An international collaborative study has led to the discovery of two new "Alzheimer's genes" and the detection of a third gene. A genetic alteration in one of these genes can lead to a significantly increased risk of Alzheimer's disease. The study was published Nov. 21, 2022, in the journal Nature Genetics.
The Cologne group around CECAD member Univ.-Prof. Dr. Dr. Alfredo Ramirez from the University Hospital of Cologne and the Faculty of Medicine, which was also involved, was responsible for the preparation and quality control of the German samples provided for this study.
"Beyond the novel AD genes, this manuscript also provides complementary and supportive information to the genome-wide association study published in April of this year in the sense that we have now identified coding variants in specific genes within genomic regions already named by the genome-wide association study. Typically, genomic regions identified in genome-wide association studies can contain multiple genes, making it difficult to name the correct gene. By using sequencing technologies, we can determine which genes within a genomic region might be causative for that particular locus," explains Prof. Ramirez, head of the Section of Neurogenetics and Molecular Psychiatry at the Department of Psychiatry and Psychotherapy at the University Hospital of Cologne and the Faculty of Medicine. Prof. Ramirez also conducts research at the CECAD Cluster of Excellence for Aging Research at the University of Cologne.
In collaboration with a large international group of researchers, more than 32,000 genomes of Alzheimer's patients and healthy individuals were compared. The researchers found that rare deleterious gene mutations in five genes, SORL1, ABCA7, TREM2, ATP8B4 and ABCA1, lead to an increased risk of Alzheimer's disease. While this was already known for the first three genes, the finding that deleterious mutations in ATP8B4 and ABCA1 can lead to Alzheimer's disease had not previously been observed. In addition, the researchers noted that deleterious mutations in a sixth gene, ADAM10, are also likely to lead to an increased risk of Alzheimer's disease. However, the authors observed very few individuals with genetic mutations in this gene, so a comparison of an even larger collection of genomes from Alzheimer's patients and healthy individuals is needed to classify ADAM10 as an "Alzheimer's gene."
Function of the genes
All of the identified genes are involved in maintaining brain health, and genetic impairment of these genes suggests processes that go awry in the brains of Alzheimer's patients. The previously discovered Alzheimer's genes SORL1, ABCA7, and TREM2 are involved in the processing of amyloid-β protein by neurons or the brain's immune system. The newly discovered genes go beyond this: ABCA1 maintains healthy cholesterol and phospholipid levels in brain cells and is associated with lower levels of aggregated amyloid protein. High levels of this protein are a hallmark of Alzheimer's disease. Like ABCA1, the newly discovered gene ATB8B4 is involved in the transport of phospholipids, particularly in immune cells of the brain. ADAM10 is also involved in amyloid-β precursor protein processing, but in a way that prevents amyloid-β protein formation. Taken together, the identified genes represent the molecular mechanisms most affected in Alzheimer's patients, providing targets for developing treatments.
Towards a future without Alzheimer's
An estimated 60 to 80 percent of Alzheimer's risk can be explained by genetic factors, and for early-onset Alzheimer's disease (age at onset < 65 years), this rises to more than 90 percent. Therefore, using each person's unique genome, it may become possible to identify individuals at increased risk of Alzheimer's disease before symptoms appear, so that personalized treatment strategies can be implemented in a timely manner in the future.
DOI: 10.1038/s41588-022-01208-7