The Risks and Genetics of Alzheimer’s Disease
Summary
- Researchers from the John P. Hussman Institute for Human Genomics presented research findings illuminating the complex biology of Alzheimer’s disease at the recent Alzheimer’s Disease/Parkinson’s Disease annual meeting.
- The Miller School’s Dr. James Galvin is building the Brain Health Index, a measurement which takes into account six factors that can make a person’s brain healthier.
- A key theme among Miller School researcher presentations was the role of genetic ancestry in modifying Alzheimer’s disease risk and pathology.
University of Miami Miller School of Medicine researchers from the John P. Hussman Institute for Human Genomics and the Comprehensive Center for Brain Health were a major presence at the recent Alzheimer’s Disease/Parkinson’s Disease annual meeting. Several scientists presented research findings illuminating the complex biology of Alzheimer’s disease.
Researchers from the Miller School have been a regular presence at the annual conference.
“The meeting is a great venue to present our science to a large, international audience, but also to make connections, have meetings and network. We’ve been able to develop a number of collaborations with other researchers and with industry to help advance our research goals,” said James Galvin M.D., M.P.H., professor of neurology and chief of the Division of Cognitive Neurology at the Miller School and director of the Comprehensive Center for Brain Health.
The presentations focused on genetics and the ways environment can influence an individual’s risk of developing Alzheimer’s. The work will help lead to more personalized prevention strategies and treatments for the disease.
The Brain Health Index
Over the last several years, Dr. Galvin and his team have worked to develop a way to prospectively measure resilience to and risk of Alzheimer’s disease. Doing so, he said, allows researchers to customize prevention and treatment to the individual. Drug developers can also benefit by finding new targets for medications and better ways to evaluate their efficacy.
Currently, researchers can use autopsies or extensive biomarker tests to determine the extent of someone’s disease process. They compare that to their symptoms to retrospectively assess how resilient they were to the damage Alzheimer’s did on their brain. But they can’t predict how resilient someone might be to future damage.
Over the past five years, Dr. Galvin and his team have been building the Brain Health Index, a measurement which takes into account six factors that can make a person’s brain healthier, including physical activity, sociability and diet. The index also assesses 12 factors that can make a person more vulnerable to Alzheimer’s disease and conducts a brief, cognitive test that doesn’t rely on language or memory.
Together, these measures “tell us in that cross-sectional moment how healthy their brain is, and it will tell us some predictive value of how likely they are to develop disease in the future,” said Dr. Galvin.
He and his team have enrolled 500 participants in the Health Brain Initiative, in which they test the measure in a variety of models. They’ve studied how physical activity might improve someone’s Brain Health Index score and how social determinants of health like living in a neighborhood with green space and parks can improve brain health.
They’ve also begun looking at epigenetics—how genes change their expression levels in response to experiences and environment. Researchers have found 37 distinct sites in the genome that are correlated with greater resilience.
“We validated in an external, independent research sample, and showed a significant delay in cognitive decline if you have these signals. So, this gives us a potential druggable target,” said Dr. Galvin. “As we go on, we can think about how we can combine medical interventions with social interventions, health guidelines and potentially even public policy to lower people’s risks of developing Alzheimer’s disease.”
Genomics, Ancestry and Alzheimer’s Risk
Researchers from the Hussman Institute gave six separate talks, paving the way for a better understanding of Alzheimer’s disease and potential new therapeutics.
The fact that the institute’s researchers gave so many presentations is a “testament to the type and breadth of work we’ve been doing,” said Margaret Pericak-Vance, Ph.D., director of the Hussman Institute and Dr. John T. Macdonald Foundation Professor of Human Genetics at the Miller School. “We covered everything from statistical analyses to functional modeling to bioinformatics of Alzheimer’s disease genetics.”
