(Left to right) Vickie Naylor, Bernadine Clay, and Donna Maxey read a memory prompt as they take part in the Sharing History through Active Reminiscence and Photo-Imagery (SHARP) study, September 20, 2017.
That your risk of Alzheimer’s disease depends on your salary, what you ate as a child, or the block where you live may seem implausible. But researchers are discovering that social determinants of health (SDOH) play an outsized role in Alzheimer’s disease and related dementias, possibly more than age, and new strategies are emerging for how to address these factors.
At the 2022 Alzheimer’s Association International Conference, a series of presentations offered evidence that a string of socioeconomic factors—such as employment status, social support networks, education and home ownership—significantly affected dementia risk, even when adjusting data for genetic risk. What’s more, memory declined more rapidly in people who earned lower wages and slower in people who had parents of higher socioeconomic status.
In 2020, a first-of-its kind study in JAMA linked Alzheimer’s incidence to “neighborhood disadvantage,” which is based on SDOH indicators. Through autopsies, researchers analyzed brain tissue markers related to Alzheimer’s and found an association with these indicators. In 2022, Ryan Powell, the lead author of that study, published further findings that neighborhood disadvantage was connected with having more neurofibrillary tangles and amyloid plaques, the main pathological features of Alzheimer's disease.
As of yet, little is known about the biological processes behind this, says Powell, director of data science at the Center for Health Disparities Research at the University of Wisconsin School of Medicine and Public Health. “We know the association but not the direct causal pathway.”
The corroborative findings keep coming. In a Nature study published a few months after Powell’s study, every social determinant investigated affected Alzheimer’s risk except for marital status. The links were highest for income, education, and occupational status.
Clinical trials on new Alzheimer’s medications get all the headlines but preventing dementia through policy and public health interventions should not be underestimated.
The potential for prevention is significant. One in three older adults dies with Alzheimer's or another dementia—more than breast and prostate cancers combined. Further, a 2020 report from the Lancet Commission determined that about 40 percent of dementia cases could theoretically be prevented or delayed by managing the risk factors that people can modify.
Take inactivity. Older adults who took 9,800 steps daily were half as likely to develop dementia over the next 7 years, in a 2022 JAMA study. Hearing loss, another risk factor that can be managed, accounts for about 9 percent of dementia cases.
Clinical trials on new Alzheimer’s medications get all the headlines but preventing dementia through policy and public health interventions should not be underestimated. Simply slowing the course of Alzheimer’s or delaying its onset by five years would cut the incidence in half, according to the Global Council on Brain Health.
Minorities Hit the Hardest
The World Health Organization defines SDOH as “conditions in which people are born, work, live, and age, and the wider set of forces and systems shaping the conditions of daily life.”
Anyone who exists on processed food, smokes cigarettes, or skimps on sleep has heightened risks for dementia. But minority groups get hit harder. Older Black Americans are twice as likely to have Alzheimer’s or another form of dementia as white Americans; older Hispanics are about one and a half times more likely.
This is due in part to higher rates of diabetes, obesity, and high blood pressure within these communities. These diseases are linked to Alzheimer’s, and SDOH factors multiply the risks. Blacks and Hispanics earn less income on average than white people. This means they are more likely to live in neighborhoods with limited access to healthy food, medical care, and good schools, and suffer greater exposure to noise (which impairs hearing) and air pollution—additional risk factors for dementia.
Related Reading: The Toxic Effects of Noise and What We're Not Doing About it
Plus, when Black people are diagnosed with dementia, their cognitive impairment and neuropsychiatric symptom are more advanced than in white patients. Why? Some African-Americans delay seeing a doctor because of perceived discrimination and a sense they will not be heard, says Carl V. Hill, chief diversity, equity, and inclusion officer at the Alzheimer’s Association.
Misinformation about dementia is another issue in Black communities. The thinking is that Alzheimer’s is genetic or age-related, not realizing that diet and physical activity can improve brain health, Hill says.
African Americans are severely underrepresented in clinical trials for Alzheimer’s, too. So, researchers miss the opportunity to learn more about health disparities. “It’s a bioethical issue,” Hill says. “The people most likely to have Alzheimer’s aren’t included in the trials.”
