December 15, 2025
Alzheimer’s disease has long been a mystery—packed full of twists and tangles that slowly destroy a person’s memory until they are no longer the person we once knew—and we have barely begun to decipher it. Approximately 7 million people in the United States, and over 55 million people worldwide, live with this devastating disease, and nearly two-thirds of them are women.
Alzheimer’s disease is a neurodegenerative disorder characterized by the abnormal accumulation of amyloid-beta plaques and the formation of tau tangles in the brain. Although scientists know this process begins years—even decades—before symptoms appear, they still don’t know exactly what triggers it. Research has shown that there is likely an underlying genetic component to Alzheimer’s disease, but other factors such as environment and lifestyle are likely to also play a role.
How do amyloid-beta plaques and tau tangles cause Alzheimer’s disease?
Alzheimer’s disease occurs when a toxic form of amyloid proteins, called amyloid-beta, accumulate and form plaques around neurons and when tau proteins become damaged and form neurofibrillary tangles within neurons, in the part of the brain that controls memory (the neocortex and hippocampus). These plaques and tangles damage the neurons, causing them to die and triggering an immune reaction leading to inflammation in the brain.
There are two main forms of Alzheimer’s disease. Familial Alzheimer’s disease is a rare, hereditary form and sporadic Alzheimer’s disease is much more common. While some individual genes contribute to an increased risk for sporadic Alzheimer’s disease, such as APOE, studies have shown that multiple genetic variants are likely involved in disease development.
Emma Luckett, a data manager and postdoctoral fellow at the Department of Radiology and Nuclear Medicine, at the Amsterdam University Medical Center in the Netherlands, hopes to understand how genetic variants and epigenetic mediation may be influencing the early pathology of Alzheimer’s disease. Luckett is the winner of the 2025 Illumina Epigenetics Research Grant Contest. The grant will provide her with 1008 samples of the Infinium Methylation Screening Array-48 Kit, allowing her to go beyond genetics and investigate the potential epigenetic mechanisms underlying Alzheimer’s disease. Luckett is primarily interested in studying how DNA methylation may interact with genetic risk variants to affect amyloid-beta accumulation. She plans to use data from the AMYPAD cohort, a large pan-European cohort of 3,000 participants with an amyloid-beta PET scan. Many of the participants also have a structural MRI scan as well as genetic data, and Luckett spent two years harmonizing and integrating this data with data from the PET scans. The next logical step in her research is to perform methylation profiling on each available; however, she did not have funding to pursue this next phase of her research. That’s when Luckett came across the Illumina Epigenetics Research Grant Contest. “The grant is a really nice bridge between the genetic and the functional aspect of Alzheimer’s disease,” says Luckett. “The Illumina grant is key, because without that, it would just be an idea. This grant allows me to explore how genes may influence DNA methylation, and how DNA methylation may affect gene expression, which may then influence Alzheimer’s disease pathology.”
How does DNA methylation affect gene expression?
DNA methylation is a type of epigenetic modification that causes changes in gene function and gene expression without changing the DNA sequence. These modifications are thought to be triggered by environmental and lifestyle factors. In DNA methylation, a methyl group is added to part of the DNA sequence called a CpG site, which blocks the transcription process and inhibits gene expression.
She hopes that, once equipped with both genetic and epigenetic data, she can perform biological enrichment analysis and, ideally, uncover dysregulated biological processes in Alzheimer’s disease—opening possibilities for new therapeutic targets. But Luckett’s ultimate goal (several years down the line) is to identify a panel of genetic and epigenetic biomarkers that can help clinicians identify Alzheimer’s disease individuals early, before symptoms appear. These individuals would, in theory, still be cognitively healthy but would eventually accumulate toxic amyloid-beta and would therefore receive the largest benefit from an anti-amyloid treatment. Anti-amyloid drugs comprise most of the current FDA-approved and clinical trial drugs for Alzheimer’s disease.
“I think it’s important to understand how these methylation sites are interacting with our genetic variants to influence this disease,” says Luckett. “If we could find a combination of markers—genetic, transcriptomic, proteomic, and epigenetic—that are working together, we could develop a panel of markers in combination with already established markers, such as those from plasma, that could be used to improve clinical trial stratification.”
As with most research, there are limitations. The AMYPAD cohort is a pan-European cohort and, while the results may be generalizable to people of European ancestry, they will not be generalizable to non-European ancestries. “It’s important to acknowledge the lack of global generalizability,” says Luckett. “There will be limitations to our findings, but it doesn’t have to end there. We could collaborate with research groups that have participants from other ancestries to see if there are similar findings across other populations.”
Luckett hopes that down the road, her research will have a real impact for the 55 million people worldwide—and their loved ones—who are affected by Alzheimer’s disease.
