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by Gary Stix
The study also provides the most compelling evidence to date of how the biggest risk factor for Alzheimer's later in life—having the so-called Apolipoprotein E (APOE) gene, identified in the early 1990s—might yield a strategy for new therapies. The gene for apolipoprotein E comes in three versions, one of which, the e4 variant, confers a significantly higher risk of getting the disease—a roughly 60 percent chance at age 80 for those who carry a copy from both their mother and father, as against a less than 10 percent overall risk at that age in the general population. The gene variant, known informally as the Alzheimer's gene, is common: about 20 percent of the U.S. population has at least one copy. The e4 carriers may be vulnerable to Alzheimer's because they have a diminished ability to clear amyloid, a hypothesis that seems to be reinforced by this Case Western study.Jumping the gun?
That idea, though, is not universally endorsed. Some experiments have shown that the e4 version may also impair the brain in other ways, perhaps by bollixing the biochemical functioning at the synapses, the connection points between neurons, or by producing toxic fragments of the lipoprotein that damage neurons. If so, increasing the production of this form of apolipoprotein E could actually worsen the pathology of the disease and would complicate greatly bexarotene's development.
This potential hurdle does not dissuade one researcher experienced in Alzheimer's clinical trials. "I am not particularly concerned" about potential toxic effects of extra e4 production, says Paul Aisen of the University of California, San Diego, who heads the Alzheimer's Disease Cooperative Study, which organizes clinical trials for drugs to combat the illness. "If it significantly enhances amyloid clearance and reduces the burden of brain amyloid, there is a good chance it will succeed." David Holtzman, a prominent Alzheimer's researcher from Washington University in Saint Louis, echoes the sentiment about bexarotene's prospects: "I do think it is promising to go into humans."
Landreth and Cramer certainly think so. They have formed a company called ReXceptor Therapeutics that intends to begin a preliminary trial in humans in the next few months to determine whether the drug crosses the blood–brain barrier and clears amyloid, as it does in mice. If those processes occur, clinical trials on the drug's effectiveness in humans could begin even this year, and they would probably last from 18 months to three years. The drug loses patent protection for cancer this year, but Case Western has filed for patents for its use in Alzheimer's.
Despite their optimism, scientists say it's important not to overplay the progress. After all, drugs that work in mice do not necessarily help humans. Moreover, the genetically engineered version of mice used in this study do not recapitulate every aspect of the human disease. For instance, the mice do not experience the effects of dying neurons (despite having impaired cognition), and they do not go on to develop a hallmark characteristic of a later disease stage in humans—namely, the accretion of so-called tau proteins that seem to abet the killing of nerve cells. "Transgenic mouse experiments have not reliably predicted therapeutic effects in humans," Aisen says, "so caution is essential until human studies confirm target engagement," that is, the removal of amyloid plaques.
And bexarotene does not come without risk: it raises levels of triglycerides, blood fats implicated in cardiovascular disease and diabetes. The Case Western mouse work suggests that Alzheimer's patients may benefit with doses lower than those ingested for cancer treatment, which might produce less of an effect on fat levels. Whether the drug remains effective over time is another question. The levels of amyloid plaques—although not the apparently more toxic soluble form of the peptide—rose after 90 days, a suggestion that the drug may be metabolized differently after ingestion over long periods.
The enthusiasm generated for a mouse study stems from the desperation for new ideas as the number of Alzheimer's cases, now at 5.4 million in the U.S., is expected to more than double by the year 2050 as the nation's demographic profile continues to gray. A better understanding of the disease process—the knowledge that pathology begins 10 or 20 years before the first symptom—has shifted focus toward earlier drug trials. New technologies that combine brain imaging and spinal fluid tests might identify at-risk patients and test new drugs. A relatively inexpensive drug that can be ingested orally, such as bexarotene, could then be prescribed to at-risk but symptom-free patients, who would take them over the course of their lifetimes, like a cholesterol-lowering drug.
As ReXceptor moves forward with its clinical trial plans, it will inevitably have to contend with the demands of the families of Alzheimer's patients. Landreth emphasizes that calling your physician after reading an article like this one is a bad idea. "Don't try this at home," he cautions, "because we don't know we what dose to give, we don't know how frequently to give it, and there are a few nuances to its administration. So one shouldn't be prescribing it off-label." It is also unclear whether a drug like bexarotene would work at a middle or advanced stage of the disease, when neurodegenerative processes have already set in.
Bexarotene's genesis as an Alzheimer's treatment comes as an outgrowth of Landreth's long-time fundamental work on cell receptors. If it succeeds, it will demonstrate that new ideas for treating this seemingly intractable disease may come from beyond the sometimes narrowly focused strategies of large pharmaceutical companies.