The Miller School at the Alzheimer’s Disease and Parkinson’s Disease International Conference 2026
The Miller School’s flurry of Alzheimer’s research at this year’s AD/PD Conference highlights a field pivot toward genetics, ancestry and natural protection.
Scientists from around the world gather each year at the AD/PD International Conference to share advances in the science and treatment of Alzheimer’s disease, Parkinson’s disease and related disorders. This year, the meeting landed in Copenhagen, and University of Miami Miller School of Medicine researchers arrived with a clear message: the Alzheimer’s field is increasingly treating APOE4 not only as a major genetic risk factor but as a promising therapeutic target.
With nine oral presentations, the Miller School’s John P. Hussman Institute for Human Genomics team delivered one of the conference’s most robust, single-team showings. Across the talks, researchers traced new clues in ancestry and natural protection that are helping refine how APOE (especially APOE4)-related biology might be targeted in future therapies.
“APOE is probably the top candidate we’re looking at for possible therapies now,” said Margaret Pericak-Vance, Ph.D., director of the John P. Hussman Institute for Human Genomics and the Dr. John T. Macdonald Foundation Professor of Human Genetics at the Miller School. “The APOE abstracts tie together what we know about APOE and its protective effects, identifying higher-risk populations. All these things are leading us to target APOE as a therapy.”
From Amyloid to APOE: A Shift in Alzheimer’s Research
For years, the field’s largest storyline centered on amyloid, while APOE4, discovered by Dr. Pericak-Vance in 1993, hid in plain sight. Later ancestry mapping work in her lab helped clarify that the APOE4-associated risk can be lower when the gene sits on an African background in the surrounding genomic region.
APOE has three common forms, APOE2, APOE3, and APOE4. APOE4 is the heavyweight. One copy significantly raises risk, and two copies virtually guarantee Alzheimer’s if you live long enough. Scientists have debated whether APOE4 causes harm because it is toxic or it functions less effectively. Jeffery Vance, M.D., Ph.D., professor and founding chair of the Dr. John T. Macdonald Foundation Department of Human Genetics, led a group of researchers showing APOE4 is toxic and a strong candidate for therapy.
“APOE4 was overshadowed for a long time by everyone pursuing amyloid,” Dr. Vance said. “Now APOE4 is the target.”
How Ancestry Is Unlocking Natural Protection Against Alzheimer’s
A key theme across the presentations is that, while APOE4 is identical as a protein across populations, the risk is not.
“Same protein, different risks,” Dr. Vance said. “We’ve shown the difference is driven by gene regulation, not changes in APOE4 itself.”
This turns ancestry into a scientific tool and suggests personalized medicine might be the answer.
“If we are developing therapies, they may not be the same for everyone,” Dr. Vance said.
A Genetic Roadmap to New Therapies
Together, the talks traced a path from gene discovery to mechanism to therapeutic logic.
A protective region
One of the team’s most consequential findings involves a protective genetic segment they identified about 2 million base pairs away from APOE4 on African ancestry backgrounds. In people with two APOE4 copies, the region is associated with roughly a 75 percent reduction in Alzheimer’s risk.
“It’s a monumental study,” Dr. Pericak-Vance said.
Luciana Bertholm Nasciben, Ph.D., a Miller School assistant scientist, used the conference to discuss her work using long-read DNA sequencing.
“Because the region sits in a complex stretch of the genome, I used long-read DNA sequencing to capture longer stretches of DNA and reconstruct the area more accurately. We identified several unique insertions that were inherited with the protective allele, suggesting further research is needed to understand their importance and function,” said Dr. Bertholm Nasciben.
“Understanding this protective change could inform therapies for everyone,” Dr. Vance said.
ABCA7 and lipids
Several presentations focused on ABCA7, a gene involved in lipid metabolism, because lipid metabolism affects how APOE functions. Hussman Institute investigators have previously shown that a 44 bp deletion, found only in African ancestry, is associated with Alzheimer’s, though some older carriers are still cognitively normal. Several talks focused on ABCA7.
YounJi Nam, Ph.D., a Hussman Institute assistant scientist, discussed his findings that the ABCA7 deletion disrupts how neurons manage key fats, especially ceramides. This could help explain its link to higher Alzheimer’s risk and suggest lipid pathways as treatment targets.
Assistant scientist Oladotun V. Olalusi, Ph.D., provided a talk demonstrating that a known protective variant in ABCA7 has a stronger protective effect when found in deletion carriers.