The Cure: Systemic Change
People think of lifestyle as a choice but there are limitations, says Muniza Anum Majoka, a geriatric psychiatrist and assistant professor of psychiatry at Yale University, who published an overview of SDOH factors that impact dementia. “For a lot of people, those choices [to improve brain health] are not available,” she says. If you don’t live in a safe neighborhood, for example, walking for exercise is not an option.
Hill wants to see the focus of prevention shift from individual behavior change to ensuring everyone has access to the same resources. Advice about healthy eating only goes so far if someone lives in a food desert. Systemic change also means increasing the number of minority physicians and recruiting minorities in clinical drug trials so studies will be relevant to these communities, Hill says.
Based on SDOH impact research, raising education levels has the most potential to prevent dementia. One theory is that highly educated people have a greater brain reserve that enables them to tolerate pathological changes in the brain, thus delaying dementia, says Majoka. Being curious, learning new things and problem-solving also contribute to brain health, she adds. Plus, having more education may be associated with higher socioeconomic status, more access to accurate information and healthier lifestyle choices.
New Strategies
The chasm between what researchers know about brain health and how the knowledge is being applied is huge. “There’s an explosion of interest in this area. We’re just in the first steps,” says Powell. One day, he predicts that physicians will manage Alzheimer’s through precision medicine customized to the patient’s specific risk factors and needs.
Raina Croff, assistant professor of neurology at Oregon Health & Science University School of Medicine, created the SHARP (Sharing History through Active Reminiscence and Photo-imagery) walking program to forestall memory loss in African Americans with mild cognitive impairment or early dementia.
Participants and their caregivers walk in historically black neighborhoods three times a week over six months. A smart tablet provides information about “Memory Markers” they pass, such as the route of a civil rights march. People celebrate their community and culture while “brain health is running in the background,” Croff says.
Photos and memory prompts engage participants in the SHARP program.
OHSU/Kristyna Wentz-Graff
The project began in 2015 as a pilot study in Croff’s hometown of Portland, Ore., expanded to Seattle, and will soon start in Oakland, Calif. “Walking is good for slowing [brain] decline,” she says. A post-study assessment of 40 participants in 2017 showed that half had higher cognitive scores after the program; 78 percent had lower blood pressure; and 44 percent lost weight. Those with mild cognitive impairment showed the most gains. The walkers also reported improved mood and energy along with increased involvement in other activities.
It’s never too late to reap the benefits of working your brain and being socially engaged, Majoka says.
In Milwaukee, the Wisconsin Alzheimer’s Institute launched the The Amazing Grace Chorus® to stave off cognitive decline in seniors. People in early stages of Alzheimer’s practice and perform six concerts each year. The activity provides opportunities for social engagement, mental stimulation, and a support network. Among the benefits, 55 percent reported better communication at home and nearly half of participants said they got involved with more activities after participating in the chorus.
Private companies are offering intervention services to healthcare providers and insurers to manage SDOH, too. One such service, MyHello, makes calls to at-risk people to assess their needs—be it food, transportation or simply a friendly voice. Having a social support network is critical for seniors, says Majoka, noting there was a steep decline in cognitive function among isolated elders during Covid lockdowns.
About 1 in 9 Americans age 65 or older live with Alzheimer’s today. With a surge in people with the disease predicted, public health professionals have to think more broadly about resource targets and effective intervention points, Powell says.
Beyond breakthrough pills, that is. Like Dorothy in Kansas discovering happiness was always in her own backyard, we are beginning to learn that preventing Alzheimer’s is in our reach if only we recognized it.
Miniature lab-grown models of human organs have major advantages over standard animal testing.
But he wasn't the only one to follow this train of thought. In the year since the pandemic began, many researchers have been using organoids to study how the coronavirus infects human cells, and find potential treatments. Beumer's pivot represents a remarkable and fast-emerging paradigm shift in how drugs and diseases will be studied in the coming decades. With future pandemics likely to be more frequent and deadlier, such a shift is necessary to reduce the average clinical development time of 5.9 years for antiviral agents.
Part of that shift means developing models that replicate human biology in the lab. Animal models, which are the current standard in biomedical research, fail to do so—96% of drugs that pass animal testing, for example, fail to make it to market. Injecting potentially toxic drugs into living creatures, before eventually slaughtering them, also raises ethical concerns for some. Organoids, on the other hand, respond to infectious diseases, or potential treatments, in a way that is relevant to humans, in addition to being slaughter-free.
Human intestinal organoids infected with SARS-CoV-2 (white).
