Miller School Researchers Have Major Impact at International Alzheimer’s Conference
The Alzheimer’s Association International Conference (AAIC) 2023 was held in Amsterdam July 16-20, and neurologists and scientists with the University of Miami Miller School of Medicine played a key role. One of the meeting’s major themes was diversity — studying diverse cohorts to determine how Alzheimer’s impacts people with different ancestries — a path Miller School researchers have been walking for decades.
“We are one of the largest groups working on the genetics of Alzheimer’s disease, especially focusing on the inclusion of diverse groups,” said Margaret Pericak-Vance, Ph.D., director of the John P. Hussman Institute for Human Genomics. “The importance of including diverse individuals from all ancestral backgrounds was a highlight of this conference, which was fantastic because it’s been a long time coming.”
In addition to presenting on a wide range of topics, experts across disciplines participated in extensive media interviews on late-breaking studies and their own research and were featured in The Washington Post, USA Today, Stat News, Prevention, Miami Herald, Healio and Axios, among other outlets.
Dr. Pericak-Vance and colleagues have proven the value of studying diverse groups. Last year, her team showed that the APOE4 gene variant — a major risk factor for Alzheimer’s disease — can behave differently in European and African populations. African communities have reduced APOE4expression, which can lower their risk of developing the disease.
Understanding the regulatory mechanisms that increase or decrease risk could lead to new therapies and/or diagnostic tests. Hussman Institute researchers are working with collaborators in nine African countries, as well as colleagues in Peru, to increase diversity in Alzheimer’s disease research, work that was highlighted several times at the conference.
“Diversity provides an excellent tool for us to probe this disease,” said Jeffery Vance, M.D., Ph.D., a neurologist and professor of human genetics in the Dr. John T. Macdonald Foundation Department of Human Genetics and a senior investigator in the Hussman Institute. “Health equity is important, and different ancestries have different pathways to the disease. Researching Alzheimer’s in diverse ancestries provides different information to understand the disease process.”
The Fruits of Diversity
Collections of misfolded proteins, called amyloid plaques, have long been implicated in Alzheimer’s, and many drugs have been tested to reduce these plaques or prevent them from forming in the first place. Unfortunately, this approach has either failed or produced limited therapeutic benefits.
The problem may be that amyloid storage is just one step in a cascade of brain changes that leads to Alzheimer’s. Genetics can be a major contributor and scientists must investigate genetic underpinnings, such as APOE4, to develop effective therapies. Researchers in the institute’s Alzheimer’s Disease Sequencing Project have spent the past decade studying the genetic variations associated with Alzheimer’s disease.
“Drugs based on genetic studies are twice as likely to succeed,” said Dr. Pericak-Vance. “So, drug companies want targets that have a biological basis. In one of the sessions, we showed results from a large, multiethnic project with cohorts from all over the world, and more than 300 people came to see it. We identified genes that we wouldn’t have found if we hadn’t taken this global inclusive approach.”
Identifying Molecules that May Contribute to Alzheimer’s
Tatjana Rundek, M.D., Ph.D., professor of neurology and director of the Evelyn F. McKnight Brain Institute, presented new research on a protein called osteopontin, which has long been implicated in neuroinflammation.
The research team showed that participants in the multiethnic study who experienced dementia and cerebral small vessel disease (CSVD) had elevated osteopontin levels. This indicated that the combination of vascular dysfunction from the CSVD and inflammation associated with osteopontin may contribute to Alzheimer’s disease and other forms of dementia.
Dr. Rundek’s group continues to study osteopontin’s association with dementia — studies that could eventually produce more effective therapeutics, diagnostics or both.
“Osteopontin may be a potential therapeutic target in people with dementia and cerebral small vessel disease,” said Dr. Rundek. “There is already some work being done in which targeting osteopontin production in the brain reduced amyloid-beta plaques, with promising results.”
Pursuing Early Detection
There’s evidence that Alzheimer’s starts years or even decades before the damage becomes apparent. As a result, early detection could have profound implications for health care, clinical trials, drug development and other areas.
Currently, clinicians use combinations of imaging and cerebrospinal fluid (CSF) tests to detect the disease. These are expensive and, in the case of CSF testing, quite invasive.
Researchers at the Hussman Institute and elsewhere are intently looking for blood biomarkers that could provide cheaper, easier and more precise ways to identify people with early-stage Alzheimer’s, offering new opportunities to intervene before they show signs of dementia.
Anthony Griswold, Ph.D., associate professor of human genetics, has been using data from the Alzheimer’s Disease Sequencing Project to identify and validate effective biomarkers. He presented this data in a featured research session at AAIC.
“We have genetic data from African Americans, Puerto Ricans, Peruvians and Europeans,” said Dr. Griswold. “We also have comprehensive clinical data, including cognitive tests, which can help us determine if a person is cognitively unimpaired, is on their way to Alzheimer’s or has Alzheimer’s. Then we measure these molecules in their plasma to determine if there is a relationship between their clinical status and these biomarker levels.”
So far, the biomarkers have shown good predictive capabilities — and have been relatively consistent between groups — but they need to be better. The tests product correct results for between 65% and 80% of patients. It’s a great start, but not good enough yet for clinical use.
In addition, there are other complications to consider. Sometimes, people have amyloid plaques and other disease pathology but do not experience dementia. Protective genes and other factors, such as education, may counteract the disease. Researchers need to unwind these complexities to provide more precise results.
“We need to take biomarkers and other types of data to build a more comprehensive model,” said Dr. Griswold. “Looking at genetics, social determinants of health and imaging biomarkers, we have to put all that together to get a better picture of what this disease looks like in a diverse set of individuals.”