A large-scale international study, led by Danielle Posthuma and carried out by Douglas Wightman and Emil Uffelmann from Vrije Universiteit Amsterdam, offers new insights for understanding the disease and developing future treatments.
The research, published in Nature, sheds clearer light on the role of immune cells within the brain, as well as several specific neuronal cell types.
The scientists identified 127 regions in human DNA associated with the risk of developing Alzheimer’s disease - 48 of which had not previously been mapped in this context. These findings provide researchers with a deeper understanding of the biological processes that contribute to the onset of the disease and may aid in the development of new therapies.
For this study, the researchers analyzed genetic data from approximately 2.8 million individuals, including 183,620 people with Alzheimer’s. “This is the largest genetic association study on Alzheimer’s to date, bringing together data from individuals with diverse genetic backgrounds,” says first author Douglas Wightman.
Immune cells in the brain play a key role
A significant finding is that the results further underscore the role of microglia - immune cells in the brain involved in tasks such as clearing away harmful substances and damaged cellular material.
“We discovered new genetic evidence for processes related to the activation of these cells, the recruitment of immune cells, and the clearance of material within the brain. This helps us better understand how the immune system may contribute to the onset and progression of Alzheimer’s,” explains research lead Danielle Posthuma. In addition, the researchers identified genes linked to other key processes in the brain. For instance, there is evidence of involvement in the processing of amyloid - a protein that can accumulate in the brain in cases of Alzheimer’s - as well as in the repair of nerve cells. The researchers also discovered genetic associations with the activation of astrocytes (supporting brain cells) and the maintenance of the protective insulating layer surrounding nerve fibers.
Importantly, the study also reveals new insights beyond the immune system. For the first time, the researchers identified several specific types of neurons that are enriched for genetic signal and may play a key role in the development of Alzheimer’s disease. This opens up new directions for investigating how the disease develops.
"We already knew that immune processes play an important role in Alzheimer’s disease. What makes this study particularly valuable is that we can now connect new genetic risk factors to more specific biological processes, while also uncovering evidence pointing to the involvement of other brain cell types. This gives us a more detailed picture of the biology underlying Alzheimer’s and provides new directions for investigating potential treatments,” explains Posthuma.
Genetics plays a larger role than previously thought
The study also shows that common genetic variants (small differences in DNA that many people carry) contribute considerably more to Alzheimer’s risk than previously estimated. The researchers estimate that together these variants explain about 16 percent of the differences in Alzheimer’s risk between people. That is nearly three times earlier estimates of around 5 percent, which had led some to suggest there was little left to discover with this type of research. The higher estimate comes mainly from a statistical method that better accounts for APOE, a gene with an unusually large effect on Alzheimer’s risk.
“This shows that large genetic studies still have more to find than some assumed. But it is a population-level figure. It does not mean that 16 percent of any one person’s Alzheimer’s is caused by their genes, and it does not mean a genetic test can determine whether someone will develop the disease. Age, environment, and other biological and personal factors also play an important role,” explains co-first author Emil Uffelmann.
The researchers were also able to predict genetic risk better than earlier models. For now, this is mainly relevant for research. Whether and how such models might be responsibly implemented in clinical care in the future remains a subject for further investigation.
What do these results mean for future treatments?
Alzheimer’s disease is the leading cause of dementia. The number of people living with dementia is expected to rise sharply worldwide, with projections suggesting more than 150 million cases by 2050. Although genetic factors play a significant role in the risk of developing Alzheimer’s, it is not yet fully understood which specific genes and biological processes cause or influence the disease.
These new findings help researchers more precisely identify which genes and processes warrant further investigation. For instance, they can be used to develop laboratory models that allow scientists to study disease processes in greater detail, as well as to identify potential targets for new medications.
These genetic associations serve as a starting point rather than proof that targeting a specific gene will necessarily result in an effective treatment. Follow-up research is required to determine which of these identified associations play a causal role, and whether intervening in these processes is both safe and meaningful.
International collaboration as a foundation for progress
The scale of this study demonstrates the value of collaboration between academic researchers, biobanks, and industry. By pooling data from 30 research groups, the investigators were able to detect genetic associations that might have gone unnoticed in smaller-scale studies. The study was conducted under the umbrella of the international Psychiatric Genomics Consortium, whose Alzheimer’s disease working group is co-led by Posthuma and Ole Andreassen of the University of Oslo.
Furthermore, making these research results and the associated data available to the broader scientific community can accelerate future research. Other research teams can use these findings to test new hypotheses and further explore potential therapeutic targets. The researchers also emphasize the importance of continued investment in large-scale genetic research, with particular attention given to population groups that have thus far been underrepresented in scientific studies. This is essential for better understanding the results and ensuring that future insights and treatments are relevant to a broad range of people.