexpected discovery. An older woman in Columbia carried a gene that had caused thousands of her relatives to develop Alzheimer’s in middle age. But she had defied the genetic odds, not showing any signs of dementia until late in life. Dr. Kosik and his collaborators figured out that she carried another gene that protected her from decline.
He thought Linde might be another remarkable woman with answers hidden in her genome.
They arranged a call, and Linde took Dr. Kosik through her mother’s story. He was stunned — a cellmate diagnosis, really? Linde was so impressive, he would say later, and so forthright.
Dr. Kosik told Linde that an elite group of researchers, known as the Tau Consortium, would gather in Boston in a few months for its annual meeting. Dr. Clelland would be there, as would other “Michael Jordans” in the field. We should try to get you there, he said, so the scientists can be reminded of the human toll of tau-related diseases.
A few weeks later, Linde received an invitation to be the keynote speaker. Jenica and Ashlyn could come, too.
She texted her sisters, “Holy shit.”
A researcher changes course
One morning in Boston in June 2023, Linde and her sisters got all dolled up, only to arrive in a grand hotel ballroom filled with 100 scientists in oxfords and sneakers.
Dr. Kosik introduced Linde to the members of the Tau Consortium. Too nervous to look anyone in the eye, she stared at a screen showing her slides and read from her prepared remarks.
“You will notice the lack of credentials following my name,” she began. But she said her life had brought her other titles: Caregiver. Jail-Bailer. Carrier. She was the heartbeat, she said, of the cells they studied.
“Because this is a medical conference,” she went on, “I will present to you some numbers of significance.” She clicked through slide after slide of figures representing the burden of Allison’s disease.
8 years to receive a diagnosis
3 different attempts of foreclosure on the home I grew up in
10 times I appeared in court on her behalf
100+ hours I have spent in therapy to work through the guilt
Linde showed a photo of the scrawled letter from Allison’s cellmate. This incarcerated stranger, she said, had easily diagnosed dementia before any doctor did.
Watching Linde from the audience, Melissa Murray began to cry.
As a director of a brain bank at the Mayo Clinic in Jacksonville, Fla., Dr. Murray saw the stark anatomical consequences of dementia every day. She had met many patients and families, but Linde was different. She was about Dr. Murray’s age, fluent in scientific jargon, sitting right there in front of her, trying. “I like fighters,” she recalled.
The next evening, Dr. Murray reveled with Linde and her sisters at a themed dinner — the “Boston Tau Party” — at the Boston Tea Party Museum. The museum allows visitors to re-enact the famous rebellion by boarding a ship and throwing boxes of tea into the harbor. The scientists had covered the boxes in schematics of tau. At Dr. Murray’s urging, Linde, Jenica and Ashlyn chucked three boxes overboard while shouting curses at FTD.
For more than a decade, Dr. Murray and her team had analyzed postmortem brain tissue of people with dementia. They had discovered, for example, that there were different subtypes of Alzheimer’s based on the pattern of tau tangles across the brain. Dr. Murray felt she was making a contribution to the field.
But after getting to know Linde and her sisters, she realized that she couldn’t do anything for them. She didn’t know enough.
On her flight back to Jacksonville, she decided to shift the direction of her life’s work. Her 23-person lab would now try to make computer models of MAPT mutations to see how they changed the shape of tau. If successful, the models might predict which drug therapies could reverse those changes.
Dr. Murray had often spoken with her team about her grandmother, who had died of Alzheimer’s. After the tau conference, she began talking to them about Linde. This was someone they could help now. “I just want us to all be thinking about the why,” she told them.
Finding other families
After the Boston talk, Linde received a flurry of invitations to tell her story. She was interviewed on YouTube by Emma Heming Willis, the wife of the actor Bruce Willis, the most famous person known to have frontotemporal dementia. She came face to face with monkeys that carried MAPT mutations in Madison, Wis. And though she detested the crowds and grime of big cities, she flew to places like Philadelphia and Washington, D.C., to attend scientific meetings.
Linde, who by then had moved to River Falls, Wis., always returned home exhausted. But the trips were also fortifying. Learning about the latest research quelled her anxiety — and her husband’s. When she rattled off data reported by this or that scientist, Taylor would ask, “How old are they?” The young ones, he thought, would be around long enough to help his family.
During her travels, Linde met other families with MAPT mutations. They were all frustrated by the lack of clinical trials for their genetic glitch, especially because several promising treatments were in the pipeline for other dementia genes. Linde and the others started a global survey of people with MAPT mutations. If an opportunity came along for a clinical trial, they would make it as easy as possible for scientists to find volunteers.
They organized a video meeting with Dr. Timothy Miller, whose laboratory at Washington University in St. Louis designed drugs that muzzled specific genes. Dr. Miller explained that one of those compounds, targeting a gene that causes a rare form of A.L.S., had been licensed by a pharmaceutical company, Biogen, and greenlit by U.S. regulators.
Dr. Miller’s team had made a similar drug that seized on MAPT and curbed the production of tau. Biogen was testing that drug, too — but for Alzheimer’s disease, in which tau also accumulates.
In October 2023, the company released promising, if preliminary, results from the first phase of its tau drug trial, which included 46 people with mild Alzheimer’s. Volunteers who received the drug through a spinal infusion formed less tau in their brains than did those who received a placebo.
The findings were tantalizing for Linde’s group. If the drug cleared out tau so well, then at least theoretically, it should help them, too.
