Every weekday, a steel machine inside the concrete vault basement of a research building near UW Hospital produces radioactive atoms used to detect signs of Alzheimer’s disease.
The atoms, some with short half-lives, are rushed in lead containers to the nearby Waisman Center, where in a lab they are attached to drugs. The drugs, or tracers, are injected into study volunteers as they undergo PET scans of their brains.
One tracer binds to amyloid, a sticky protein associated with Alzheimer’s that forms plaques between brain cells, disrupting their function.
Another tracer attaches to an Alzheimer’s-related protein called tau, which creates tangles inside brain cells, blocking communication between the cells.
A third compound sticks to synapses, the points where brain cells exchange information.
The scans, given mostly to healthy middle-age people with a family history of Alzheimer’s disease, could help UW-Madison researchers answer key questions facing dementia research today: Why have drugs that clear amyloid from the brain failed to stop Alzheimer’s? Why do some people with plaques and tangles develop dementia and others don’t? What else might be contributing to the disease?
The scans “can show a signal maybe 20 years or so before symptoms appear,” said Sterling Johnson, a neuropsychologist who heads the university’s Wisconsin Registry for Alzheimer’s Prevention, or WRAP. It’s a study of nearly 1,600 people, most with a family history of the disease.
With more people receiving a variety of scans, data from the images is “going to accelerate research in ways we couldn’t have imagined 10 years ago,” Johnson said.
UW-Madison, which received a $19 million federal grant last year to continue the research, has given about 800 amyloid scans to about 450 people in the past decade. More than 350 people have received tau scans since the university started offering them two years ago. A dozen people have had synapse scans, which began last year.
The synapse scan study seeks to measure the decline in synapse density over time in people with and without Alzheimer’s disease. The marker, distinct from the hallmark buildup of amyloid and tau, could offer a new clue to how the disease progresses.
Synapse density “might be an even earlier measurement of things going wrong in the brain,” said Barb Bendlin, a neuroscientist leading the study. “Maybe someday there will be drugs that could protect the synapses.”
Volunteering for scans
Sara Tirner has undergone 11 brain scans in dementia studies at the university, including one looking at her synapses.
Her mother died from Alzheimer’s two years ago at age 87, and her aunt has the disease. Their mother and grandmother also likely had it, as did Tirner’s paternal grandmother.
“Who knows if I can avoid it,” said Tirner, 58, of Madison. The family history, she said, “is pretty motivating.”
After getting a finance degree at UW-Madison and working as a banker in Chicago, San Francisco and New York City, Tirner became a yoga instructor and returned to Madison.
In 2015, when her parents were no longer able to care for themselves, she moved in with them in Two Rivers, where she grew up. Her father died, at 94, from heart failure the following year; he also had vascular dementia.
By then, her mother’s dementia was so advanced she didn’t realize her husband was gone. She was diagnosed with dementia in 2012, but the first signs came years earlier, Tirner said.
Her mother, a real estate broker, Sunday school teacher and meticulous homemaker, stopped cleaning the house. When washing clothes, she started using too much detergent. One Christmas, she panicked because she forgot how to start making dinner.
Eventually, she could no longer dress or feed herself. Unlike some people with dementia who become agitated and aggressive, she was mostly docile and had a hard time talking.
“She couldn’t find the words,” Tirner said. “She was like an old computer that just keeps getting slower.”
Tirner hopes the studies she’s participating in yield findings that help her and others avoid dementia. With research suggesting exercise can delay or slow cognitive decline, she figures her yoga and other physical activity should help.
Unlike Tirner, Karen Ingmundson has no family history of Alzheimer’s. But the retired state Capitol electrician has undergone a dozen brain scans in dementia studies at UW-Madison. She has friends whose parents have had the condition.
“I’ve seen what it’s done to people,” said Ingmundson, 66, of Waunakee. “It’s a really devastating disease.”
Amyloid theory questioned
No drugs have been approved for Alzheimer’s disease since 2003, and the four medications available treat only symptoms.
Drug trials by Biogen, Eli Lilly, Johnson & Johnson, Merck and others have failed in recent years. In March, Biogen stopped two studies of aducanumab, an antibody to clear amyloid plaques in the brain, after partial results suggested it didn’t work. In October, however, the company said it would apply for federal approval for the drug because further analysis showed a reduction in cognitive decline.
Pfizer, another pharmaceutical powerhouse, stopped Alzheimer’s research altogether last year.
The lack of progress has spurred debate over the “amyloid hypothesis,” the decades-old idea that amyloid causes Alzheimer’s and removing it is the key to curing the disease.
