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.
Many unknowns
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.
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23 Comments
Add CommentWOW!! If this pans out this is big news.
Reply | Report Abuse | Link to thisWith 5.4 million people currently suffering from this horrible disease, sounds to me like they should move immediately to human trials.
If the drug is 13 years old, does that mean it will only be under patent for another 12, even if a new use is found for it? If so, that's potentially doubly-good news. The fact that it's already a well-tested drug should speed up the approval of human trials for Alzheimer's, or at least one would hope.
Reply | Report Abuse | Link to thisA quick correction - with ApoE, the allele of interest is ε4 (epsilon 4), not e4.
Reply | Report Abuse | Link to thisOf greater interest is whether amyloid β is actually the driver of AD pathology in humans. Even if having a lot of amyloid sludge in the brain is impairing memory in these mice, there is a healthy debate as to whether it is the driving force in the decades-long depletion of neurons which occurs in human AD. None of the mouse models are universally accepted as close analogies of the human disease - for starters, you have to load mice up with multiple genetic defects, each one of which triggers full-blown AD in humans, before they start to show any kinds of problems at all. Responding to the first comment, that's why they don't jump from a drug which affects a genetically damaged mouse, to trials on humans suffering a slow, subtle degeneration whose cause and mechanism are very poorly understood after decades of intensive study.
Sorry - looks like the Sci Am website can't handle standard unicode characters - please imagine epsilon and beta in place of those marks in the previous comment.
Reply | Report Abuse | Link to thisEven with it's uncertainties, this is still very promising. See what can be done when one scientist shares information with another scientist?
Reply | Report Abuse | Link to thisIts approved use if for T-cell lymphoma which has a fairly low incidence. Apparently some treatments involve topical application. I'd be very worried about off-label use presuming that the drug is "well studied" in humans. In other reports, I've seen bexarotene characterized as an "orphan drug."
Reply | Report Abuse | Link to thisIn reply to Bruce Byrne:
Reply | Report Abuse | Link to thisYou write: "...I'd be very worried about off-label use"
I guarantee you, this is way past "worry". A tsunami of off-label use is underway even as we speak. Friends, already in the grip of the Alzheimer's horror -- loved ones in their care, mostly -- are already in contact with their physician, saying, "Will you prescribe this drug, or do I have to find someone who will?"
Done deal. We'll know in a few weeks whether this works in humans or not. Predictably, there will be a lot of palaver about whether this is the right way to do science or medicine, but it won't matter. Anyone familiar with human desperation knows that, as the drug is available for purchase, no force on the planet will prevent its massive "unapproved" use.
Better bet: find the companies offering the drug for sale, and invest in them. Or start such a company yourself. Buy the stuff in bulk -- Chinese suppliers can be found on the internet -- and start "dealing" in the black, grey, and/or "white" market.
There'll be no external force stopping this flood. If the drug turns out to be ineffective, it will stop on its own. If effective, the medical community will quickly get on board. In reply to Bruce Byrne:
You write: "...I'd be very worried about off-label use"
I guarantee you, this is way past "worry". A tsunami of off-label use is underway even as we speak. Friends, already in the grip of the Alzheimer's horror -- loved ones in their care, mostly -- are already in contact with their physician, saying, "Will you prescribe this drug, or do I have to find someone who will?"
Done deal. We'll know in a few weeks whether this works in humans or not. Predictably, there will be a lot of palaver about whether this is the right way to do science or medicine, but it won't matter. Anyone familiar with human desperation knows that, as the drug is available for purchase, no force on the planet will prevent its massive "unapproved" use.
Better bet: find the companies offering the drug for sale, and invest in them. Or start such a company yourself. Buy the stuff in bulk -- Chinese suppliers can be found on the internet -- and start "dealing" in the black, grey, and/or "white" market.
There'll be no external force stopping this flood. If the drug turns out to be ineffective, it will stop on its own. If effective, the medical community will quickly get on board.
Undoubtedly medical tourism will soar as offshore clinics use this information to market to Alzheimer patients. Perhaps our testing regimen is too restrictive for those patients who are willing to accept the risks.
Reply | Report Abuse | Link to thisWhy not create a category of patient that waives ALL legal recourse?
ditto
Reply | Report Abuse | Link to thisTruly this disease is such a nightmare for us.Will other cancer drugs bring similar effects to the amyloid?Does it help in all kinds of Alzheimer's diseases with different causes?Anyways,good news though.
Reply | Report Abuse | Link to thisGiven the normal course of Alzheimer's I'm sure patients and carers/relatives would be willing to take a risk of toxix side effects from small explaoratory doses.
Reply | Report Abuse | Link to thisParkinson's disease is beleived to have a similar mechanism to Alzheimer's and mice with induced PD are widley used to test therapies. Has anyone tried bexarotene on them?
A subsatnce used to prebent amhylloidosis in arthriris patients is ATNF (Anti Tumour Necrosis Factor) but any frug to be used for neurological diseases has to pass the blood brain barrier and I'm not sure that ATNF would.
Apologies for the typos in my comment. I have PD and my typing, like my speech and my writing, is too fast.
Reply | Report Abuse | Link to thisYet even more good news for mice. The catalogue of 'complete complete breakthroughs' are filled with so many epic success stories its hard to believe rodents still die.
Reply | Report Abuse | Link to thisThose researchers with brains the size of mice or at a fairly advanced stage of Alzheimers will naturally say this is yet another complete breakthrough for anthropoids , and invariably there are plenty of people with more fear than sense. We do no need any more ineffective agents on this or any other market for the present thanks.
"Why not create a category of patient that waives ALL legal recourse?"
Reply | Report Abuse | Link to thisYou don't think there might be competence and consent issues in a population of patients with dementia?
Bexarorene/Targetin has been used for treating skin cancer for more than 10 years. Skins cancers are very common in older people so some of these patients must have some degree of dementia/Alzheimers disease too. Not that this is very scientific, but did anyone notice any improvment in their mental abilities? Pat
Reply | Report Abuse | Link to thisAmong the billions of people inhabiting earth, some must have both t-cell lymphoma and AD. Find them and test them?
Reply | Report Abuse | Link to thisAmong the billions of people inhabiting earth, some must have both t-cell lymphoma and AD. Find them and test them?
Reply | Report Abuse | Link to thisPithycus Among the billions of people inhabiting earth, some must have both AD and t-cell lymphoma. Find them and test them?
Reply | Report Abuse | Link to thisAmong the billions of people inhabiting earth, some must have both AD and t-cell lymphoma. Find them and test them?
Reply | Report Abuse | Link to thisPithycus
Among the billions of people inhabiting earth, some must have both AD and t-cell lymphoma. Find them and test them?
Reply | Report Abuse | Link to thisI’m not sure where you are getting your info, but good topic. I needs to spend some time learning much more or understanding more, read this : http://strepthroatsymptomsinfo.com/
Reply | Report Abuse | Link to thisI have read many positive results about the <a href="http://www.buy-bexarotene-online.com/" rel="nofollow">drug</a>. But the clinical trials for human are still on going and we will have to wait until 2020 for the drug to be approved by the FDA.
Reply | Report Abuse | Link to thisBexarotene has a great potential to be a treatment for AD.The progression of the studies is like a glue to a broken hope. It was also found out that bexarotene kills the first sign of AD and that is loss of sense of smell. It is also proven that it can improves memory deficits and behavior and acted to reverse the symptoms of Alzheimer’s. For more click <a href="http://www.buy-bexarotene-online.com/">here</a>
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