The result is a rich — and in some ways unmatched — trove of data that’s helping scientists figure out why some people develop dementia and others don’t. The goal is to find ways to prevent or delay the erasure of memory and identity that many people fear above all else as they age.
While cures and effective medications remain out of reach, ACT has helped lead the way in identifying the now-familiar litany of harmful behaviors or experiences that seem to boost the risk of dementia: smoking, being a couch potato, social isolation, obesity and high blood pressure, among others.
WANT TO DONATE YOUR BRAIN TO SCIENCE?
More information on brain donation, even for people who are not part of the Adult Changes in Thought study, is available at: dlmp.uw.edu/research-labs/keene/braindonation or braindonorproject.org/. You also can email uwnp@uw.edu or contact your local Alzheimer’s Disease Research Center (nia.nih.gov/health/alzheimers-disease-research-centers) or medical school.
Some of the best evidence that exercise can lower Alzheimer’s risk in older people comes from ACT. So do landmark studies that linked elevated blood sugar, traumatic brain injuries and exposure to air pollution with higher dementia risk.
A Google Scholar search for “Adult Changes in Thought” returns more than 1,000 scientific publications that rely on the study’s data or mention its results.
“They’ve been extremely successful,” says Nina Silverberg, director of the Alzheimer’s Disease Research Centers Program at the National Institute of Aging, which has supported the project from the beginning. “They’ve done a huge amount of research that has impacted multiple fields by having all of this data over so much time.”
The project got a major boost in 2021, when the National Institute on Aging more than quadrupled its funding with a $56 million, five-year grant. The money is allowing researchers to expand the number of participants, increase racial and ethnic diversity in a cohort that historically has been mostly white, and share data more widely.
They’re also launching new projects to delve more deeply into the exercise link and the way medications affect brain cells and influence risk. Another new initiative focuses on the growing realization that Alzheimer’s is probably not a single disease but can manifest in multiple ways.
“This new grant is a dream come true for us,” Larson says. “There are so many opportunities for discovery.”
Which is another way of saying how little is known about Alzheimer’s disease and its causes, despite a century of study.
THE NEW FUNDING comes at a time when many Alzheimer’s researchers are pushing for a reset. Billions of dollars have been invested in the quest for drugs with little to show for it. The U.S. Food and Drug Administration recently approved two medications that target protein plaques in the brain — Aduhelm and Leqembi — but both are enormously expensive and have dangerous side effects. The potential benefits to patients are so slight, Larson says, they probably would be unnoticeable.
“People are just so desperate for anything that gives them hope,” he says.
Public health experts argue that instead of chasing blockbuster drugs, it makes more sense to focus on prevention by targeting known risk factors with affordable solutions, such as uncontrolled high blood pressure and diabetes. Other scientists insist it’s time to look beyond plaques and tangles and double down on basic research to get at the root causes of the disease.
ACT and its collaborators are coming at the problem from both directions.
Alzheimer’s disease usually creeps up silently, over decades. By the time a person is diagnosed, it can be too late to pinpoint contributing factors. That makes ACT’s combination of long-term medical records and regular checkups invaluable. Some participants have prescription records going back to the 1970s.
“Such complete medication data is more or less unheard of,” says Dr. Edo Richard, a neurologist at Radboud University Medical Center in the Netherlands who’s trying to identify the best blood pressure medications to lower dementia risk. “That’s one of the unique selling points of the study.” Richard is not part of ACT but is among the many researchers around the world who collaborate with the team and tap into the data.
Study participants also fill out a 21-page questionnaire about the places they lived as children, the kind of work they did as adults, their family relationships, income, traumatic events, and a host of other experiences and exposures that might be important.
“Probably from the day we’re born … there are things that are happening, whether it’s our diet or the air we breathe or genetics, that are affecting our brains,” says Dr. Dirk Keene, head of neuropathology at UW Medicine. “The ACT study is able to focus in on this in a way that many others are not.”
Health records, life histories and genetic information are particularly powerful when they can be linked to actual changes in the brain — something that’s only possible due to ACT’s collection of nearly 1,000 donated brains.
“These are so precious,” Keene says. “ACT participants are just remarkable in how much they dedicate to this study.”
ACT PUBLIC RESEARCH SYMPOSIUM
ACT’s annual Research Symposium is open to the public. This year’s event, which focuses on hearing and vision impairment and dementia risk, is set for May 15-16. Register and read more at: actagingresearch.org/news-and-results/act-research-symposium.
MANY PARTICIPANTS GET brain scans during the course of the study that can reveal changes over time. After death, researchers create three-dimensional MRI images of participants’ brains and map out key brain structures. Then they slice and stain the organs, looking for alterations across dozens of regions involved in memory and cognition.
Among ACT’s most cutting-edge collaborations is a project with researchers at the Allen Institute for Brain Science to identify the biological triggers that instigate Alzheimer’s. Using freshly autopsied brain tissue from ACT participants, they are compiling a detailed atlas showing how different types of brain cells are damaged or killed as the disease progresses. Among the findings is that neurons making connections across the cerebral cortex are particularly vulnerable — which aligns with the havoc Alzheimer’s inflicts on memory, language and other higher thought processes.
