Multidisciplinary Alzheimer’s Researchers Offer New Insights at AAIC 2024
More than 30 Miller School scientists shared their research and plotted paths forward at this year’s Alzheimer’s Association International Conference.
Each year, the Alzheimer’s Association International Conference (AAIC) showcases the latest developments in Alzheimer’s research and clinical practice, and University of Miami Miller School of Medicine scientists and clinicians always play a major role. Held in Philadelphia this year, the meeting brought in 12,000 researchers from around the world to discuss the latest science and how that could improve care.
More than 30 Miller School scientists shared their research and plotted paths forward. Their work fell into three major buckets: prevention, early detection and genetic diversity. Their investigations have identified healthy habits and advanced techniques to identify disease, and showed how research in diverse cohorts can produce new insights. Indeed, scientists with the John. P. Hussman Institute for Human Genomics played a prominent role at the conference. This year, more than 20 Hussman scientists presented on genetics and Alzheimer’s disease.
The Alzheimer’s Disease Sequencing Project
Margaret Pericak-Vance, Ph.D., director of the Hussman Institute, and Jeffery Vance, M.D., Ph.D., founding chair and professor in the Dr. John T Macdonald Foundation Department of Human Genetics, participated in a highly attended session titled “Accelerating Therapeutic Development: A Global Commitment by the Alzheimer’s Disease Sequencing Project (ADSP).” The symposium also included presentations by Dr. Rufus Akinyemi from the University of Ibadan, Nigeria, on the African Dementia Consortium ADSP work in Africa, and Dr. Mario Cornejo-Olivas from the Instituto Nacional de Cienias Neurológicas (Neurogenetics Research Center) in Lima, Peru, presented on ADSP studies in Peru and Bolivia.
Established in 2012 by the National Institute on Aging (NIA), the ADSP investigates genes that increase dementia risk and seeks to translate those findings into potential therapies. When the project began, virtually all Alzheimer’s-related sequencing had been done in European groups. Dr. Pericak-Vance and her Hussman Institute colleagues have been instrumental in diversifying those studies.
“We started with discovery in Europeans, and we’ve been able to build our cohorts to include African, Hispanic and Asian ancestries,” said Dr. Pericak-Vance. “Now, we’re getting to the point where new drugs are starting to come out of genetic research.”
APOE4
One emerging drug target is the APOE4 variant, the strongest Alzheimer’s genetic risk variant, which Dr. Pericak-Vance helped discover. Most current Alzheimer’s drugs target amyloid protein accumulation but have produced disappointing results. Targeting APOE4, and other driving mutations, could provide more clear-cut benefits, as about 50% of Alzheimer’s patients have at least one APOE4 gene.
However, one question that has held back therapeutic efforts in using APOE4 as a therapeutic target was how it acts to increase the risk for Alzheimer’s disease. For example, is the APOE4 form toxic to the cell or does it lack normal activity so the cell can’t function correctly?
At the AAIC, Dr. Vance presented the data and conclusions of the National Institutes of Health/NIA APOE4 working group, which was recently published in the journal Annals of Neurology. The leading author of the report demonstrated the reasoning leading this group of senior researchers to unanimously conclude that APOE4 is a toxic molecule. This important confirmation will lead to new therapeutic efforts to reduce APOE4 as a therapy for carriers.
The DAWN Study
The Hussman Institute also hosted “The DAWN Alzheimer’s Research Effort” meeting which drew a full room of fellow researchers at Case Western Reserve University, Wake Forest University, Columbia University and their collaborators from the African Dementia Consortium (AfDC), which includes 10 African nations (Nigeria, Ghana, Cameroon, Kenya, Ethiopia, Tanzania, Mozambique, the Democratic Republic of Congo, Benin and Uganda) as well as collaborators from Peru. Led by Hussman scientists, the DAWN study is aimed at recruiting thousands of diverse research participants across Africa and the U.S., including Puerto Rico.
“We’re really excited that we’ve been able to expand our studies, especially across both West and East Africa, which will have a worldwide impact,” and Dr. Pericak-Vance, the DAWN study principal investigator.
She kicked off the meeting with a welcome speech and research overview that highlighted the study’s goals and recruitment milestones.
“It’s great that we can meet with our collaborators in person, get to know each other and share updates and research findings,” said Dr. Pericak-Vance.
DAWN collaborators from the U.S., Ethiopia, Ghana, Kenya, Uganda and Nigeria presented updates on their recruitment efforts, including successes in recruiting (having already reached one-third of their five-year target) and challenges with community engagement and outreach. The presentations touched on cultural and religious sensitivity, when collecting blood samples and other logistical issues.
Diverse Investigations
The University of Miami is a major hub for Alzheimer’s research, innovative care and outreach. In addition to the Hussman Institute, the Miller School is home to the UM Brain Endowment Bank, the Evelyn F. McKnight Brain Institute, the Comprehensive Center for Brain Health (CCBH) and the Center for Cognitive Neuroscience and Aging.
At the conference, CCBH investigators focused mainly on early detection.
“We presented seven abstracts at AAIC, and collectively these studies highlighted novel methods to identify at-risk patients who are experiencing early disease,” said James Galvin, M.D., M.P.H., professor of neurology, chief of the Division of Cognitive Neurology, founding CCBH director and director of the Lewy Body Dementia Research Center of Excellence. “These findings may lead to tailored therapeutic programs that could enhance clinical care.”
Dr. Galvin explained that most people are diagnosed with dementia based on cognitive exams and sophisticated imaging. Unfortunately, these are lagging indicators. By the time Alzheimer’s shows up in a person’s behavior or a scan, the disease has generally progressed quite far. Earlier detection offers numerous benefits, including more productive therapeutic interventions and clinical trials.
