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Vitamin E for Alzheimer’s

Recently you may have seen headlines like “Vitamin E slows decline in patients with mild Alzheimer’s” or “There’s still no cure for Alzheimer’s disease, but the latest hope for slowing its progression is already on drugstore shelves.” They were referring to an article in the January 1, 2014 issue of the Journal of the American Medical Association (JAMA) announcing the results of the TEAM-AD VA Cooperative Randomized Trial of vitamin E and memantine (Namenda) for Alzheimer’s disease (AD).

The study attracted a lot of media attention. Most of the news reports I have seen were accurate and cautious, explaining the nuances of the study rather than suggesting that everyone should run out and buy vitamin E; but I wouldn’t be surprised to learn that a lot of readers ignored the fine print and did just that. It would be interesting to track sales of vitamin E and see if there was a bump following the publicity.

We know of no treatment that will delay, prevent or cure Alzheimer’s disease, or that affects the underlying disease process. It’s a tragic, frustrating disease that takes away the very things that make us who we are: memory and personality. It is affecting more and more people as the numbers of elderly increase. Available prescription medications are only modestly effective in slowing functional decline and delaying the need for institutionalization. They are expensive, they don’t help everyone, and when they do help, they only help for a limited time. It is very exciting to think an inexpensive vitamin could help patients with mild to moderate AD, but we must resist the temptation to read too much into this study.

Study design

The study was a large, rigorous, multicenter randomized placebo-controlled trial with 33 authors, carried out at 14 Veterans Affairs (VA) medical centers. It enrolled 613 patients age 53 to 96 with a diagnosis of possible or probable AD of mild to moderate severity who were already taking an acetylcholinesterase inhibitor (AChEI). 65% were on Donepezil, 32% on Galantamine, and 3% on Rivastigmine); 97% were male, 86% were white, 13% black, and 11% Hispanic. (Note: these were classified as possible or probable cases, since definitive diagnosis of AD is only possible at autopsy.)

Participants were randomized to one of four groups:

  • Alpha tocopherol (vitamin E) 1,000 IU twice a day + memantine-matching placebo
  • Memantine 10 mg twice a day + vitamin E-matching placebo
  • Both vitamin E and memantine
  • Two placebos

Primary outcome measure was the Alzheimer’s Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL), a validated questionnaire that assesses functional abilities to perform activities of daily living. A difference of 2 points on this scale is generally considered significant because it potentially represents, for example, a loss of dressing or bathing independently. Secondary outcome measures included tests of cognitive function and dementia severity, memory, language and praxis functions, assessment of psychological and behavioral problems, the time required for caregivers to assist patients in major areas of daily activities, and a measure of functional dependence.

Annual assessments included physical exams, review of concomitant medications, blood concentrations of the study drugs to assess adherence, and careful questioning about adverse experiences. 42% of subjects failed to complete the trial, most commonly due to death (50%), withdrawal of consent (30%) and adverse events possibly related to the study medication (1%). Mean follow-up time was 2.27 years.

Findings

All participants got worse over the period of the study. Subjects in the vitamin E group had a significantly slower decline than those in the placebo group (3.15 units less on the ADCS-ADL Inventory, annual rate of decline 19% less, delay in progression of 6.2 months). There was no significant difference between the placebo group and the memantine or memantine + vitamin E groups. The group taking both vitamin E and memantine did significantly worse than the group taking vitamin E alone.

Adherence was estimated at 65-68%, which isn’t all that bad considering the age of patients and the effects of Alzheimer’s.

Secondary outcomes showed no significant differences between the four groups except that caregiver hours increased less in the vitamin E group than in the memantine group.

Safety: there were no significant differences between groups for serious adverse events. The annual mortality rate was 7.3% for vitamin E, 11.3% for memantine, 9% for vitamin E + memantine, and 9.4% for placebo.

Discussion

They concluded that 2,000 IU of vitamin E significantly delayed clinical progression in activities of daily living in patients with mild to moderate AD who were also taking AChEI. Paradoxically, the combination of memantine and vitamin E had less effect than either drug alone; the authors could not think of a plausible mechanism for this finding. No significant changes were seen in cognition or memory, but the researchers considered the 6.2-month delay in progression of functional loss to be of more practical importance. Mortality rate was reduced with vitamin E, in contrast to a previous meta-analysis of vitamin E studies that had showed an increase in all-cause mortality with doses typically lower than the 2,000 IU used in this study. Interestingly, only one study in that meta-analysis involved Alzheimer’s patients, and that one also showed a decrease in mortality.

