and maybe we can do something for their kids.”
One Family Leads To Another
In John Ringman’s office at the University of Southern California in Los Angeles, the shelves are filled with volumes on neurology and memory, accompanied by a model of the brain and a Sigmund Freud doll.
Ringman, though sometimes gruff, betrays a wry humor and a deep passion for science. He easily recalls patients’ stories over the years.
For the 51-year-old neurologist, who has two young children, working with families predestined to forget their own stories and die young can be “very depressing.” “It doesn’t get easier to be delivering the bad news,” he said.
At the same time, he likes getting to know his patients and watching their children grow up.
He became interested in neuroscience while in college at the University of California, Berkeley. But he knew lab work wasn’t for him. “I realized all these Ph.D.s study one molecule their entire lives and sit in a laboratory,” he said. “I didn’t want that.”
In the late 1990s, after completing medical school and specialty training, he joined the medical staff at the University of California, Irvine, where he saw patients with dementia and Huntington’s disease. He liked the personal interaction, combined with the scientific challenge.
In 1999, a 42-year-old woman came to see him, brought in by her young adult daughter. Rosa Maria Navarro had signs of early Alzheimer’s disease. Her daughter Rosemary was distraught, reporting that something similar had afflicted many other relatives.
Rosemary Navarro, 40, at her home in La Habra, California, on Monday, December 22, 2016. Navarro looks through old childhood photographs to find a picture of her mother, Rosa Maria Navarro, who also had the familial Alzheimer’s. (Heidi de Marco/KHN)
It was the beginning of a long relationship, and a new line of scientific inquiry for Ringman.
The young neurologist was aware of recently identified familial Alzheimer’s mutations, and he immediately suspected Rosa Maria had one. He sent her blood sample to get the genetic test, and it came back positive for the A431E mutation of a gene known as presenilin 1.
Rosemary Navarro suspects her mother sensed even before then what was wrong, having seen her own father lose his memory and die young. “But she was quiet,” Navarro said. “She never said, ‘I might have this.’”
Soon afterward, another patient came into Ringman’s office with similar symptoms. That patient tested positive for the same mutation. Both had families originating from Jalisco, Mexico. “I was already getting suspicious,” he said.
Familial Alzheimer’s intrigued Ringman. It was a relatively new field. Families with the disease had been known to exist since Alzheimer’s first described the disease in 1906, but the genes weren’t identified until about 90 years later. The research touched on so many parts of science — neurology, biology and psychology.
Later, Ringman came across an article co-authored by a Mexican neuropsychologist he had worked with before, Yaneth Rodriguez. It was about four families in Mexico that had early Alzheimer’s disease, and they had symptoms similar to his two patients.
In 2000, Ringman traveled to Mexico and met with both Rodriguez and a geneticist, Maria Elisa Alonso. Alonso told him that another family there had tested positive for the A431E mutation. Now, there were three, all of Mexican heritage.
Ringman collected DNA samples of members of seven more families who were being treated in Mexico. Test results not only confirmed members of each family had A431E, they indicated the patients all shared the same chunk of DNA. That’s when he knew. They were all related, distant cousins who had never met.
Over the next few years, Ringman saw more and more patients with relatives from Jalisco and symptoms of memory loss at about age 40. In addition to their cognitive problems, they sometimes suffered from leg stiffness and fleeting seizures.
In 2006, the Mexican geneticist, Alonso, published a report in Neurogenetics, describing nine families who didn’t know they were related but all shared the A431E mutation. She concluded that the disease likely started with one ancestor in Jalisco. Ringman published a response describing 15 additional families with the same mutation.
The findings meant that Ringman’s patients owed their suffering to an unidentified individual who likely lived in Jalisco perhaps hundreds of years ago. Somehow, as his or her DNA copied itself during cell division, a fatal mistake occurred. And now, in places like La Habra and Colton, Calif., whole families were coping with the awful results.
Relatives gathered around a dining room table as neurologist John Ringman gave a presentation about Alzheimer’s disease and current research in Riverside, California, on Sunday, November 22, 2015. (Heidi de Marco/KHN)
Meanwhile, other scientists around the world had found families with different early-onset mutations in one of three identified genes, including a group in Puerto Rico and one in Colombia. Each group was believed to share a common ancestor.
Ringman saw the tragedy but also the scientific opportunity in these discoveries.
He worked on his Spanish and delved deeper into the cases on both sides of the border. He published reports on specific characteristics of Jalisco mutation carriers, such as the leg stiffness and weakness called spastic paraparesis. He described biochemical changes at the very early stages of the disease, such as changes in beta amyloid and tau, protein associated with Alzheimer’s, in the cerebral spinal fluid. And he reported how cognitive decline among carriers was similar to those with late-onset Alzheimer’s.
Ringman is continuing to identify new patients with familial Alzheimer’s. Some are referred by doctors in the U.S. and some by doctors in Mexico. He helps people get tested for free when they suspect the Jalisco mutation.
“Some people have no idea that there is a genetic test for this,” he said.
In homes across Jalisco, he and Rodriguez’s team are educating families about the disease — so that they will be informed enough to participate in future clinical drug trials. Some take comfort from helping with the research. Some have decided not to have children.
Ultimately, Ringman joined the Washington University School of Medicine network in its international quest for knowledge and treatment options for familial Alzheimer’s disease. The research now includes different sites in Europe, Asia and Australia.