“The deleted protein is stable in the cell’s membrane and the protective SNP lies in the same part of the saved protein. This suggests an strong protein interaction and could provide insight into the mechanism of how ABCA7 contributes to AD risk,” said Dr. Olalusi.
Modeling human brain cells
The Hussman Institute’s Aura Ramirez, Ph.D., described the use of adult blood cells from people with African, European and Peruvian ancestries to generate induced pluripotent stem cells (iPSC) and build complex brain-like cell models. Comparing regulatory mechanisms across ancestries, researchers also identified evidence of early differences in brain cell features among APOE4 carriers, suggesting some changes start very early in life.
“It raises questions about when therapy should begin,” said Dr. Ramirez.
Peru and genetic history
Through a collaboration in Peru, Bilcag Akgun, MD, Ph.D., reported a higher risk for Alzheimer’s in Amerindian carriers of APOE4.
“This surprised us,” Dr. Akgun said, whose research team also found a rare mutation linked to Alzheimer’s risk that had previously been seen mainly in Asia. “These findings are interesting, as the risk for AD from APOE4 is highest in Asians, implying that the risk may have traveled from Asia through the Bering Strait during the migration of humans into South America.”
Methylation signals in APOE4 carriers
In the MAGENTA project, the Anthony J. Griswold, Ph.D., associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and associate director of the Hussman Institute Center for Genome Technology, and collaborators analyzed whole-blood DNA methylation profiles from more than 600 people across global populations to study ancestry-related variation in Alzheimer’s biology.
“This analysis suggests whole-blood DNA methylation patterns may be ancestry-specific signatures of Alzheimer’s,” said Dr. Griswold. “However, there remain overarching convergences of molecular pathways, highlighting the importance of the study of multi-ancestry individuals for a comprehensive understanding of epigenetic risk for Alzheimer’s.”
Hypertension’s effect on APOE4
Postdoctoral researcher Daniel Dorfsman, Ph.D., and Farid Rajabli, Ph.D., an assistant professor of human genetics at the Miller School, highlighted an actionable risk factor for AD — hypertension.
“APOEε4 risk is significantly worsened by the presence of hypertension, reflecting an interactive rather than additive effect,” they noted. “That is, the effect of the two together is greater than expected if one added the individual risks of each together. Among APOEε4 carriers, rigorous blood pressure control emerges as a particularly important clinical factor to monitor to slow cognitive decline.”
APOE3 may not be neutral
APOE3 has always been used as the “neutral” allele to compare the protective effect of APOE2 and the risk affect of APOE4. Assistant scientist Sofia Moura, Ph.D., reported her findings on the expression of APOE3 and APOE4 in different ancestries.
“We found that the expression of APOE3 is actually higher in African ancestry, opposite of APOE4 expression, which is lowest in African ancestry,” Dr. Moura said. “Thus, the regulation of the two alleles do not behave the same way across ancestries. Differences in these expression patterns suggest neutrality assumptions might oversimplify biology in diverse populations.”
Not all APOE4 risk is equal
Finally, Olabode E. Omotoso, a senior research associate, presented findings from the Hussman Institute-led DAWN Alzheimer’s Research study, including data from 10 African countries and U.S. partners. The findings suggest that APOE4-related Alzheimer’s risk is not the same across Africa and appears to vary by region. East African groups showed the lowest observed risk. West African groups showed relatively higher risk.
“This is exciting because it’s a major step toward large-scale genetic understanding across Africa and helps refine what we think we know about APOE4 penetrance,” Dr. Pericak-Vance said.
With the Alzheimer’s clinical trials historically failing at a rate near 99 percent, researchers are increasingly looking to natural protective effects as a path forward.
“Protective effects can be powerful tools,” Dr. Vance said. “If something is naturally protective, it likely has minimal side effects and works biologically. We just need to understand why they work.”
More from the Hussman Institute
A University of Miami study shows how an ancestry‑specific ABCA7 gene deletion disrupts lipid metabolism, increasing Alzheimer’s disease risk.
Miller School of Medicine researchers are examining the genetic roots of inflammatory bowel disease in Hispanic populations.
A new Miller School study explores how two genes influence the age at onset of Alzheimer’s disease in individuals of African ancestry.
Researchers from the John P. Hussman Institute for Human Genomics taught the wonders of DNA to children at the Miami Children’s Museum.
Tags: Alzheimer's disease, brain health, cognitive decline, Comprehensive Center for Brain Health, 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, John P. Hussman Institute for Human Genomics, neurology