Rare variants of RAB10 gene could be key in Alzheimer’s disease resilience

In the last decade several genetic risk factors for Alzheimer's disease have been found by comparing cases with normal controls. Unfortunately discoveries of these gene variants have so far failed to lead to effective therapies. Now, in a research article published in Genome Medicine, researchers have taken the opposite approach by examining elderly people with a high risk of for Alzheimer’s disease who remain cognitively healthy. They find that rare variants in the RAB10 gene may provide protection from the disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia in the elderly; it is emotionally and financially devastating to those affected and their caregivers. The cost of caring for this deadly disease is projected to rise as high as $1.1 trillion by 2050 and yet there is not an adequate method to prevent, treat or cure the disease.

Genetic risk factors

It is known that genetics plays an important role in risk for Alzheimer’s disease, and having a parent or sibling with the disease increases your risk by about 3-fold.

Variants in the apolipoprotein E gene (APOE) are the strongest known genetic factors for Alzheimer’s disease. Extensive studies have demonstrated that APOE has three forms: e2 – a rare allele in the general population and is associated with the protection against developing the disease, e3 — the most common form in the population has a neutral effect on disease risk, and e4 — a moderately common allele that increases risk for by more than 5-fold per copy.

Nearly half of the genetic risk for Alzheimer’s disease remains unexplained.

In the last decade several other genetic risk factors for Alzheimer’s disease have been discovered by comparing cases to cognitively normal controls. To date these variants have not led to effective therapies and nearly half of the genetic risk for Alzheimer’s disease remains unexplained.

Genes protecting against Alzheimer’s

In a recent study, a team of researchers are tackling the problem from a different angle, asking why some elderly people that are very high risk for Alzheimer’s disease remain cognitively healthy. This strategy has led to the discovery of a protective genetic change that may provide important insights into therapeutic interventions.

To find protective mutations for Alzheimer’s, the scientists used two unique datasets from Utah: the Cache County Study on Memory in Aging and the Utah Population Database. The Cache County Study, which includes over 5,000 subjects over the age of 65 who have 15 years of longitudinal cognitive assessment, was used to identify individuals who exhibit Alzheimer’s disease resilience. This is defined as people who are cognitively normal, over the age of 75, and carry at least one APOE e4 allele. They then selected pedigrees from the Utah Population Database, which combines genealogical records with medical records for the original founders of the State of Utah and their descendants (over 6 million people and 12 generations).

The goal was to find families with above-average rates of Alzheimer’s disease that also had at least four people who were resilient to the disease and several relatives who died from Alzheimer’s disease. In other words, they were cognitively normal, despite being 75 years old or older, and had the APOE e4 allele. The key question was simple, “Do these resilient people have something unique in their DNA that is protecting them from Alzheimer’s disease?”

Both variants are rare and both genes (RAB10 and SAR1A) interact with amyloid precursor protein, which is thought to be key in the development of the disease.

The group found 5 families that matched the criteria and had DNA samples from Alzheimer’s patients and Alzheimer’s-resilient people. The team then found areas of the DNA that were shared among resilient members of the family and absent in those who had Alzheimer’s disease. They found plausible protective variants in two families. These variants where in the genes RAB10 and SAR1A. Both variants are rare and both genes interact with amyloid precursor protein, which is thought to be key in the development of the disease.

The researchers checked two separate datasets to confirm this finding, and found confirmation that the RAB10 variant was associated with reduced Alzheimer’s risk. To see how this variant might be protective, the scientists performed a series of experiments where they altered expression of RAB10 in neuroblastoma cells. Knockdown of RAB10 resulted in amyloid beta secretion patterns that are associated with protection from Alzheimer’s. Consistent with these findings and a possible role in the disease, the team also found that RAB10 expression was significantly higher in the brains of Alzheimer’s patients.

These results suggest that RAB10 may be an ideal drug target to prevent Alzheimer’s. It may be possible to reduce its expression or limit its activity in ways that could mimic the effect of the variant in resilient people. This could offer others the protection from Alzheimer’s disease that these resilient individuals have, leading to reduced rates of the disease.

Video abstract

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