The number of people diagnosed with Alzheimer’s disease is set to rise dramatically around the world in the coming decades, but existing treatments have limited efficacy. Insights into the genetic drivers of Alzheimer’s have never been more vital; they may reveal new ways to predict risk, and ultimately to individualize treatment and prevention. Researchers have already established that genetics play a major role in the onset and progression of the disease – the estimated heritability of Alzheimer’s is 58% to 79%, and over 90% in its early-onset forms (Sims, R. et al. Nat Neurosci 23, 311-322; 2020). But there is much more to discover.
“There are variations in ancestry that make a difference in terms of different variants causing risk or offering protection against disease,” says geneticist Margaret Pericak-Vance, director of the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine.
But the genetic data gathered so far hides a serious problem. Historically, some 80% of Alzheimer’s disease research subjects have been non-Hispanic white people of European descent, says Pericak-Vance. Thanks to a US$46 million, five-year grant from the US National Institute on Aging (NIA), researchers from the Miller School are leading efforts to address this imbalance. The Miller School will partner with an international group from five US cities and nine African countries to study the genetic and environmental factors contributing to Alzheimer’s disease for African Americans, Latinx Americans and Africans.
“This is one of the largest NIA-funded projects that focuses on the genetics of Alzheimer’s disease among individuals of African ancestry that includes a substantial number of individuals from Africa,” says researcher Michael Cuccaro, associate director of the Miller School’s Center for Genomic Education and Outreach.
These are populations for which more data is sorely needed. In the US, Black and Latinx adults aged 65 and older face a higher risk of developing Alzheimer’s dementia; 19% of Black and 14% of Hispanic adults have Alzheimer’s compared with 10% of older white adults, reports the Alzheimer’s Association. Not only do African Americans and Latinx people face higher rates of Alzheimer’s and dementia, they are also at greater risk for vascular disease, a potential contributing factor in Alzheimer’s, says Jeffery Vance, professor of human genetics and neurology at the Miller School.
Combining genetic and environmental data
The study cohort will include 5,000 people from various African countries, 4,000 African Americans and 4,000 Latinx Americans. The participants’ data will be added to an existing global database available to all researchers as part of the Alzheimer’s Disease Sequencing Project. Partner institutions on the project include Case Western Reserve University, Columbia University, Wake Forest University, the University of Pennsylvania, and 11 institutes across Africa, including the University of Ibadan.
In addition to studying ancestry and genetics, the team is looking at social determinants of health. These include education level and quality and whether study subjects have access to quality health care, clean air, economic stability, a healthy diet and regular exercise and the level of stress in their lives, including from living with racism.
By studying both ancestry as well as social and environmental factors, the international team hopes to predict and detect Alzheimer’s disease in its earliest stages and, eventually, provide medications tailored to patients’ genetic code and recommendations tailored to modifiable social and environmental determinants.
“I think it’s going to be really powerful,” Pericak-Vance says. “We want to integrate the studies of social risk and biological risk. For too long, it’s been far apart. It’s both.”
Researchers already know that if someone carries the apolipoprotein E type 4 allele (APOE- ε4) gene they’re at high risk for developing Alzheimer’s no matter how healthy their lifestyle, says Vance. But for those without that genetic marker, lifestyle factors such as keeping socially and intellectually active could potentially delay the onset of the disease.
Building trust in communities
Researchers face a long history of justified mistrust in African American communities towards medical research institutions, a sentiment informed by multiple transgressions, including the infamous Tuskegee experiments, says Pericak-Vance. “Our team goes out and addresses up front the historical abuses,” she says. “We have to talk about it.” Universities’ outreach teams reflect the community they are trying to engage, she says, and they bring in consultants to “tell us what we can do better”.
Each partner university is using outreach strategies tailored to the study subjects they’re trying to recruit, seeking input from community advisory boards and a global advisory board, says Cuccaro. To avoid cultural insensitivity, the advisory board vets outreach materials.
“You’re talking about different types of outreach events and recruitment strategies. It’s not one-size-fits-all,” he says. “Among the nine African countries, you have different populations. You need to tailor your message to those different regions. We’re relying on our African colleagues to frame the message.”
Engaging with communities in the right way could yield important genetic details. By studying Latinx people living in both New York and Miami, researchers will be able to gather different mixes of ancestry data. Hispanic/Latinx individuals living in Florida tend to have a mix of American Indian, African and European ancestry, Vance says. “By understanding those three major ancestries, it helps us to understand the populations that are most prevalent in the US.”
The road to personalized treatment
The researchers hope that by providing the genetic diversity currently lacking in the Alzheimer’s Disease Sequencing Project, they will better understand how ancestry contributes to whether and how people develop the disease, Cuccaro says. Doctors and psychologists will use objective measures of cognitive abilities, memory, executive function and other traits to determine whether study subjects have dementia and follow them over time. To avoid study biases, their African counterparts are adapting cognitive tests to account for cultural differences in education and literacy, he says.
They will look for biomarkers that, if detected early in the disease’s progression, may make existing medication more effective at postponing onset, Cuccaro says. Ultimately, adds Brian Kunkle, assistant professor of human genetics at the Miller School, the goal is to fill gaps in data on how ancestry, and social and environmental determinants of health, contribute to disease risk. The teams hope this data can be mined to aid future development of personalized medications that address the ancestral variations of the disease, coupled with environmental and lifestyle factors.
“The whole point is to find new targets for therapies,” says Pericak-Vance. “If everybody had the same ancestry, we’d find one pill. People are different. This study is putting the pieces of the puzzle together.”