Growing up in the 1970s, Jary Larsen heard his mother say their extended family had been haunted for years by a strange disorder. It changed personalities and caused odd behavior. She called it Larsen disease.
Larsen, the ninth of 10 children raised on a farm in Minnesota, was always skeptical — until 2006, when his older brother Peter drove a car into a ditch. Police found him sitting listlessly behind the wheel, confused about which direction he had been heading.
They assumed he was drunk or high, but a blood test showed otherwise. The retired 57-year-old postal worker ended up at the nearby Mayo Clinic in Rochester, where doctors eventually diagnosed him with frontotemporal dementia.
Frontotemporal dementia, or FTD, is an umbrella term for group of rare degenerative brain disorders that attack people in their fifth or sixth decade — generally, much earlier than Alzheimer’s. Together, the diseases make up what appear to be the most prevalent form of dementia in people under age 60.
As many as 40 percent of the cases appear to be inherited. And in contrast to Alzheimer’s, whose early signs usually involve memory loss, the first symptoms of frontotemporal dementia tend to be peculiar behavior that is often mistaken for signs of a psychiatric illness.
There are no treatments for FTD. But at least two drug companies in Massachusetts, Alkermes and Arkuda Therapeutics, are working on potential medicines for the Larsens’ strain, which experts say affects only about 5,000 people in the United States.
When family members went to Peter’s house after the accident, they found shocking evidence of apathy and compulsions: years of unopened mail, five identical leather coats, and thousands of empty soda cans.
Since Peter Larsen’s diagnosis — he died of the disease in 2013 — Jary Larsen, a neuropsychologist at the University of California San Francisco, has determined that at least 20 relatives going back four generations apparently suffered from their particular strain. They include his father, whose 2004 death the Larsens had attributed to Parkinson’s disease.
Jary Larsen, 58, a member of the board of the nonprofit Association for Frontotemporal Degeneration, hopes the research pays off. He and his siblings each had a 50-50 chance of inheriting a defective gene for the disease from their father. At least three found out through genetic testing that they didn’t get it, Larsen said. He took the test about a decade ago but never sought the results.
“I have chosen not to learn, at this point,” he said during a recent visit to Boston for a conference. “Once you know, you can’t put the genie back in the bottle.”
Larsen, who became a neuropsychologist before his brother was diagnosed, seems particularly concerned about how he would react if he didn’t inherit the defective gene. He would feel survivor’s guilt, he said, and worries that journalists and advocates would take him less seriously as a proponent of FTD research if he had no chance of getting the disease.
FTD causes shrinking of the frontal and temporal lobes of the brain and shares some characteristics of Alzheimer’s disease, including misfolded proteins and loss of brain cells, according to the National Institute on Aging.
But FTD is far less common. Alzheimer’s afflicts about 5.8 million Americans, according to the nonprofit Alzheimer’s Association, which helps explain why the search for an effective treatment is the holy grail for many of the world’s drug makers.
In contrast, experts estimate that only about 25,000 to 50,000 people in the United States have one of the several forms of frontotemporal dementia, which used to be called Pick’s disease, after the German neuropsychiatrist who first described it in 1892.
About 60 percent of frontotemporal dementia cases occur from age 45 to 64, but people in their 30s can also get it. Most people with Alzheimer’s do not exhibit symptoms until their mid-60s or older.
“It typically happens in midlife, much earlier than Alzheimer’s disease, so the impact on patients and their families is great,” said Rodney Pearlman, president of the Bluefield Project to Cure FTD, a San Francisco nonprofit foundation. “These are the prime wage-earning years.”
The Larsen family has been afflicted by a form called GRN-related frontotemporal dementia. That strain is caused by mutations in a gene for progranulin, a protein found in tissues throughout the body. People with the mutated gene have abnormally low levels of the protein.
After Peter Larsen’s 2006 accident, Jary Larsen made an appointment for him at the Mayo Clinic because he had heard of relatives scattered across the country with early-onset dementia. To his surprise, Jary Larsen ultimately discovered that since the 1970s Mayo doctors had diagnosed at least five of his father’s first cousins — whom he had never met — with frontotemporal dementia and that they had participated in research studies.
Peter, his siblings, and their mother all ultimately gave blood samples at the famed hospital. Their timing couldn’t have been better. In 2006, the journal Nature published an article in which researchers identified the mutation that causes their form of FTD.
Within several months, doctors confirmed that Peter had inherited the gene, Jary said. Mayo also tested a vial of blood from Jary’s late father, Lawrence Larsen, that the hospital had stored when the elder Larsen participated in a Parkinson’s disease study. That blood sample also tested positive for the FTD mutation. Jary believes his father had frontotemporal dementia as well as Parkinson’s.
Although Jary has never gotten the results of his genetic testing, he has undergone magnetic resonance imaging tests of his brain and spinal taps to gauge progranulin levels.
So far, there’s no indication he has the disorder.
Jary’s sister, Janis Brooks, who lives near Rochester, said she had a duty to find out whether she inherited the defective gene. She has an adult daughter who was considering whether to have children, and she didn’t want to start a family if her mother might have inherited the deadly gene and passed it on to her.
Fortunately, Janis Brooks’s test results were negative.
“I don’t know what I would have done if I’d been positive,” said Brooks, 61, a retired Mayo surgical technologist.
Peter, a Vietnam War veteran, ended up in a memory care facility in Rochester, where he complained about living with people considerably older than him, Brooks recalled. Peter, who had avidly followed the Minnesota Twins and collected classical music and jazz albums, ultimately lost his ability to walk and talk. He died at age 64.
Through research, Jary Larsen has concluded that relatives in both the United States and Denmark probably had the same disease, including a great-grandfather who had a farm in Minnesota and was known as “a wanderer,” Larsen said.
Even though the Larsen strain of FTD is rare, drug makers are working on potential treatments. Just last month, Alkermes, which is headquartered in Ireland but does research and development in Waltham, bought the Boston startup Rodin Therapeutics for $100 million, in part for experimental compounds the firm has for the disease.
The Larsens’ type of frontotemporal dementia is “incredibly attractive as a target for drug development because there’s a clear line of sight on how you could treat it by increasing levels of [the protein] progranulin,” said Blair Jackson, senior vice president of corporate planning at Alkermes.
Dr. David Knopman, a professor of neurology at Mayo who has studied FTD for 30 years, said development of a treatment might have implications for research into Alzheimer’s. Both the Mayo and UCSF, where Jary Larsen works, were recently awarded a five-year grant totaling more than $63 million to advance treatments for frontotemporal dementia.
Although the disease has stalked the Larsens for generations, Jary says he is optimistic that these efforts will ultimately bear fruit. “Coming from a family that has a long history of the progranulin mutation, this is extremely important,” he said.
Jonathan Saltzman can be reached at firstname.lastname@example.org.