Found in the Finnish population, a rare variant of the TYROBP gene significantly increases the risk of Alzheimer’s disease, a new study led by the University of Eastern Finland shows. This gene variant affects the function of microglia, the cells which regulate inflammation in the brain. The findings further confirm the role of altered inflammatory response and protein stress response in the early stages of Alzheimer’s disease.

The Finnish disease heritage contains genetic disorders that are extremely rare elsewhere in the world. One such disorder is Nasu-Hakola disease characterized by bone cysts as well as personality changes and dementia starting between the ages of 30 to 40. In Finns, it is caused by a partial deletion in the TYROBP gene. The disease is recessively inherited, i.e., only manifesting if the deletion is inherited from both parents. However, it was previously assumed that monoallelic carriers, who inherit the deletion from one parent only, would not be affected. Now, the new study shows that carriers of the TYROBP deletion have a significantly increased risk of Alzheimer’s disease.

Alzheimer’s disease is the most common progressive memory disorder, with recent years seeing the discovery of several new risk genes. In the brain tissue, many of them are primarily expressed in microglia. Researchers have now shown, for the first time, that the monoallelic deletion in the TYROBP gene expressed in microglia is also associated with an increased risk of Alzheimer’s disease. The gene variant also led to an earlier onset of the disease, by two years on average, compared to individuals not carrying the deletion.

The association of the TYROBP gene with Alzheimer’s disease has not been observed before, because TYROBP variants are extremely rare globally. The deletion of the TYROBP gene occurs almost exclusively in Finns.

“The Finnish FinnGen project has compiled genetic and health data from half a million Finnish biobank sample donors, providing a unique dataset for our research," says Academy Research Fellow Henna Martiskainen of the Institute of Biomedicine at the University of Eastern Finland.

To explore the disease mechanisms, elderly asymptomatic individuals from the Biobank of Eastern Finland were recontacted for the study based on their genetic data. Cell models produced from blood samples of TYROBP deletion carriers and controls were used to investigate the effects of the gene variant. Cells from TYROBP deletion carriers and those with Nasu-Hakola disease showed a higher inflammatory response and a lower endoplasmic reticulum stress response compared to controls. The study suggests that while Nasu-Hakola disease and Alzheimer’s disease share some common biological mechanisms, they also have unique ones. Identifying these mechanisms can help in developing treatments for both conditions. The TYROBP gene produces a protein called DAP12 associated with the TREM2 signalling pathway, which regulates the function of microglia and is currently a focus of drug development for Alzheimer’s disease.

“With effective treatments for Alzheimer’s disease available in the future, people’s genetic background may influence the choice of treatment. Therefore, it is important to know the variants that predispose the Finnish population to Alzheimer’s disease and what is their mechanism of action. Our research also gives hope that some of the drug treatments being developed for Alzheimer’s disease could, in the future, also bring relief to patients with Nasu-Hakola disease,” Martiskainen says, summarizing the significance of the study.

“This study is a new opening in a continuum that is based on the pioneering work by Professor Panu Hakola, who first reported Nasu-Hakola disease, and other Finnish researchers over the years. In addition, the results highlight the importance of translational research, which combines basic research with clinical expertise, thus providing significant added value in elucidating the disease mechanisms,” Professor Mikko Hiltunen of the University of Eastern Finland says.

The study was conducted in collaboration between Kuopio University Hospital and Oulu University Hospital, and it constitutes part of research projects funded by the Research Council of Finland and the Sigrid Jusélius Foundation.