African ancestry genes linked to higher risk for Alzheimer’s, stroke : Shots

Black Americans are known to be at higher risk of some neurological disorders, and the reasons for this disparity remain unclear. Now, after examining the postmortem brains of 151 people, researchers in Baltimore have identified genes that may help explain why.

In those people, who all identified as Black or African American, the scientists analyzed the influence of two different ancestries: African and European.

They found that genes associated with African ancestry appear to affect certain brain cells in ways that could increase the risk of Alzheimer’s disease and stroke.

But genes associated with European ancestry seem to influence other brain cells in ways that could increase the risk of Parkinson’s disease, a disorder that is less common in Black Americans.

The study also probed whether genetic ancestry influenced neurons, which are critical to memory, movement, and thinking.

Neurons appear to play an important role in certain psychiatric disorders, including schizophrenia, which are diagnosed more frequently in Black Americans than their white counterparts.

Yet the researchers found no evidence that genetic ancestry influenced neurons. This could mean that societal factors, such as economic and psychological stress, exposure to traumatic events, and racial bias in diagnosis, account for the disparity — though the study did not include any direct measure of this possibility.

The results, published in the journal Nature Neuroscience, are a first step toward “mitigating some of the increased risk that comes along with different ancestries,” says Dr. Kafui Dzirasa, an investigator and professor of psychiatry at Duke University who was an advisor to the study, but not an author.

A community effort

Black Americans have been underrepresented in most genomic studies of neurological disorders.

As a result, scientists know relatively little about whether African ancestry affects a person’s risk for these disorders, or their response to a particular treatment.

This dearth of research led to the creation, in 2019, of the African Ancestry Neuroscience Research Initiative, a collaboration involving African American community leaders, the Lieber Institute for Brain Development, Duke University and Morgan State University.

One of the early challenges for the initiative was to earn the trust of Baltimore’s Black residents. That meant involving prominent African American educators, business people, and church leaders, including the Rev. Alvin Hathaway, Sr., who served as pastor of Union Baptist Church until 2021.

“You had to build relationships with families and communities such that when their loved ones passed away, they were willing to donate their brains to medical research,” says Dzirasa, who advises the initiative.

The Baltimore team’s study is the first to come out of the effort.

Because so much brain research has focused on people who identify as white, the team decided to look only at brains from people who identified themselves as Black or African American. Each brain was donated for research by a person’s next of kin.

But a person’s self-identified race allowed for a wide range of genetic ancestry.

As a result of centuries of intermixing — including the rape of enslaved women and girls before 1865 — the genomes of most Black individuals contain a combination of European and African ancestry.

“We leveraged the history of the U.S. to pinpoint how European ancestry vs. African ancestry affects gene expression in the brain,” says Kynon Jade Benjamin, a researcher at the Lieber Institute and at Johns Hopkins University who led the work.

Genes vs. environment

Gene expression describes how certain genes are turned on or off in a particular cell. That process can be influenced by a person’s genes, experiences, and environment.

The study was designed to minimize the differences that could be attributed to two of those factors: experience and environment. As a result, they accounted for an estimated 15% of the differences in gene expression, while genetic ancestry accounted for more than 60%.

A person’s ancestry was most likely to influence gene expression in immune cells and cells that form the walls of blood vessels, Benjamin says.

The blood vessel finding could be one reason that strokes caused by a blocked artery are 50% more common in African Americans than in their white counterparts.

And the two lineages’ immune cell differences could help explain why African Americans are more likely to be living with Alzheimer’s dementia, but less likely to get Parkinson’s disease.

Both of those disorders have been linked to an overreaction by the brain’s immune cells, which results in inflammation. And those immune responses are more likely when certain genes are switched on, or “upregulated,” Benjamin says.

“For Parkinson’s, we saw an upregulation in European ancestry,” he says. “When we looked at stroke and Alzheimer’s, we saw an upregulation in the genes associated with African ancestry.”

African Americans 70 and older are about twice as likely as their white counterparts to be living with Alzheimer’s. But they are just half as likely to be diagnosed with Parkinson’s.

“We see these health disparities, which we know are partly to do with environment,” Benjamin says, “but there’s also a huge genetic component.”

Neurons and psychiatric disorders

The study did not offer much insight into why Black Americans are about 20% more likely than white Americans to experience serious mental health problems, including schizophrenia and depression.

These disorders are thought to involve neurons, the cells that generate electrical impulses and are known as the brain’s gray matter. But the study found that ancestry had no effect on gene expression in these cells.

That could mean that a person’s environment and experience, rather than their genes, play a key role when it comes to mental illness.

But Dzirasa, who has spent his career studying genes and mental illness, thinks there may be a different explanation.

In adult brains, immune cells respond to injury or infection, he says. But earlier in life, “those same brain cell types may be giving rise to psychiatric disorders.”

For example, immune cells called microglia “can prevent too many brain cells from being connected with each other by sort of trimming [the connections] away,” Dzirasa says. “They’re almost like a gardener trimming down bonsai trees to the right shape.”

Disturbances in that process, called synaptic pruning, have been linked to schizophrenia and autism spectrum disorder, Dzirasa says.

A path to precision medicine

Even though the study used self-identified race as a starting point, it also shows why racial categories are a poor indicator of a person’s genetic background, Benjamin says.

A look at the overall European ancestry of each person in the study found a range from zero to more than 60 percent.

That means doctors need to look beyond race when assessing a Black person’s risk for a disease like cystic fibrosis, which is most common in people of Northern European ancestry, Benjamin says.

“If a patient comes in with some particular kind of symptoms, don’t rule it out just because someone is African American,” he says. “At that particular gene, they could be European.”

The study also shows “clearly and scientifically” why genetic research needs to be more diverse, Dzirasa says.

Finding genes that protect someone with a particular ancestry from a disease like Parkinson’s could help scientists figure out how to protect all people.

Race is a social construct, not a biological one, Dzirasa says. Even so, he still notes race when glancing at a patient’s chart because it does indicate something about their life experience and disease risk.

But he looks forward to an emerging approach, known as precision medicine, that doesn’t look at race.

“The more optimal future is one in which we understand each person’s individual genomic architecture, and then prescribe medicines based on this,” Dzirasa says.