“We’re having a total rethink about this amyloid hypothesis,” Dr. Scott Turner, director of Georgetown University’s Memory Disorders Program, told journalists earlier this year at a National Press Foundation seminar on dementia issues.
Other factors — such as inflammation, hormones, oxidative stress or even infections like herpes — may contribute to dementia, Turner and other researchers say. Like HIV, which wasn’t successfully treated until combination therapies became available in the mid-1990s, Alzheimer’s might require several drugs to collectively target amyloid, tau and factors like inflammation, Turner said.
“It may take this combination before we really have a breakthrough,” he said.
Federal funding for Alzheimer’s disease research has ramped up, with $2.3 billion available this year, up from $631 million in 2015, said Dr. Marie Bernard, deputy director of the National Institute on Aging.
About 140 clinical trials looking at ways to prevent or treat dementia are underway, and more than 30 genes associated with Alzheimer’s have been identified in recent years, Bernard said.
Johnson, of UW-Madison, said the drug trial failures are discouraging but instructive. Most patients in the studies have long had amyloid plaques, which generally appear about a decade before tau tangles emerge, he said.
“It may be too late to stop the disease at that point,” Johnson said. “The optimal time to deliver an amyloid-busting drug is before the tangles kick in.”
Detecting precisely when people build up amyloid and tau, and deciding when to intervene with drugs, is a key goal of the university’s expanding imaging studies, Johnson said.
“I haven’t given up yet on the amyloid hypothesis,” he said.
Already, by analyzing rates of change in amyloid scans, researchers have been able to estimate when individuals first developed amyloid, he said.
UW’s WRAP study, in which nearly three-quarters of participants have a family history of Alzheimer’s, continues to reveal other findings.
One involves a gene called APOE4. If a person has one copy of the gene, their risk for Alzheimer’s disease triples. Two copies increases the risk about 10 times.
But having parents or other close relatives with Alzheimer’s doesn’t appear to contribute additional risk beyond APOE4 status, Johnson said.
The lack of a strong link to family history, separate from the gene, is surprising and may be reassuring to people whose parents develop Alzheimer’s, he said.
Synapses and stool
The synapse study could help scientists figure out why some people with amyloid plaques and tau tangles don’t develop dementia, Bendlin said.
An unidentified factor might protect their synapses, she said.
“Is there some other marker we need to look for, something that’s making these people resilient to this building pathology?” Bendlin said.
UW-Madison is one of only two centers given federal funding for the synapse imaging research; the other is Yale University. That’s largely because of the cyclotron located in the basement of the Wisconsin Institutes for Medical Research, which produces the radioactive atoms used in the PET scans.
The atoms used in the amyloid and synapse tracers have half-lives of 20 minutes, and the tau tracer half-life is about two hours, said Brad Christian, a medical physicist whose lab makes the tracers. The cyclotron’s proximity to two PET scanners at the Waisman Center enables such research.
While most dementia research on campus focuses on the brain, a new study is also looking elsewhere: in feces.
In a study analyzing stool samples from 50 people, half of whom had Alzheimer’s disease, Bendlin and other researchers found that those with the disease had fewer kinds of gut bacteria than healthy people. Also, some bacteria were more abundant, and others less abundant, in people with Alzheimer’s.
The findings support the emerging idea of communication between gut microbes and the brain.
Now, the UW researchers are giving fecal transplants to 30 people, half with early Alzheimer’s. The transplants are given orally in pills produced by OpenBiome, a stool bank in Cambridge, Massachusetts.
Enriching gut bacteria in people with dementia or at risk for the condition could prevent progression, Bendlin said.
“We don’t expect that fecal microbiota transplant will be the miracle treatment for Alzheimer’s disease,” he said. “We’re trying to see if we change the system in this way, what are the mechanisms and could those be targets for new drugs?”
Photos from a Special Report — Fading away: Wisconsin’s dementia crisis
People who live in disadvantaged neighborhoods may have smaller centers of learning and memory in their brains, according to a UW-Madison study.
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Karen Ingmundson of Waunakee prepares to undergo a PET scan at UW-Madison's Waisman Center, as part of a research study on Alzheimer's disease. Researchers are injecting people with radioactive tracers to see if they have proteins associated with Alzheimer's. Some scans also look at synapses, where brain cells exchange information.
Sara Tirner, shown doing yoga at Tantra Yoga and Wellness in Madison, became a yoga instructor herself after working in banking for many years. Before her mother died from Alzheimer's disease two years ago, Tirner moved in with her and her father, in Two Rivers, to care for them.
Karen Ingmundson, left, talks with PET technologist Barb Mueller before getting a PET scan. Ingmundson doesn't have Alzheimer's disease or a family history of it, but she has participated in several studies to help increase scientific understanding of the disease.