The study, published in Genome Medicine, identified a genetic variant in high-risk people who showed no signs of the disease in old age. This genetic marker seems to have a protective influence and could potentially be targeted with drugs to decrease the risk of Alzheimer's disease.
'Instead of identifying genetic variants that are causing disease, we wanted to identify genetic variants that are protecting people from developing disease,' said lead author Dr Perry Ridge of Brigham Young University, Provo, Utah.
Past studies have tended to compare people affected by Alzheimer's with healthy controls, but the genetic factors identified this way have not yet resulted in effective treatment. Using a novel approach, this research focused on protective genetic variants which may be a plausible target for interventions.
The study focused on unaffected individuals within families with unusually high rates of Alzheimer's disease. The resilient individuals were cognitively healthy despite being at least 75-years-old, and carried a genetic variant strongly associated with increased risk of the disease, APOE e4. The researchers used whole genome sequencing and linkage analysis to look for genetic changes that were common among the healthy subjects but were not shared with the family members who developed Alzheimer's.
A variant of the RAB10 gene was discovered, which was present only in the resilient individuals. The researchers found that standard RAB10 is over-active in the brains of people with Alzheimer's, and that by deactivating this gene in mouse cells, there was a reduction in the amount of disease-related protein produced.
These multiple lines of evidence increase the understanding of the relevant mechanisms involved in the disease and point towards potential treatments. In the future, it may be possible to design drug interventions aimed at affecting the expression of this gene.
Alzheimer's disease is the most common cause of dementia and it is known to be highly heritable. The cost of caring for affected individuals is substantial and predicted to rise in the coming decades.
'There are currently no meaningful interventions for Alzheimer's disease; no prevention, no modifying therapies, no cure,' said Professor John Kauwe, senior author of study. 'The discoveries we're reporting in this manuscript provide a new target with a new mechanism that we believe has great potential to impact Alzheimer's disease in the future.'