Abstract
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Using an unusual approach that combines linkage analysis, whole–genome sequencing (WGS), and biological studies, researchers have found evidence for a new genetic variant (in the gene RAB10) that may be protective against Alzheimer's disease (AD). Scientists at Brigham Young University (BYU), led by John S. Kauwe, Ph.D., published results of the study in Genome Medicine in November. The study aims to help explain why some patients with a family history of the condition and carrying an APOE ε4 allele live long lives without showing symptoms of the disease. Kauwe is an associate professor of biology at BYU.
“We did not expect to find RAB10 variants implicated,” said Kauwe. But the group prioritized that gene in their study because other findings had suggested it could play a role in AD, specifically in the rate of amyloid beta production, which is thought to be a key process in progression of the disease. New evidence for how AD progresses is sorely needed. “If you look at the landscape now, variants for late–onset Alzheimer's are spread out across inflammation, endocytosis, the immune response, and cholesterol regulation,” said Kauwe.
The new finding from the BYU team adds to a growing list of variants implicated in the development of AD or protection from it. The paper also describes a potentially powerful new approach for uncovering functional variants in AD, which are the most attractive targets for drug discovery. “The goal of Alzheimer's genetic studies is to generate drug targets,” noted Gerard Schellenberg, Ph.D., principal investigator of the Alzheimer's Disease Genetics Consortium, which is the largest sequencing project focused on AD. He is also head of the Penn Neurodegeneration Genomics Center at the University of Pennsylvania Perelman School of Medicine.
Advanced age and carrying the APOE ε4 allele are both major risk factors for AD, but people with these characteristics can still live well beyond 75 without ever showing AD symptoms. In searching for protective variants, part of the challenge is how to define “resilience” said Rudolph Tanzi, Ph.D., professor of neurology at Harvard University, and director of the Genetics and Aging Research Unit at Massachusetts General Hospital. His group does its studies on the brains of people who died while deemed cognitively normal, but still had a lot of the plaques and tangles that are typically in people who have died of AD. But, as he points out, those brains are “hard to come by. “
The BYU team defined people as “AD resilient” if they were at least 75 years old, cognitively normal, and carried at least one APOE ε4 allele. Having one or more of those alleles, Kauwe explained, can increase a person's risk of AD by five to 12 times. The “resilient” patients were evaluated multiple times. “They had to be normal from their first through their final cognitive assessment to be defined as resilient,” Kauwe added.
In this study, the researchers used a pedigree-based approach. They started by performing linkage analyses among families with a “statistical excess” of AD mortality but which also included at least four individuals with an APOE ε4 allele who lived to advanced age without clinical symptoms of cognitive decline. The study ended up including data from more than 200 subjects. They next used WGS to look for candidate variants.
The BYU team found promising variants in RAB10 and SAR1A, and did further analysis of both. They ultimately concluded that Rs142787485 in RAB10 appears to confer significant protection against AD and thus could be a promising target for AD-related drug development. Kauwe noted this result needs to be further replicated. But the team also tested two independent populations to see if its findings held up. In addition, the team performed lab tests to further corroborate their results and demonstrated experimentally that RAB10 knockdown results in significant decrease in Aβ42 and in the Aβ42/Aβ40 ratio in neuroblastoma cells. RAB10 expression is also significantly elevated in the brains of former AD patients.
The families studied came from the Utah Population Database (UPDB). This is a unique resource that includes the computerized genealogy of Utah pioneers and their descendants and is linked to other state health data repositories including death certificates, which have listed AD as a cause-of-death since 1979. More than 8 million people are included in the UPDB, and for 2.5 million of them, the database has three generations of genealogical data. Over a million of these people have at least a dozen of their 14 immediate ancestors in the database.
“We don't know if they were resilient because of resistance to the pathology or if they were just asymptomatic,” Kauwe said. “But in any case, they were living cognitively normal lives.” The search for variants that impact risk of AD has been long and tortured. Most genetic variance between people who suffer from AD and those who don't is not explained by known markers. The markers identified to date are not diagnostic, and not much is known about how they impact biological pathways implicated in AD. These issues have fueled the search for new variants and for further understanding of their biological impacts. It has also led to innovation in study design because AD is such a difficult disease to research, in part because it cannot be diagnosed until after death.
Researchers in the Kauwe Lab at BYU discovered a genetic variant that can protect some people from developing Alzheimer's disease despite the presence of the APOE ε4 allele and a strong family history of developing the disease.
Rudolph Tanzi, professor of neurology at Harvard University, and director of the Genetics and Aging Research Unit at Massachusetts General Hospital.
Variants that either heighten risk or protect agains, described so far, include some in APP, APOE, PLD3, and TREM2. Given the amount of study that has already gone into this topic, it is expected that any further such variants will be relatively rare, but it is still important to map out as many as possible.
Multiple large-scale AD sequencing projects are currently in the works, and papers announcing their results are expected soon, making this a time of great anticipation in AD research.
“At the end of the day we are going to end up with several dozen genes that either increase risk or are protective,” says Tanzi. “I would not be surprised if it ends up being as many as 100.”