Credit: Joep Beumer/Clevers group/Hubrecht Institute
Urgency Sparked Momentum
Though brain organoids were previously used to study the Zika virus during the 2015-16 epidemic, it wasn't until COVID-19 that the field really started to change. "The organoid field has advanced a lot in the last year. The speed at which it happened is crazy," says Shuibing Chen, an associate professor at Weill Cornell Medicine in New York. She adds that many federal and private funding agencies have now seen the benefits of organoids, and are starting to appreciate their potential in the biomedical field.
Last summer, the Organo-Strat (OS) network—a German network that uses human organoid models to study COVID-19's effects—received 3.2 million euros in funding from the German government. "When the pandemic started, we became aware that we didn't have the right models to immediately investigate the effects of the virus," says Andreas Hocke, professor of infectious diseases at the Charité Universitätsmedizin in Berlin, Germany, and coordinator of the OS network. Hocke explained that while the World Health Organization's animal models showed an "overlap of symptoms'' with humans, there was "no clear reflection" of the same disease.
"The network functions as a way of connecting organoid experts with infectious disease experts across Germany," Hocke continues. "Having organoid models on demand means we can understand how a virus infects human cells from the first moment it's isolated." Overall, OS aims to create infrastructure that could be applied to future pandemics. There are 28 sub-projects involved in the network, covering a wide assortment of individual organoids.
Cost, however, remains an obstacle to scaling up, says Chen. She says there is also a limit to what we can learn from organoids, given that they only represent a single organ. "We can add drugs to organoids to see how the cells respond, but these tests don't tell us anything about drug metabolism, for example," she explains.
A Related "Leaps" in Progress
One way to solve this issue is to use an organ-on-a-chip system. These are miniature chips containing a variety of human cells, as well as small channels along which functions like blood or air flow can be recreated. This allows scientists to perform more complex experiments, like studying drug metabolism, while producing results that are relevant to humans.
An organ-on-a-chip system.
Credit: Fraunhofer IGB
Such systems are also able to elicit an immune response. The FDA has even entered into an agreement with Wyss Institute spinoff Emulate to use their lung-on-a-chip system to test COVID-19 vaccines. Representing multiple organs in one system is also possible. Berlin-based TissUse are aiming to make a so-called 'human on a chip' system commercially available. But TissUse senior scientist Ilka Maschmeyer warns that there is a limit to how far the technology can go. "The system will not think or feel, so it wouldn't be possible to test for illnesses affecting these abilities," she says.
Some challenges also remain in the usability of organs-on-a-chip. "Specialized training is required to use them as they are so complex," says Peter Loskill, assistant professor and head of the organ-on-a-chip group at the University of Tübingen, Germany. Hocke agrees with this. "Cell culture scientists would easily understand how to use organoids in a lab, but when using a chip, you need additional biotechnology knowledge," he says.
One major advantage of both technologies is the possibility of personalized medicine: Cells can be taken from a patient and put onto a chip, for example, to test their individual response to a treatment. Loskill also says there are other uses outside of the biomedical field, such as cosmetic and chemical testing.
"Although these technologies offer a lot of possibilities, they need time to develop," Loskill continues. He stresses, however, that it's not just the technology that needs to change. "There's a lot of conservative thinking in biomedical research that says this is how we've always done things. To really study human biology means approaching research questions in a completely new way."
Even so, he thinks that the pandemic marked a shift in people's thinking—no one cared how the results were found, as long as it was done quickly. But Loskill adds that it's important to balance promise, potential, and expectations when it comes to these new models. "Maybe in 15 years' time we will have a limited number of animal models in comparison to now, but the timescale depends on many factors," he says.
Beumer, now a post-doc, was eventually allowed to return to the lab to develop his coronavirus model, and found working on it to be an eye-opening experience. He saw first-hand how his research could have an impact on something that was affecting the entire human race, as well as the pressure that comes with studying potential treatments. Though he doesn't see a future for himself in infectious diseases, he hopes to stick with organoids. "I've now gotten really excited about the prospect of using organoids for drug discovery," he says.
The coronavirus pandemic has slowed society down in many respects, but it has flung biomedical research into the future—from mRNA vaccines to healthcare models based on human biology. It may be difficult to fully eradicate animal models, but over the coming years, organoids and organs-on-a-chip may become the standard for the sake of efficacy -- and ethics.