Linde sent a series of emails to various Biogen accounts, asking the company to make the drug available to MAPT carriers.
“I am asking that you look at my family and see the value that our lives are worth saving,” she wrote to one executive.
The company responded a few days later with a form letter of links related to clinical trial access. “We are unable to discuss specific medical matters,” it said.
A few months later, Linde and the group started a nonprofit, called Cure MAPT FTD. They have since found more than 500 people with confirmed or possible MAPT mutations in 10 countries, all of whom have expressed interest in participating in future clinical trials.
‘That is wild Linde!!!’
In March of this year, Linde got an astonishing offer from Dr. Clelland. Along with collaborators at Washington University and the Neural Stem Cell Institute in New York, she wanted to collect skin cells from Linde and her sisters and turn them into clusters that divide infinitely, known as cell “lines.”
“We propose to make new lines that can be shared with academics and also with industry so that people can do drug screening” and CRISPR projects, Dr. Clelland wrote.
Linde read the email on her phone at work, while on a break in an operating room.
“Holy balls, read the email claire just sent me!!!” she wrote to Taylor.
She texted her sisters and they wrote back instantly.
“That is wild Linde!!!” Ashlyn wrote. Jenica agreed: “Linde! We would never have gotten this without you!”
“I hate all that we had to go through with mom because it always felt like we failed,” Linde replied. “But had we not gone through all of that hell, I don’t think I would be doing any of this work.”
The sisters flew to St. Louis in May. One at a time, they walked into a small exam room at the university, where a doctor punched out bits of their lower back the size of a pencil eraser. They already had matching wrist tattoos — the roman numeral III, representing the three of them — and joked about getting new ones to cover the scars.
The chunks of skin were dropped into small tubes, which were placed in a cooler and walked to a nearby lab. Over the next few months, the cells were mixed with a powerful slurry that reversed their memory of what it means to be a skin cell, transforming them back into stem cells. Then they could eventually be programmed into brain cells and used to test new treatments.
By the end of the year, the sisters’ cells would be shipped to four labs across the country.
Regret for her mother, hope for her girls
Linde is now 36. She calls this the “dot dot dot” phase of life — when she is no longer a caregiver to her mother, but instead is waiting for the time she will need a caregiver of her own.
Based on what happened to Allison and Bev, Linde figures she has at least 10 more years before she starts showing symptoms. But there’s no guarantee; some MAPT carriers begin to change in their 20s. Whenever Linde tells a joke a little too loudly, or has a dulled emotional response to a dramatic event, she worries: Is this tau?
That anxious metronome never shuts off. It compels her to fill any moment of downtime reading the latest study or sending another email. She has spent thousands of dollars and hundreds of unpaid hours on travel. But sometimes, like when she finds herself alone in a hotel room, FaceTiming her daughter about a rough day at school, she questions whether these scientific pursuits are really the best way to run out the clock.
She resents that so much of her life revolves around a disease she doesn’t yet have. If a new friend asks why she doesn’t drink, the answer can easily become an awkward sob story. In May, Taylor’s mother, whom Linde adored, died of cancer. At the funeral, people kept approaching Linde, praising her FTD advocacy work. It was the last thing she wanted to think about just then.
Despite everything she did for her mother, she still shoulders guilt. Her mind can’t shake certain scenes, like the day Allison stood in a courtroom in an orange jumpsuit, frantically waving with shackled wrists. Or the day of her fall, alone in a Walgreens.
The photos in Linde’s slide presentation, she said recently, are “evidence of all the times we failed to protect my mom.” Sharing this humiliation publicly is something like penance for her, an attempt to derive a larger purpose from Allison’s suffering.
Linde has not yet told her daughters, ages 9 and 6, about the scary gene inside her cells, and maybe inside theirs. They know only that their Gaga died of dementia and that their mom works with scientists to try to prevent other people from getting it. By the time they are old enough to understand the full story, Linde hopes that the conversation will include some real options.
Will Linde receive a useful treatment before her mind begins to slip away? Of the 10 tau experts interviewed for this article, nine said they were optimistic that it would happen, whether with a drug like Biogen’s that suppresses tau or, in the longer term, a gene-editing cure. The other expert was more cautious, pointing out that it was impossible to predict the pace of stuttering scientific advances.
Dr. Clelland said designing a CRISPR molecule that could precisely excise the MAPT mutation from a cell’s genome was not the hard part. The major unsolved challenge is delivering those molecular scissors into the brain. Still, she and her colleagues at U.C.S.F. have set an ambitious goal of getting MAPT therapy into clinical trials within four years.
On a visit last month, Linde met with the leader of the university’s Memory and Aging Center, Dr. Bruce Miller, a pioneer of FTD research in the 1980s.
“We think about you,” he told her in his sunlit office. Asked about the odds that Linde would be treated in time, he said: “I wouldn’t say I’m cautious about that. I really, really believe it.”
Linde had come to the institute to give a talk about her mother. As she told her story, sniffles echoed through the room.
Afterward, Dr. Clelland walked Linde over to a small laboratory enclave and invited her to look into a microscope on the counter. Linde squinted through the eyepiece at a plastic dish holding about 2.5 million stem cells — the descendants of the skin chunk she had donated six months before.
“They’re like bubbles,” Linde said. “Something that just seems so simple, like, what?”
She looked for a couple of minutes. In her pants pocket, she carried some of Allison’s ashes in a polished red stone.
The post Fighting to Avoid Her Mother’s Fate, for Her Daughters’ Sake appeared first on New York Times.
