A genetic analysis of 2.8 million people points to specific brain cells that may influence Alzheimer’s, offering researchers new leads to investigate in the search for treatments.

Alzheimer’s disease is the leading cause of dementia, which is projected to affect more than 150 million people worldwide by 2050. Genes play a substantial role in Alzheimer’s risk, but scientists still do not fully understand which genes matter or how they influence the disease. Connecting those genetic clues to what happens inside the brain could help researchers identify possible targets for treatment.

An international team has now identified 127 regions of human DNA associated with Alzheimer’s risk, including 48 that had not previously been mapped in this context. The findings offer a more detailed view of the biological processes involved, pointing to roles for both the brain’s immune cells and several specific types of nerve cells.

Led by Vrije Universiteit Amsterdam and published in Nature, the research is the largest genetic association study of Alzheimer’s to date. Researchers analyzed genetic data from approximately 2.8 million people with diverse genetic backgrounds, including 183,620 people with Alzheimer’s.

Alzheimer’s clues point beyond immune cells

“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,” said research lead Danielle Posthuma of Vrije Universiteit Amsterdam.

The analysis strengthened the evidence for the involvement of microglia, immune cells in the brain that help clear away harmful substances and damaged cellular material. Linking genetic risk factors to the processes these cells carry out gives researchers more specific biological connections to investigate.

For the first time, the researchers also identified several specific types of neurons, the cells that receive and transmit information, that were enriched for genetic signals associated with Alzheimer’s. In other words, the genetic evidence pointed toward these particular cell types more often than expected. The findings suggest that they may play a key role in the disease’s development, opening research directions beyond the immune system.

Shared data expands Alzheimer’s genetic map

Pooling data from 30 research groups allowed the team to detect genetic associations that might have gone unnoticed in smaller studies. The collaboration brought together academic researchers, biobanks, and industry under the International Psychiatric Genomics Consortium. Its Alzheimer’s disease working group is co-led by Posthuma and Ole Andreassen of the University of Oslo.

Among the contributors was the University of Exeter-led PROJECT study. Professor Anne Corbett of the University of Exeter, who leads PROTECT, said, “This exciting new genetic analysis has uncovered new information on how our genes influence our risk of Alzheimer’s disease. We’re delighted that the PROTECT-UK study contributed to these important new findings. PROTECT collects genetic samples from all participants through a simple at-home saliva sample. This data can then be combined with cohorts from around the world to help us to better understand dementia risk and how it can be treated.”

The genetic associations provide starting points for further investigation, rather than proof that targeting a particular gene will produce an effective treatment. Follow-up research must establish which associations reflect a causal role in Alzheimer’s and whether intervening in the processes involved would be safe and meaningfully beneficial.