Washington: For the first time, research has identified two; extremely rare genetic variants associated with Alzheimer disease (AD).
According to the findings appeared in the Journal of JAMA Network Open, the variants, one located in the NOTCH 3 gene and the other in the TREM 2 gene, were observed in persons with AD.
According to the researchers, the NOTCH 3 variant has not been implicated in AD in previous large genetic studies, however, other mutations in this gene cause a very rare form of dementia called cadasil.
Cadasil begins with severe headaches and strokes in young adulthood followed by dementia by midlife (decades before the typical age when late-onset AD occurs).
Other mutations in the TREM 2 gene have been associated with AD, and it was previously shown that persons who carry two copies of this particular mutation (referred to as Q33X) have a very rare disorder called Nasu-Hakola disease which is characterised by the onset of dementia in midlife and polycystic bone lesions with fractures.
Although the NOTCH 3 mutation causing AD is very rare in virtually all racial and ethnic groups, it is much more frequent in Ashkenazi Jews, and the researchers determined that nearly all of the AD cases with the NOTCH 3 mutation were of that descent.
“Our findings indicate that different mutations in the same gene or a different number of copies of a particular mutation may lead to very distinct forms of dementia,” explained Lindsay Farrer, corresponding author.”
“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 added.
These findings emerged from analyses of the entire DNA sequence for the portions of the genome that encode genes (called exons) of more than 5,600 participants with AD and nearly 4,600 cognitively healthy elderly controls.
DNA sequence data were generated by the Alzheimer Disease Sequencing Project and screened for variants that were present in persons with AD but not in the controls.
The researchers also showed that the study participants with AD compared to controls had a significantly greater burden of mutations in genes known to have a role in AD.
Farrer believes that if the findings of the NOTCH 3 mutation are confirmed in a large independent sample of Ashkenazi Jews, a diagnostic and predictive test for AD could be developed for that specific population.