Anti-cancer drug bexarotene (Tagretin), which had extremely promising results in reversing Alzheimer’s disease symptoms in mice last year, was found not to be as promising in later trials, according to articles published in the journal Science. In other words, scientists have not able to fully replicate the original findings.
Last year, researchers from Case Western Reserve University claimed that bexarotene cleared amyloid plaques from the brains of transgenic laboratory mice. None of the latest studies – carried out at the University of Chicago, Northwestern University, Massachusetts General Hospital, Washington University in St Louis and University of Tubingen in Germany – have been able to link bexarotene with the clearing of amyloid plaques in mice.
In 2012, Gary Landreth, PhD, and team had excited Alzheimer’s patients and caregivers desperate for bexarotene, even before human trials had started to determine its safety and efficacy.
Landreth and colleagues had found that bexarotene could reduce areas of beta amyloid plaques in transgenic mice by half within three days – it also improved cognition; the “Alzheimer’s” mice were seen to start resuming instinctive activities, such as nest-building.
Two teams managed to replicate results regarding lower levels of interstitial fluid beta-amyloid, which can build up in plaques.
Another team detected slight cognitive benefits among the genetically altered mice that expressed human APOE3 or APOE4 genes that were administered bexarotene.
However, none of the four teams was able to replicate a reduction in plaque burden, as occurred in the 2012 experiments.
MedPageToday quotes Dr. Robert Vassar, from Northwestern University, as saying “Anecdotally, we have all heard that physicians are treating their Alzheimer’s patients with bexarotene, (which can have]) severe side effects.” Dr. Vassar co-authored one of the new reports.
As scientists have been unable to replicate bexarotene’s plaque-lowering effects in animal experiments, it should not be used by doctors for the treatment of Alzheimer’s disease, Vassar added. In 1999, bexarotene was approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma (type of skin cancer). Once a medication is FDA approved, doctors can legally prescribe it “off label”, i.e. for other illnesses and conditions.
Dr. Sisodia said:
“We were surprised and excited, even stunned, when we first saw these results presented at a small conference. The mechanism of action made some sense, but the assertion that they could reduce the areas of plaque by 50 percent within three days, and by 75 percent in two weeks, seemed too good to be true.
We all went back to our labs and tried to confirm these promising findings. We repeated the initial experiments – a standard process in science. Combined results are really important in this field. None of us found anything like what they described in the 2012 paper.”
Senior author, Rada Koldamova, M.D., Ph.D., from the University of Pittsburgh, believes that her team’s findings make a solid case for continued exploration of bexarotene as a therapeutic treatment for Alzheimer’s disease.
Koldamova and team were examining transgenic mice that expressed human APOE4. APOE4 is the only known genetic risk factor for late-onset Alzheimer’s when the “promising” findings were released by the team at Case Western Reserve University were published in 2012.
“We were already set up to repeat the Case Western Reserve University 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.”
The Pitt team believe bexarotene works by reducing soluble oligomers, which are made up of toxic amyloid beta protein pieces, like the plaques are. Unlike the plaques, oligomers (which are made up of amyloid beta) can move.
Koldamova explained that they detected a considerable decrease in soluble oligomers. Maybe the oligomers are more dangerous for Alzheimer’s patients than the plaques. Koldamova added that the cognitive improvements that had been observed in the bexarotene-treated mice might not be related to amyloid beta – perhaps the medication works through a completely different, unknown mechanism.
Berxarotene has never been tested for Alzheimer’s treatment in humans, not even to determine its optimal dosage or best treatment duration.
Bexarotene has several serious side effects, including:
- liver function test abnormalities
- major blood-lipid abnormalities
- thyroid axis alterations
- weight gain
Written by Christian Nordqvist