The formal name is the Dominantly Inherited Alzheimer’s Network, because the gene is passed down from one parent. USC is one of the research sites.
The network’s investigators — who all use the same standardized measures — are monitoring biological changes among carriers and non-carriers and are testing medications.
In addition to finding the early emergence of amyloid plaques, researchers have discovered decreased beta-amyloid peptides and increased tau proteins in spinal fluid 15 years before symptoms appear. Measurable shrinkage in some parts of the brain also occurs five years before symptoms.
The research essentially has presented a timeline of brain changes leading up to memory loss and cognitive decline and has helped lead scientists to decide when and where to aim drugs.
A promising target is beta amyloid. Many researchers believe that flaws in how the sticky substance is accumulated and disposed of in the brain can lead to the disease.
Scientists are studying two drugs aimed at attacking beta amyloid, with the equally unpronounceable names of Gantenerumab and Solanezumab. Both are antibodies that bind to the beta amyloid and help remove it from the brain.
Another encouraging finding, the researchers say, is that early-onset and late-onset Alzheimer’s seem to share many characteristics, and findings that help with one disease are likely to help with the other.
‘Praying For A Miracle’
Neither of the Kitchen brothers is participating in the research. Both are in precipitous decline.
As John’s symptom’s worsened, Michelle Lopez invited him to move back in with her and their son, Reese, who is 14.
John, now 43, can still hold a conversation, but he struggles to find the right words. He gets frustrated at his inability to do simple tasks, like write his own name. He feels he is losing control of his life and worries about his family. “I want to be around for my son,” he said.
Lopez said she’s happy to have him back home. She is still “praying for a miracle.”
The changes have been hard to watch — and not just for her. Within a week after John moved back into the house, Reese asked his mom, “Is that going to happen to me?”
“That was the worst day of my life,” Lopez said.
Michelle Lopez, John Kitchen’s wife, tears up after the Alzheimer’s presentation in Colton, California, on Sunday, November 22, 2015. Lopez says she is relieved to finally have a diagnosis for the disease that is destroying her family. (Heidi de Marco/KHN)
Reese said his dad forgets things easily. “It’s like very slowly he is fading away.”
Reese tries not to think too much about his dad’s disease or what the mutation could mean for his own life. Lopez said Reese will wait until he becomes an adult to decide whether or not to get tested. Right now, he just focuses on school and helping his mom and dad.
John takes one medication, donepezil, used in many later onset Alzheimer’s patients to improve cognition and behavior. The neurologist recently told them it may only prolong cognitive abilities a month longer. “That was disheartening to hear,” Lopez said.
In December 2015, relatives realized Jay Kitchen could no longer live on his own. They arranged for him to rent a room from a friend. But soon after, he couldn’t figure out how to open a door and climbed, barefoot, out of the window.
He told relatives people were trying to kill him. Alarmed by the paranoia, the family took him to the emergency room. The family decided to place him in a nursing home but he scaled a fence and left without telling anyone.
“We were flabbergasted,” said his aunt, Linda Ramos. “We don’t know what to anticipate — is it all downhill from here? It all seems incredibly quick.”
Now, Jay Kitchen is in a locked facility. He recognizes family only occasionally and regularly misplaces his belongings. He can no longer speak in complete sentences and has trouble getting dressed.
“We get a glimmer of hope, but then we think we are foolish for even hoping,” Ramos said. “This is just devastating. It’s a horrible disease.”
Fear And Faith
Navarro’s 19-year-old daughter, Lizeth, and her 22-year-old son, Ricardo, live with her in a three-bedroom trailer in La Habra. They depend heavily on her, emotionally and financially.
Both say their mom has started forgetting little things — the movie they saw last week or what they need from the grocery store. “I usually have to say things more than once,” said Lizeth Navarro.
Rosemary Navarro’s 22-year-old son, Ricardo, and her 19-year-old daughter, Lizeth, live with her in a three-bedroom trailer in La Habra, California. They depend heavily on her, both emotionally and financially. (Heidi de Marco/KHN)
Lizeth, a chemical engineering major, decided to attend college nearby partly just to keep an eye on her mother. She hasn’t decided whether to get tested for the mutation herself. But her brother said he won’t.
“I would rather live my life not knowing,” said Ricardo Navarro, who is studying broadcast journalism at the California State University, Fullerton. “What is the point of living my life if I know I am going to die in my 40s or 50s?”
Their mother, meanwhile, works in customer service. She doesn’t make a point of telling employers about her condition. At a recent temp job, she had trouble focusing and remembering some of the things her trainers taught her. She didn’t get hired on permanently.
Navarro tries to focus on her family rather than the disease. “I can’t let it overcome me,” she said.
She puts a lot of hope in a drug trial out of Washington University. Each month, a nurse visits her in La Habra and injects a medication, which she’s pretty sure is not a placebo.
“I have to have faith in the drug,” she said. “That’s my only solution for now.”
She didn’t finish her thought.
By Anna Gorman, Kaiser Health News
Photos by Heidi de Marco
Kaiser Health News is an editorially independent program of the Henry J. Kaiser Family Foundation, a nonprofit, nonpartisan health policy research and communication organization not affiliated with Kaiser Permanente. KHN’s coverage in California is funded in part by Blue Shield of California Foundation. This story was also shared by NPR.