Years Before Alzheimer's Appears, African Americans with a Specific Gene Variant Show a Decline in Brain Network Flexibility

Rutgers-Newark researchers have shown that a genetic variant specific to African ancestry alters the brain in a way that could foretell the eventual development of Alzheimer's Disease.

At the same time, their study revealed some good news: A far more well-known genetic mutation doesn't seem as malevolent in African Americans as it is in people of primarily European descent.

The finding may help explain why African Americans develop Alzheimer's at more than twice the rate than people whose genetic ancestry is mostly European. The results will appear in the May edition of the scientific journal Neurobiology of Aging.

The full name of the culprit is ABCA7 rs115550680. Called ABCA7 for short, it is present in just 30 percent of people of African descent. Yet those carriers are two-and-a-half times more likely to get Alzheimer's.

“That's why we know it's pretty important,” said Miray Budak, the J. Seward Johnson Postdoctoral Fellow in Aging Neuroscience, and one of the lead authors of the study.

Researchers at the Rutgers Aging & Brain Alliance asked 146 people to submit saliva samples for genetic testing, then get a 15-minute MRI of their brains. In order to qualify, they had to be 60 or older with no sign of the disease.

The MRI scans focused on seven regions of the brain's Medial Temporal Lobe, the section that is crucial for learning and memory. The goal was to see how efficiently those sections communicate with each other.

Budak likened these regions to guests at a cocktail party. Did they just converse with one or two people the whole time, or did they make new friends then move on to meet more guests? Limited communication between the nodes – known as rigidity – is a harbinger of Alzheimer's down the road.

In an MRI, this communication is seen in the way these different nodes “light up.” When memory regions light up together, they are presumed to be communicating.

Previous Rutgers research by the same team has shown this brain network rigidity to be an early sign of Alzheimer's disease – one that shows up years before problems are apparent to patients, their loved ones, or even their doctors.

“They look healthy,” Budak said. “They don't have any symptoms.”

To get an accurate measure of the resting brain, the study participants were told to avoid thinking of complicated topics during the scan: No math problems. No grocery lists. No singing.

“Don't think about any other thing. Just rest, close your eyes,” Budak said. “But don't fall asleep!”

Peggy Koon, 86, one of the program's community participants, volunteered to be in the study and thought of music and friends from her youth during the scan.

“I told myself I would listen to church hymns in my mind, and rhythm and blues,” she said. “I told myself I was going to think of childhood friends.”

The East Orange resident was strongly motivated to participate in research because she saw how illness cast a lifelong shadow over her mother, her father, and her grandmother.

“I want to know if there's anything wrong with me,” she said. “So anything health-wise, I would be involved with.”

Study subjects have the option of receiving the scans to pass along to doctors, but researchers are barred from sharing genetic information unless it’s in the context of a clinical referral with a genetic counsellor involved.

The study's hypothesis – that people with the ABCA7 mutation are more likely to display brain rigidity – was shown to be true.

Yet paradoxically, a more well-known genetic mutation linked to Alzheimer's, called APOE-e4, turns out to have less of an impact on brain flexibility in African Americans.

Why would the same gene variation behave differently in different races?

“The most likely explanation has to do with genetic background. Genes do not act alone. They sit within larger stretches of DNA inherited over many generations,” Budak said. “Research suggests that the surrounding African-origin genetic background near the APOE gene may partially reduce or modify the risk associated with the e4 variant.”

The genes that get passed down in our family trees reflect where our ancestors lived hundreds of thousands of years ago.

In the case of Alzheimer's, that's especially relevant, said Mark Gluck, professor of neuroscience and public health, director of the Aging & Brain Health Alliance, and senior author on the new paper.

“Many of the genes associated with Alzheimer’s risk are also closely linked to variations in the immune system. Immune genes tend to vary by race because they reflect a history of the diseases that are predominant in the geographical regions of one’s ancestors,” he said. Different parts of the world have different plants, bugs, and diseases, giving rise to differences in the immune system. 

The study also further validates that rigidity in the dynamics of the Medial Temporal Lobe network – first discovered by Rutgers – is a potential early biomarker for Alzheimer's risk.

The take-home message of this latest study to come out of the Newark-based lab? Said Budak, “Genetic risk for Alzheimer’s disease is not one-size-fits-all and can vary across ancestry groups.”