Pauline Anderson

July 25, 2016

TORONTO — Researchers have identified a genetic variant linked to reduced risk for Alzheimer's disease (AD), even in individuals with other elevated genetic risks for the disease. This discovery, they believe, could have important implications for a therapeutic intervention.

The research, presented here at the Alzheimer's Association International Conference (AAIC) 2016, suggests that a variant of the RAB10 gene protects against AD.

RAB10 is known to have higher expression in AD cases than in controls and has been previously linked to functional effects on amyloid secretion.

This specific variant confers loss of function that improves resilience to AD and "provides us with a meaningful therapeutic target," study investigator Keoni Kauwe, PhD, associate professor, Department of Biology and Coordinator of the Bioinformatics Program, Brigham Young University, Utah, told a press briefing.

"This is not just another gene report," he said.

"Exciting, Promising"

Dr Kauwe and colleagues identified individuals from the Cache County Study on Memory and Aging who were older than age 75 years, carry at least one APOE4 allele, but remain cognitively normal.

They used the Utah Population Database, which, Dr. Kauwe explained, is a "unique combination" of Utah's medical records and the Church of Jesus Christ of Latter Day Saints genealogic records for the state's founders.

The database, which includes over 12 million individuals spanning more than 12 generations, "allows us incredible power for developing pedigrees for genetic research," said Dr Kauwe.

From this database, the researchers identified five pedigrees that exhibit an excess of AD mortality, several AD cases, and their AD-resilient relatives. Within each pedigree, some individuals have a unique genetic variant that helps them escape AD risk.

Researchers detected suggestive linkage in two pedigrees where DNA is shared between AD individuals. They used whole genome sequencing to "identify and prioritize variants" that could likely explain that linkage signal, said Dr Kauwe.

"We did this by looking at both quality control and biological impact of the variants."

They found variants that showed a protective effect on AD, but in a subsequent analysis, only the RAB10 variant was associated with significantly reduced AD risk in the Cache County study (odds ratio, 0.69; P = .028).

"So it showed a fairly significant, strong protection, even in the presence of E4 alleles and at a very elderly age," said Dr Kauwe.

The researchers then carried out a biological validation step. Dr Kauwe explained that elevated levels of amyloid β (Aβ)-42 relative to Aβ-40 are a "signature" of several mutations that are known to cause AD.

"So we hypothesized that higher expression of this gene would result in a bad amyloid β-42 to -40 ratio or a bad amyloid profile and that knockdown of this gene would result in an improved amyloid β-42 to amyloid β-40 ratio and therefore Alzheimer's risk profile."

To test that hypothesis, the research team overexpressed and knocked down the RAB10 gene in neuroblastoma cells from a mouse model and measured their amyloid production.

"We found exactly what we predicted — the individual cell lines that had the overexpression of RAB10had a negative Aβ 42-40 profile and those that had been knocked down had an improved profile."

The results implicate RAB10 as a potential AD resilience locus and suggest that reduced expression may result in resilience to AD via reduced Aβ-42.

Dr Kauwe called the results "exciting" and "promising."

"We have an opportunity as a field to develop protective variant targeted approaches that will hopefully facilitate faster movement from genetic research into actual translational work and clinical trials."

The RAB10 variant occurs in about 1% of the general population but at a higher rate in people with other genetic AD risks.

It might not take that long before testing of a therapeutic target gets under way. As an example, Dr Kauwe used PCSK9, a gene linked to high levels of low-density lipoprotein, a rare variant of which also causes a loss of function.

Within 7 years of discovering this genetic variant, drugs had been developed and were being used in patients, he said.

New Approach

This new research represents a new way of looking at AD therapies, said press briefing chair Mary Sano, PhD, professor of psychiatry, director of Alzheimer's Disease Research Center, and associate dean of clinical research, Mount Sinai School of Medicine, New York, New York, and a member of the Medical & Scientific Advisory Council, Alzheimer's Association.

"It's a way to look for treatments, pharmacological treatments, that might provide you with resilience as opposed to always looking for something that counters pathology," said Dr Sano.

The idea is that people who have a low representation of this variant are likely not to develop AD and that by targeting that biology "in the absence of the gene, one can still get the beneficial effects," she said.

"The concept is that when we identify the genetic variant, we have an opportunity to look for targets, medication that would modify those things that RAB10 controls."

Dr Kauwe and Dr Sano have disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2016. Abstract P2-158. Presented July 25, 2016.

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