TORONTO – A rare loss of function in a gene that influences gamma secretase trafficking has been found to reduce the risk of Alzheimer’s by up to 40%, even in people who are homozygous carriers of the apolipoprotein E (apo E) epsilon 4 allele.
The gene – Rab10 – is a member of a family of about 60 genes involved in intracellular protein transport, Keoni Kauwe, PhD, said at the Alzheimer’s Association International Conference 2016. In addition to influencing endocytosis, ciliary transport, phagosome maturation, and insulin transport, Rab10 appears to assist in the transport of gamma secretase to the cell membrane.
By studying a population of elders who appear resistant to developing Alzheimer’s, Dr. Kauwe of Brigham Young University, Provo, Utah, and his associates determined that many of them share a natural inhibition of Rab10 – a unique characteristic that strongly contributes to their resistance to Alzheimer’s, he said. This knocked-down function would decrease the amount of gamma secretase to reach the cell membrane, Dr. Kauwe reasoned. Therefore, the proteolytic pathway that creates amyloid beta (Abeta) should be attenuated, allowing much less amyloid beta to be created and, presumably, be around to initiate the amyloid cascade that sparks Alzheimer’s disease.
His study cohort was drawn from two large data sets of cognitively normal elders, including many who were apo E epsilon 4 homozygotes. About 5% of the sample showed the loss-of-function Rab10 variant, which Dr. Kauwe said conferred a 20%-40% risk reduction for developing Alzheimer’s disease.
To understand the gene’s effects on amyloid beta production, he both overexpressed it and silenced it in cell lines. Overexpression resulted in a significant increase in the Abeta42/Abeta40 ratio (a riskier Alzheimer’s profile), while silencing it resulted in a significant decrease in the Abeta42/Abeta40 ratio (a more favorable profile).
Rab10 could be a therapeutic target, similar to the PCSK9 gene that influences low-density lipoprotein creation, Dr. Kauwe said. Monoclonal antibodies that block PCSK9 have recently been developed after a similar observation that naturally occurring loss of functions in the gene was associated with lower LDL levels.
“We’re going to be looking at the same thing with Rab10,” he said. “We do think that Rab10 inhibition could be a big story. It’s a high-risk venture, certainly, but it could also be high reward.”
Dr. Kauwe discussed his findings in a video interview at the conference.
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