Researchers have identified two extremely rare genetic variants linked to Alzheimer's disease (AD) for the first time, a new study of Boston University School of Medicine showed on Friday.
These variants, one located in the NOTCH3 gene and the other in the TREM2 gene, were observed in persons with Alzheimer's disease but not in any of the controls.
The findings, which appeared online in JAMA Network Open, emerged from analysis of the entire DNA sequence for the portions of the genome that encode genes of more than 5,600 participants with Alzheimer's disease and nearly 4,600 cognitively healthy elderly controls.
According to the researchers, the NOTCH3 variant has not been implicated in Alzheimer's disease in previous large genetic studies. However, other mutations in this gene cause a very rare form of dementia, called CADASIL. This disease begins with severe headaches and strokes in young adulthood, followed by dementia by midlife.
Other mutations in the TREM2 gene have been associated with Alzheimer's disease, and it was previously shown that persons who carry two copies of this particular mutation have a very rare disorder called Nasu-Hakola disease. The disease is characterized by onset of dementia in midlife and polycystic bone lesions with fractures.
"Our findings indicate that different mutations in the same gene or different number of copies of a particular mutation may lead to very distinct forms of dementia," said Lindsay Farrer, chief of the Biomedical Genetics division at Boston University School of Medicine, corresponding author of the study.
"Discovery of associations of Alzheimer's risk with rare genetic variants can lead to new insights about biological pathways involved in AD and strategies for developing novel treatments and biomarkers," Farrer said.
