Identified two new genes that increases risk of Alzheimer’s disease

An international study in which researchers from the Dementia Neurobiology Group and the Memory Unit of the Research Institute of the Hospital de la Santa Creu i Sant Pau – IIB Sant Pau participated, leaded by Alberto Lleó, discovered two new genes associated with a significantly increased risk of developing Alzheimer’s disease.

The study, which has just been published in Nature Genetics, analyzes data from more than 32,000 complete genomes of Alzheimer’s disease patients and healthy controls. It’s the largest study of its kind in this pathology and that has been possible thanks to a collaborative effort by an international group led from the Amsterdam University Medical Centers, in the Netherlands; the Pasteur Institute in Lille and the University of Rouen Normandie, both in France, with the participation of the IIB Sant Pau as the only center in Spain.

The results of this work allow us to conclude that rare genetic variants in five genes: SORL1, ABCA7, TREM2, ATP8B4 and ABCA1, are associated with an increased risk of developing Alzheimer’s disease. “While this was already known for the first three genes, the finding that deleterious genetic alterations in ATP8B4 and ABCA1 can lead to Alzheimer’s disease had not been previously observed,” says Oriol Dols-Icardo, one of the authors of the study at IIB Sant Pau.

In addition, the researchers found that harmful mutations in a sixth gene, ADAM10, will most likely also lead to an increased risk of Alzheimer’s disease. However, the authors observed very few individuals with mutations in this gene, so this association will have to be confirmed by comparing an even larger population of Alzheimer’s disease patient genomes and healthy controls in order to classify ADAM10 as a “ Alzheimer’s gene”, explains Dols-Icardo.

Functions of these genes

All the genes identified in this study are involved in maintaining proper brain health, and deterioration of any of them is indicative of pathological processes associated with Alzheimer’s disease.

The previously discovered “Alzheimer’s genes”, which are SORL1, ABCA7 and TREM2, are involved in the processing of β-amyloid protein by neurons or in the brain’s immune system. Newly discovered genes go in this same direction. The ABCA1 gene maintains healthy cholesterol and phospholipid levels in brain cells and is associated with lower levels of amyloid aggregate protein, the accumulation of which in plaques is well known to be a hallmark of Alzheimer’s disease.

Like ABCA1, the (newly discovered) ATB8B4 gene is involved in phospholipid transport, primarily in immune cells in the brain. For its part, the ADAM10 gene plays a major role in the processing of the β-amyloid precursor protein, but in such a way that it prevents the formation of this protein. As explained by the IIB Sant Pau researcher, these identified genes, together, represent the molecular mechanisms that are most affected in Alzheimer’s patients, which helps to improve knowledge of the biological bases of the disease and puts on the table the possibility to investigate these genes as potential therapeutic targets.

It is estimated that between 60 and 80% of the risk of Alzheimer’s disease can be explained by genetic factors. In the case of early-onset disease (before age 65) this figure rises to more than 90%. Therefore, the single genome is postulated as a tool that could help to better stratify the risk of this disease in the future.

Reference article

Holstege, H., Hulsman, M., Charbonnier, C. et al. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nat Genet (2022). https://doi.org/10.1038/s41588-022-01208-7 DOI: 10.1038/s41588-022-01208-7