Researchers at the Buck Institute for Age Research in Novato have made a discovery that could pave the way for the development of drug therapies to reduce the risk to individuals most likely to develop Alzheimer's disease.
The research is published this week in "The Proceedings of the National Academy of Sciences."
Dr. Dale Bredesen, founding CEO of the Buck Institute and a co-author of the paper, said it was previously known that ApoE4, a protein found in about 25 percent of the population, is present in about two-thirds of people who develop Alzheimer's. Until now, however, scientists weren't sure why ApoE4 was the most important risk factor associated with the disease.
The Buck Institute's new research has found a link between ApoE4 and another protein found in the body, Sirtuin T1, that is believed to slow the aging process. Research has demonstrated that the human Sirtuin T1 behaves similarly to Sir2, which has been found to extend the life span of yeast cells.
"What this does is establish for the first time a link between the major Alzheimer's gene and the major aging pathway, the Sirtuins," Bredesen said. "What we found, surprisingly, is that ApoE4 production leads to a marked reduction in Sirtuin T1."
The paper states that the reduction was seen both in brain samples from patients with ApoE4 and Alzheimer's, and in cultured neural cells.
Researchers had previously found ways of making Sirtuin T1 more active. Lifestyle choices such as getting plenty of exercise and sleep, minimizing stress and maintaining a healthy diet all seem to activate Sirtuin T1.
Also resveratrol, one of the ingredients of red wine, has been found to be a Sirtuin T1 activator. That has led to speculation that resveratrol may extend human life span.
"It is relatively unproved. There haven't been human studies with it yet," Bredesen said. Nevertheless, people all over the world are taking resveratrol.
Bredesen said, "But again, if your ApoE4 has made it so you have much less of the Sirtuin T1 around, you may not have as effective a response."
Now that the Buck Institute has demonstrated the link between Alzheimer's and reductions in Sirtuin T1, the goal is to find a way of maintaining Sirtuin T1 levels, despite the presence of ApoE4.
Bredesen said his research team has already identified two drug candidates that appear to do this. He said the team tested thousands of compounds to identify the two that block the effect of ApoE4.
"We're not ready to put them in a human yet," Bredesen said. "That is the next step, to see if they're safe and whether we could use them long term."
In a prepared statement, Rammohan Rao, a co-author of the study and an associate research professor at the Buck, said, "One of our goals is to identify a safe, nontoxic treatment that could be given to anyone who carries the ApoE4 gene to prevent the development of Alzheimer's."
Bredesen said, "Something that is nontoxic and benign that you could start to take when you are in your 20s."
Researchers must proceed with caution. Other studies have indicated that even though ApoE4 increases risk for atherosclerosis — or hardening of the arteries — in addition to Alzheimer's, it also has a positive affect. It increases the human body's ability to resist infections.
Contact Richard Halstead via e-mail at rhalstead@marinij.com[1]
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