How about a new drug concept for treating or preventing Alzheimer's disease?

Recent research published in the journal, Nature Aging, proposes an entirely new approach to preventing and/or treating Alzheimer's disease.  It uses bumetanide, an older diuretic drug, one that's been around since 1972, to change the way the APOE4 gene can influence the development of the disease.  Researchers have found that the drug can improve cognition in mice whose genes have been edited to create a condition similar to Alzheimer's disease in humans.  They also studied health records of populations of older people who had been on the drug over an extended period of time -- they had been on it for its diuretic properties -- and compared them to those who had not been on it.  They found that people who had been on the drug had a much lower incidence of Alzheimer's disease.  Very promising.

So how would this work?  Recall that the role of genes is to describe the design of perhaps 20,000 different proteins in the body.  Messenger RNA (mRNA -- now famous for its role in the new covid vaccines) carries the design information for proteins out of the nucleus to the ribosomes, where the proteins are constructed.  

Proteins from a variety of genes, including the APOE4 gene, can encourage inflammation in the brain and other factors that create an environment in the brain where Alzheimer's disease can begin and flourish.  Proteins produced by the APOE3 gene variant, however, still perform the same function as APOE4 but without promoting Alzheimer's disease.  While many genes are associated with an increased risk for Alzheimer's disease, the APOE4 gene is most strongly correlated with the development of "sporadic" Alzheimer's disease.  That's the common form that appears later in life, generally after age 65.  (You would know this if you read Beating the Dementia Monster.)

While all of the genes you have are contained the the DNA of virtually every cell in your body, not all genes are used to produce all of the proteins in every cell.  Some cells need certain proteins, and other cells need certain other proteins.  Therefore, there must be a process of "gene regulation" to turn genes on and off.  

There are also changes that can be made to the mRNA as it travels to the ribosome that will change what the final protein looks like.  What bumetanide appears to do is change the mRNA to promote the generation of a protein that works more like APOE3 than APOE4.  Hence it should reduce the risk of developing Alzheimer's disease.

So far so good.  We have an hypothesis and some limited evidence supporting it.  What's next?  Dr. Yadong Huang, one of the originators of this hypothesis, is proposing a drug trial to begin next year.  Since the safety profile of bumetanide is already well understood, I would assume they would be able to go straight to a phase 3 trial.

Would I want to take this drug?  It probably wouldn't work for me.  According to 23andMe, I have no APOE4 genes in my genome.  I got my Alzheimer's by a different route.  And bumetanide would probably only help people whose disease began with APOE4.