Two Rare Genes Associated with Alzheimer’s Disease.

Two extremely rare genetic variants are linked to Alzheimer disease, according to a new study co-authored by School of Public Health researchers.

The study, published online in JAMA Network Open, found the two mutations, one located in the NOTCH3 gene and the other in the TREM2 gene, only in people with Alzheimer’s disease. This is the first study to link these gene variants with the disease, although other variants in both genes have previously been linked to rare forms of dementia.

“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,” says corresponding author Lindsay Farrer, professor of biostatistics. “Discovery of associations of Alzheimer’s risk with rare genetic variants can lead to new insights about biological pathways involved in Alzheimer’s disease and strategies for developing novel treatments and biomarkers.”

Previous research has found that other mutations in the NOTCH3 gene cause a very rare form of dementia called CADASIL, which begins with severe headaches and strokes in young adulthood followed by dementia by midlife—decades before the typical age of late-onset Alzheimer’s disease.  Other mutations in the TREM2 gene have been associated with Alzheimer’s, and people who carry two copies of that mutation, Q33X, have a very rare disorder called Nasu-Hakola disease, which is characterized by onset of dementia in midlife and polycystic bone lesions with fractures.

For the current study, the researchers used data 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 Alzheimer’s disease and nearly 4,600 cognitively-healthy older adults. DNA sequence data were generated by the Alzheimer Disease Sequencing Project, a large NIH-funded initiative that emerged from the National Alzheimer’s Act of 2012, and screened for variants that were present in persons with Alzheimer’s but not in the controls.

The researchers found that study participants with Alzheimer’s had a significantly greater burden of mutations in genes known to have a role in the disease than the cognitively-healthy control participants.

Although the NOTCH3 mutation identified in this study 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 Alzheimer’s cases with the NOTCH3 mutation were of Ashkenazi descent.

If the findings about the NOTCH3 mutation are confirmed in a large independent sample of Ashkenazi Jews, Farrer says, a diagnostic and predictive test for Alzheimer’s could be developed for that specific population.

The study was co-authored by Xiaoling Zhang, assistant professor of biostatistics, and Kathryn Lunetta, professor of biostatistics. The other co-authors included Devanshi Patel, Jesse Mez, Jaeyoon Chung, John Farrell, and Michael Rynkiewicz of the School of Medicine.