Hussman institute researchers who gave presentations included:
• Brian Kunkle Ph.D., M.P.H., assistant professor in the The Dr. John T. Macdonald Foundation Department of Human Genetics
• Karen Nuytemans, Ph.D., assistant professor in the The Dr. John T. Macdonald Foundation Department of Human Genetics
• Anthony Griswold, Ph.D., assistant professor in the The Dr. John T. Macdonald Foundation Department of Human Genetics and associate director of the Center for Genome Technology
• Bilcag Akgun, M.D., Ph.D., assistant scientist in the The Dr. John T. Macdonald Foundation Department of Human Genetics
• Liyong Wang, Ph.D., research associate professor in the The Dr. John T. Macdonald Foundation Department of Human Genetics
• Sofia Moura, Ph.D., assistant scientist in the The Dr. John T. Macdonald Foundation Department of Human Genetics
“A key theme among the talks,” explained Dr. Griswold, who spoke about his MAGENTA project characterizing differences in DNA methylation and gene expression across ancestral groups, “is the role of genetic ancestry in modifying Alzheimer’s disease risk and pathology.”
Identifying the Fundamental Processes of Alzheimer’s Disease
Illuminating different genetic risk factors among specific ancestries and sexes provides insights that can apply broadly to anyone, regardless of sex or ancestry.
“It’s really about finding the things that tell us about the fundamental processes that are driving Alzheimer’s disease that then give us more opportunities to identify therapeutic interventions that can be used more universally,” Dr. Griswold said.
For example, APOE is the most well-known gene to impact Alzheimer’s risk. But, another gene, ABCA7, influences risk in people with African ancestry. These two genes interact and are a part of the same pathway.
“It’s not just about discovery of different genes. It’s how these genes interact, how these pathways fit together,” said Dr. Pericak-Vance, adding that the findings can help identify new therapeutic strategies.
Additionally, Dr. Moura’s presentation described her findings that APOE gene variants confer different levels of risk in individuals with different ancestries, because the gene is often surrounded by different DNA that regulates its expression.
“There’s a big push to find a therapeutic intervention targeting APOE since the monoclonal antibodies on the market haven’t been as effective as researchers hoped they’d be,” explained Jeffery Vance, M.D., Ph.D., professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and director of the Center for Genomic Education and Outreach at the Miller School. “This research has important implications for any therapy that targets the expression of APOE.”
Dr. Nuytemans presented a similar discovery. In previous work, the team had identified a large family that had a shared variant in the INSYN2B gene, but that shared variants among other families seemed to be located outside of genes as noncoding variants. She presented data showing that in five of these families, the shared variants interacted with INSYN2B.
“We can then use what we’ve learned on these mechanisms to modulate the risk of these variants on any ancestry, which ultimately is the goal of future therapies,” she said.
Even seemingly distant genes can influence each other’s expression. Dr. Wang’s presentation focused on how DNA strands can fold into three-dimensional shapes that bring unexpected gene and regulatory sequences close together, allowing them to influence one another. DNA folds differently in people across ancestries.
Her research provided “a new way of looking at the ancestries that goes beyond just the DNA sequence differences but really shows this three-dimensional characteristic that differ among them,” said Dr. Griswold.
Dr. Kunkle probed differences between men and women in a genome-wide meta-analysis study. He explained that most existing research assesses men’s and women’s risk together, but his team found that several genetic risk factors appear to be sex-specific.
“One of the main benefits of identifying sex-specific factors influencing Alzheimer’s disease could be development of personalized preventative and therapeutic options based on a person’s biological sex and genetic profile,” he said.
Reuniting with International Collaborators
Throughout the conference, international experts congratulated the team on their findings.
“We got a lot of positive feedback about how much information we’re getting by using ancestry as a tool to probe into the disease mechanism,” said Dr. Vance.
In addition to these research presentations, the meeting provided an opportunity to meet in person with international collaborators on the DAWN study, which brings together data research participants of different ancestries from all over the world. Attendees included Dr. Rufus Akinyemi from the University of Ibadan in Nigeria, Dr. Kamada Lwere from Makerere University in Uganda and Dr. Mario Cornejo-Olivas from Universidad Científicadel Sur in Peru.
“Having a chance to spend time with these research teams in person gave the Hussman team an opportunity to come up with exciting new ideas for future research that will be presented at future international conferences and lead to new global discoveries,” said Dr. Pericak-Vance.
Tags: Alzheimer's disease, brain health, cognitive decline, Comprehensive Center for Brain Health, Dr. Anthony Griswold, Dr. James Galvin, Dr. Jeffery Vance, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Margaret Pericak-Vance, genetics, genomics, Hussman Institute for Human Genomics, neurology