A drug that is already approved by the FDA for treating a rare skin cancer greatly reduces brain levels of Alzheimer’s-associated amyloid beta (A-beta) protein in mouse models. The drug, bexarotene, works in the mice by boosting the activity of apolipoprotein E, a fat-carrying molecule that normally helps to clear A-beta from the brain (see “Why Does apoE4 Make Alzheimer’s More Likely?”). If bexarotene’s A-beta clearance effect in mice translates to humans, then it may prove useful against Alzheimer’s—though perhaps more as a preventive than as a treatment for established Alzheimer’s dementia.
“This is quite an exciting paper; the effect on A-beta clearance is dramatic and rapid,” says Sam Gandy, who chairs the Alzheimer’s research program at Mount Sinai School of Medicine.
“The drug reduces the soluble forms of A-beta within hours,” says Paige Cramer, the PhD student who was first author of the paper. Cramer works in the laboratory of Gary Landreth, director of the Alzheimer’s Research Laboratory at Case Western Reserve University School of Medicine in Cleveland, Ohio, and principal investigator for the study, which appears today in Science Express.
The study is based on observations, going back to the early 1990s, of a strong connection between Alzheimer’s and apolipoprotein-E (apoE). Researchers have found that apoE proteins normally bind strongly to A-beta, and that apoE4, one of the normal variants of apoE in the population, is linked to a much higher and earlier risk of Alzheimer’s.
Recently scientists have determined the likely reason for the connection: A-beta aggregates, which have a high affinity for fat molecules, normally cling to the fats carried by apo-E molecules, and in this way are brought into, and disposed within, immune-type cells in the brain called microglial cells. ApoE4 is comparatively inefficient at handling fat molecules, and so it does a poorer job of removing A-beta aggregates. Regardless of which apoE variants a person has, boosting apoE production should enhance the clearance of A-beta from the brain—mainly because more apoE means more A-beta-carrying capacity. ApoE production also seems to stimulate the readiness of microglial cells to digest A-beta aggregates.
Bexarotene, a drug approved by the FDA in 2000 for cutaneous T-cell lymphoma, binds and activates the retinoid X receptor, a protein that in brain cells happens to be involved in promoting apoE production. Since bexarotene can cross from the bloodstream into the brain, Landreth reasoned that it might work as an apoE-boosting, A-beta-clearing drug.
In the new study, he and Cramer and their colleagues tested it on “Alzheimer’s mice” that had been genetically engineered to overproduce aggregates of A-beta. Such mice, as they age, show subtle cognitive deficits – which are presumed to be caused by small, soluble “oligomer” aggregates of A-beta. The team found that within only a few days, a modest daily dose of the drug reduced soluble forms of A-beta in the mouse brains by about one-third, compared to control mice, and reduced insoluble A-beta deposits, or “plaques,” by about half. They observed microglial cells stuffed with A-beta, as well as increases in the levels of proteins that normally work with apoE. In mice that lacked apoE, these A-beta clearing effects did not occur. The treated mice showed immediate improvements in standard memory tests, suggesting that the drug quickly reduced brain levels of toxic A-beta oligomers.
Because the drug is already FDA-approved, its safety is already mostly known. “For skin cancer treatment, patients are often on bexarotene doses that are far higher than [the human equivalent of] the dose that we used in mice, and for long periods,” says Cramer. Long-term use of bexarotene can raise triglyceride levels and have other potentially dangerous side-effects, but Cramer says that such side-effects are generally treatable with other drugs, and bexarotene is tolerated by most cancer patients.
Cramer says that she and Landreth are forming a company and hope to set up clinical trials of bexarotene against Alzheimer’s. Even without such trials, neurologists in the U.S. could legally prescribe the drug “off-label” to people with Alzheimer’s, since bexarotine is already approved by the FDA.
However, the drug may not work well in those who already have Alzheimer’s dementia. The current thinking about Alzheimer’s is that most of the dementia is caused by the spread of neuron-killing aggregates of tau protein in the brain. This “tauopathy” process seems to be triggered by the initial, slow spread of harmful A-beta aggregates, but, once started, it probably can proceed on its own even if the A-beta aggregates are removed by bexarotene or other treatments.
“You would want to intervene [with a drug such as bexarotene] before the tauopathy phase begins,” says Gandy, although he adds, “I don’t think we can assume that it would only help presymptomatic patients until we actually do a trial.”
Finding people who are still a few years away from developing tauopathy and dementia would mean, in effect, diagnosing them using PET brain scans of A-beta deposits, and cerebrospinal fluid tests for A-beta and tau aggregates, or other “biomarkers.” A shift towards early diagnosis is already a major priority for the research community (see “Alzheimer's Prevention Trials Set to Start in 2012”) and could be accelerated by the availability of such a promising drug. Cramer and Landreth want to use early-diagnostic biomarkers in any initial clinical trial of bexarotene. “Obviously the earlier [the treatment] the better,” she says.
In principle, a drug that strongly clears harmful forms of A-beta could give clinicians a several year window to treat patients newly diagnosed as high risk — “during which we might be able to clear away amyloid completely,” says Gandy—and thus delay dementia indefinitely. The approach might turn out to be particularly useful for people who have the apoE4 variant or a strong family history of Alzheimer’s. On the other hand, many other laboratories and companies are developing Alzheimer’s drugs, and by the time pre-dementia diagnosis of the disease becomes widely used, there may be safer, cheaper, and more effective options than bexarotene.