Dr Galvin’s presentation focused on using computerized cognitive tests to detect preclinical Alzheimer’s disease, which has never been done in the clinic. These tests focus on adaptive motor control (acquiring unfamiliar movements), visual contrast and shape discrimination. So far, the test correlates well with established imaging and plasma biomarkers.
CCBH investigators have also found links between physical presentation and cognitive decline. Michael Kleiman, Ph.D., research assistant professor of neurology, presented research showing reduced gaze synchronization and speech function in people with mild cognitive impairment. These delayed responses could support early detection.
Research Assistant Professor of Neurology Magdalena Tolea, Ph.D., is investigating gait and balance. She found the inability to perform dual tasks, such as walking and talking, correlated with MRI and plasma biomarkers.
Lilah Besser, Ph.D., research assistant professor of neurology, presented on the effects of gender and social determinants of health on asymptomatic Alzheimer’s. She found that gender, education, Hispanic ethnicity, primary language, living arrangements and other factors were linked to reduced cognitive impairment.
Stephanie Chrisphonte, M.D., research assistant professor of neurology, presented a qualitative study on perceptions of research participation in Afro-Caribbean older adults. She described barriers to and facilitators for research participation that will inform future culturally tailored educational materials that address misconceptions about dementia and recruitment programs that engage older adults from diverse communities.
Experts from the Center for Translational Sleep and Circadian Sciences and the Department of Psychiatry and Behavioral Sciences collaborated with the Hussman Institute on presentations for genetic findings in Puerto Rico and also associations with sleep disturbances. The group also presented collaborative studies on underrepresented populations.
Investigators with the Miami Project to Cure Paralysis presented on how inflammatory signaling following traumatic brain injuries can influence Alzheimer’s risk. They also discussed the role that exosomes (tiny packets of DNA, RNA and other molecules associated with intercellular communication) play a role in dementia.
Heart Health = Brain Health
Life’s Essential 8 (recently expanded from Life’s Simple 7) is the American Heart Association’s recommended lifestyle changes to combat cardiovascular disease. But new research is showing these same strategies could help prevent dementia.
“We’re finding that what’s good for your heart is also good for your brain,” said Tatjana Rundek, M.D., Ph.D., professor of neurology and public health sciences and director of the Evelyn F. McKnight Brain Institute. “We found that individuals with high cardiovascular health, based on these metrics, have substantially reduced dementia risk.”
Christian Camargo, M.D., assistant professor of clinical neurology, presented on efforts to improve cognition with an oral multi-nutrient combination.
Tali Elfassy, Ph.D., assistant professor of medicine, presented the group’s research, showing that following the Essential 8 is indeed good for the brain. The team used data from 877 participants in the Northern Manhattan Stroke Study and assessed how their habits affected brain health. They showed that losing just 10 points on the study’s Essential 8 score increased dementia risk by 19%.
“We don’t generally associate diet, exercise, smoking and all the other things with both cardiovascular disease and dementia, but that’s what the data is showing,” said Dr. Elfassy. “We found that, overall, people with low cardiovascular health had a 200% increased risk of developing dementia compared to those who were more heart healthy.”
Detecting signs of Alzheimer’s in a Blood Test
Miller School researchers are part of a global effort to develop tests to identify molecules in blood that can help detect Alzheimer’s at its earliest stages. In this scenario, disease screening could be routine, as easy as measuring cholesterol or triglycerides.
There are several potential Alzheimer’s biomarkers that can be detected in blood, with phosphorylated tau, a key protein that is altered in the brain during Alzheimer’s disease, being one of the most promising. Early studies have shown that finding the protein in blood samples can differentiate between people with Alzheimer’s disease and their healthy counterparts.
“Our goal is to identify a relatively inexpensive, noninvasive approach with a highly accurate biomarker,” said Anthony Griswold, Ph.D., associate professor of human genetics and director of bioinformatics at the Hussman Institute. “We want to predict disease before people show actual symptoms, earlier than traditional diagnostic tests.”
To expand availability of these tests, Dr. Griswold and colleagues are researching the necessary infrastructure to give these tests wide reach, given that sample processing and storage can be challenging in underdeveloped regions.
Biniyam Ayele, M.D., a neurologist, DAWN principal investigator in Ethiopia and Miller School research fellow, presented work that showed samples can be successfully stored for up to 15 weeks at -20° C (-4° F), a bit colder than household freezers, paving the way to offer biomarker tests virtually anywhere. Previous studies had only tested at -20° C for two weeks.
Another issue is test generalizability. Many Alzheimer’s biomarkers were developed using data from exclusively European studies. It’s been an open question whether this strategy will benefit diverse groups.
“We mostly see the same trends in our data that others have seen in European data,” said Dr. Griswold. “For people with cognitive decline or Alzheimer’s disease, whether they are African, Caribbean Hispanic, or Peruvian, these biomarkers are still associated with disease, suggesting these tests will be widely applicable.”
Tags: Alzheimer's disease, Brain Endowment Bank, Center for Cognitive Aging and Neuroscience, Comprehensive Center for Brain Health, Dr. Anthony Griswold, Dr. Christian Camargo, Dr. James Galvin, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Lilah M. Besser, Dr. Magdalena Tolea, Dr. Margaret Pericak-Vance, Dr. Michael Kleiman, Dr. Stephanie Christophonte, Dr. Tali Elfassy, Dr. Tatjana Rundek, Evelyn F. McKnight Brain Institute, genetics, John P. Hussman Institute for Human Genomics, Lewy body dementia, neurology, neuroscience