Alzheimer's Drug Candidate Provides Benefits in Mice Without Clearing Amyloid Plaques

The cancer drug bexarotene has been shown to have potential as a treatment for Alzheimer's disease, at least in mice, but the latest research results show that it isn't working the way that researchers think it should. Incidentally, this sort of repurposing of an existing drug is a direct consequence of regulatory costs: it is so enormously expensive to go through the already excessive and expanding safety trials required by the US Food and Drug Administration for any new drug that companies prefer to eke out marginal benefits from existing drugs rather than work on building something new and better. This is one of the many ways in which the present state of medical regulation makes medicine worse.

[Researchers] reviewed previously published findings on the drug bexarotene, approved by the U.S. Food and Drug Administration for use in cutaneous T cell lymphoma. [They] were able to verify that the drug does significantly improve cognitive deficits in mice expressing gene mutations linked to human Alzheimer's disease, but could not confirm the effect on amyloid plaques.

[A] study was published last year stating that bexarotene improved memory and rapidly cleared amyloid plaques from the brains of Alzheimer's model mice expressing mouse Apolipoprotein E (APOE). Amyloid plaques consist of toxic protein fragments called amyloid beta that seem to damage neurons in the brain and are believed to cause the associated memory deficits of Alzheimer's disease and, eventually, death. Bexarotene is a compound chemically related to vitamin A that activates Retinoic X Receptors (RXR) found everywhere in the body, including neurons and other brain cells. Once activated, the receptors bind to DNA and regulate the expression of genes that control a variety of biological processes. Increased levels of APOE are one consequence of RXR activation by bexarotene.

"We were already set up to repeat the [study] to see if we could independently arrive at the same findings. While we were able to verify that the mice quickly regained their lost cognitive skills and confirmed the decrease in amyloid beta peptides in the interstitial fluid that surrounds brain cells, we did not find any evidence that the drug cleared the plaques from their brains." [Researchers] postulate that the drug works through a different biological process, perhaps by reducing soluble oligomers which, like the plaques, are composed of the toxic amyloid beta protein fragments. However, the oligomers are composed of smaller amounts of amyloid beta and, unlike the plaques, are still able to "move."

"We did find a significant decrease in soluble oligomers. It is possible that the oligomers are more dangerous than the plaques in people with Alzheimer's disease. It also is possible that the improvement of cognitive skills in mice treated with bexarotene is unrelated to amyloid beta and the drug works through a completely different, unknown mechanism."



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