The cellular and molecular analyses, combined with brain scans and clinical observations, might also help shed light on the different “flavors” of Alzheimer’s, says ACT co-leader Dr. Paul Crane. While memory loss is usually the first symptom, some people instead have trouble with spatial orientation, language or decision-making.
“Alzheimer’s disease may be several different conditions,” says Crane, a UW Medicine professor. “If we can put people into subgroups, that may go a long way toward being able to develop personalized medicine approaches.”
Six million Americans are living with Alzheimer’s disease. Among ACT participants, about 20% develop some form of dementia over their lifetimes. But one of the most surprising discoveries from the brain bank is that nearly half of donors with no symptoms nevertheless had brains riddled with plaques, tangles and other pathological changes.
That’s a hopeful finding, Crane says, because it means many people are resilient enough to absorb a lot of damage without obvious memory loss. The next step is to figure out how they do it.
“There’s a ton of interest in the resilience piece,” Crane says. “Imagine if we could bottle that?”
WHILE THE NUMBER of people with dementia continues to rise as populations age, another hopeful sign comes from steadily falling incidence rates across North America and Europe over the past three decades. In the United States, the percentage of people 65 and older with dementia dropped nearly a third — from 12.2 % to 8.5% — between 2000 and 2016.
No one really knows why, but experts credit things such as increasing education levels, rising prosperity, less smoking and improvements in treatment of heart disease.
When an international panel of experts, including Larson, reviewed the evidence in 2020, they identified 12 “modifiable risk factors” for dementia: high blood pressure, hearing loss, smoking, lower educational levels, obesity, depression, physical inactivity, diabetes, social isolation, excessive alcohol consumption, traumatic brain injury and air pollution. Collectively, the factors could account for up to 40% of all dementias, the group concluded.
Roberson seems to tick almost all the boxes for lower risk.
She’s slender and active, with excellent hearing and few chronic health problems. Though her husband died young, her family is close and loving, and she enjoys spending time with her grandkids and great-grandkids. She also has a positive outlook.
“I think mood has a lot to do with it,” she says. “I’ve always been fairly happy.”
THE BACKSTORY
Seattle aging expert shares 5 keys to building resilience and a better life
BUT CAN A DOZEN wildly varying risk factors really be blamed for causing dementia, or might there be other things at work? Maybe people exposed to more air pollution are also more likely to have stressful jobs, and less access to medical care and nutritious food? Or perhaps lean people who love to exercise are blessed with a constellation of genes that makes them less susceptible to Alzheimer’s in the first place?
The risk factor list is based mostly on studies like ACT, which are called observational. They can uncover intriguing associations but can’t prove cause and effect. That requires the type of randomized controlled trials that are exceedingly difficult to pull off for complex illnesses such as dementia.
But ACT’s results are more robust than most because participants are randomly selected, and researchers can draw on such a dense matrix of information to weed out confounding factors. “The findings, I believe, are going to stand the test of time and are now beginning to be reliable enough that we can do clinical trials,” Larson says.
In one recent trial, patients over 70 with at least two risk factors were randomized into two groups. The control group got educational materials on how to lower their risk, while the others got personalized regimens and advice from a health coach. Final results aren’t out yet, but after two years, the group that got the intensive program had an 80% higher improvement in cognitive scores than the control group.
DORI ROSENBERG, a clinical psychologist at Kaiser Permanente Washington Health Research Institute, is building on that work with a trial focused on ways to get older adults to move more and sit less. She outfits ACT participants with FitBit-like trackers to quantify how much time they spend standing, walking and sleeping through a 24-hour cycle. The devices send electronic reminders to get up and walk around.
Rosenberg is also trying to understand how physical activity might protect against dementia. Exercise improves blood flow to the brain and overall cardiovascular health, so it seems logical. But she and her colleagues plan to link the activity monitoring to brain scans and autopsied brains to see whether exercise is actually changing structures or cells and providing a buffer against dementia symptoms.
“I think physical activity is really key because it covers a lot of the other risk factors,” Rosenberg says. “It helps reduce the risk of hypertension. It helps reduce the risk of diabetes and obesity. It helps promote social activity and improves mood.”
Other researchers caution that without more solid evidence, it’s premature to claim improving lifestyle can stave off dementia. “We don’t know yet,” says Richard, who is conducting rigorous clinical trials to see whether dementia prevention is really possible.
But after working in the field, and with older patients for so long, Larson has no doubt individual actions can make a difference. He co-authored a book called “Enlightened Aging” that translates many of ACT’s discoveries into a guide to healthy aging in general. And as he eases into retirement himself, he’s putting the recommendations into action in his own life. (See The Backstory for more.)
“A lot of people are still hoping for that magic bullet against Alzheimer’s,” he says. But in the meantime, he’s convinced common sense actions including exercising, stopping smoking and controlling blood pressure are the best defense.
“It’s not just about Alzheimer’s,” he says. “It’s about our bodies, too, and being able to take care of ourselves as we age.”