The cancer medication bexarotene, aka Targretin®, made headlines when researchers reported that it quickly lowered Aβ in the brain, reduced amyloid plaques, and improved learning and memory in mice that mimic salient features of Alzheimer's disease (AD). Controversy grew when other groups reproduced only some, and in some cases none, of the data. Researchers in the AD field eagerly awaited the results of clinical studies, hoping they would clarify. Now, the first reports are coming in, and again, they are at odds about whether the drug will benefit AD patients.
In a small pilot study of 20 patients with AD, four weeks of bexarotene did not reduce plaque overall. However, brain imaging suggested that the drug slightly lowered these deposits in a subset of people who did not carry the ApoE4 allele, a genetic risk factor for AD. The authors propose that these results lay the groundwork for a larger Phase 2 trial.
Support for that idea comes from a case study of an AD patient in Belgium. Over 20 months on the drug, his memory stabilized. Amyloid imaging and analysis of his cerebrospinal fluid indicated little change in brain Aβ levels, however, leaving scientists to wonder whether bexarotene could benefit memory in a different way.
Unpublished results from a small pilot trial seem to support the idea that the drug leaves Aβ unchanged. Bexarotene increased ApoE in the brain, but had no effect on Aβ, at least over the short term. A rat study, too, found no effect of bexarotene on Aβ.
Some researchers plan to push ahead with further clinical trials, though others caution against this because of its side effects: Bexarotene can dramatically increase levels of triglycerides and cholesterol in the blood, driving up risk of cardiovascular diseases.
While researchers are at odds over testing bexarotene for AD, they also have no consensus yet on how it works. The drug was developed to activate certain nuclear receptors, but new researchers suggests it also has a totally different modus operandi. Bexarotene acts as a molecular spoiler, they say, preventing single molecules of Aβ from congregating into larger dimers, trimers, and oligomers that grow into the fibrils that make plaques. The work suggests that bexarotene not only helps clear those plaques, but stops them from forming to begin with. Could this explain any of the clinical results?
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