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Rare Genetic Variants Tied to Alzheimer's Disease

April 11, 2019

By David Douglas

NEW YORK—Two rarely encountered genetic variants that already have roles in dementias also appear to be associated with Alzheimer's disease (AD), according to a large genetic study.

For example, as Dr. Lindsay A. Farrer told Reuters Health by email, "mutations in one of the genes (NOTCH3) had been previously implicated in a very rare form of dementia (CADASIL) that is characterized by severe headaches and strokes in early adulthood followed by a vascular-type dementia in midlife (at ages 40-55) which is well before typical Alzheimer's occurs."

Dr. Farrer, of Boston University School of Medicine, and colleagues analyzed data on whole-exome sequencing of 5,617 people of European ancestry with AD and 4,594 controls. They found a total of 24 variants with moderate or high functional impact from 19 genes in 10 or more participants with AD.

These variants were not seen in controls, the team reports in JAMA Network Open, online March 29. As well as missense mutation in NOTCH3, the researchers found four carriers of a high-impact mutation of TREM2.

Dr. Farrer noted, "The Alzheimer's-associated mutation we identified in the TREM2 gene had previously been implicated in another very rare type of dementia called Nasu-Hakola disease that is also an early-onset dementia accompanied by multi-focal bone cysts often leading to fractures particularly in the hands and feet."

"However," he added, "this dementia occurs when a person has a double dose of this particular mutation whereas the AD cases we identified had only a single dose."

Dr. Farrer further pointed out, "The carriers of the NOTCH3 mutation are unrelated but the mutation in all of them appears to be descended from a common ancestor. Further study of the genetic background of these subjects revealed that they are likely to be Ashkenazi Jews."

Findings from this study, he concluded, "may lead to the development of biomarkers, predictive tests and novel therapeutic approaches related to the mechanism(s) of action of the newly implicated genes."

Dr. Lon Schneider, who directs the Alzheimer's Disease Research Center at the University of Southern California, Davis, told Reuters Health by email, "The study provides further examples of the broad heterogeneity or variability of late-life cognitive impairment and Alzheimer's disease, how several uncommon mutations can be associated with different dementias and affect the development and expression of cognitive impairment."

Dr. Schneider, who was not involved in the new work, added that "there are multiple genetic, environmental, and biological determinants of Alzheimer's disease, not just 'one' Alzheimer's disease."

SOURCE: https://bit.ly/2VKBbJW

JAMA Netw Open 2019.

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