Editorial

An accompanying editorial praised the study as reflecting the best in trials of AD therapy, especially because of its size, duration, and separation from commercial motivation; but it characterized the therapeutic effect as “modest” and more relevant to functional disability than to any effect on the disease process itself. They pointed out that functional ability is non-specific (decreasing with age as well as with disease), that the primary outcome was not confirmed by any of the secondary outcomes, and that the mechanism of vitamin E in AD is uncertain. Memantine is only approved for moderate to severe AD, and this study confirms that it is not indicated for milder disease. The results for vitamin E are encouraging, but can’t be extrapolated to situations other than the specific ones in the study.

Another opinion

An ND quoted on one website said “This new study demonstrates that scientists seeking to slam the door on vitamins, and new vitamin research, is the antithesis of what science is all about.” He is responding to a straw man. Several recent studies and editorials have discouraged indiscriminate use of multivitamins in healthy populations, especially as a substitute for a nutritious diet. But no one has recommended we stop studying individual vitamins for new indications where there is preliminary evidence that they might be helpful in specific populations or diseases.

Conclusion

This study is encouraging, but it doesn’t mean everyone should start taking high doses of vitamin E to ward off Alzheimer’s. And it would be premature to incorporate vitamin E into routine treatment of Alzheimer’s patients on the basis of this one study. There are too many unanswered questions. Women and minority groups were underrepresented, the interaction with memantine is puzzling, the secondary outcomes didn’t support the primary outcome, the beneficial effect on mortality may not be generalizable to all AD patients, and interactions with other medications or illnesses have not been studied.

I agree with the Alzheimer’s Association’s call for caution:

No one should take vitamin E to treat Alzheimer’s disease except under the supervision of a physician. Vitamin E — especially at the high doses used in the ADCS study — can negatively interact with other medications, including those prescribed to keep blood from clotting or to lower cholesterol.

Posted in: Clinical Trials, Herbs & Supplements, Neuroscience/Mental Health

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104 thoughts on “Vitamin E for Alzheimer’s

  1. Keating Willcox says:

    Your comments are misleading and not accurate. Published studies have suggested the benefits of chocolate, red wine, exercise, aspirin, and spinach against Alzheimer’s disease, and obesity, Statins, and cleanliness associated with more Alzheimer’s disease. Low fat diets are dangerous, and red meat is possibly a bad idea. Alcoholics fare badly.

    Because of the nature of the disease, studies about medications are often expensive and inconclusive,

    The comment about vitamins is instructive. Many folks carry sub-clinical problems relating to nutrition (Greenblatt, J.) and many intractable mental problems seem to be easy to test for, and quick to cure, yet few psychiatrists even bother to test for these problems. Could it be that without the immense financial incentive of testing some new medication, few physicians have any interest in testing for nutrition and vitamin based cures, even though many studies suggest both the mechanism and offer a cure.

    Since Vioxx, and all the numerous scandals regarding Big Pharma, I have been a complete skeptic regarding modern pharmacology. Big Pharma (Big Pharma: Exposing the Global Healthcare Agenda) has provided evidence that suggest I am correct.

    1. windriven says:

      @Keating Wilcox

      “Published studies have suggested the benefits of chocolate, red wine, exercise, aspirin, and spinach against Alzheimer’s disease, and obesity, Statins, and cleanliness associated with more Alzheimer’s disease.”

      Citations are required if you expect anyone to take your assertions at all seriously. Without those citations how is one to determine if the size, design, or blinding are adequate? If the results have been duplicated? If there are better studies that contradict the reported results?

      The rest of your tantrum is just that: inchoate rage against a machine you dislike and the physicians whom you believe to be in its thrall. The makers of statins are poop eating dogs but the makers of vitamin supplements are the salt of the earth.

      Grow up. Come back with an articulate argument supported by citations and be prepared to defend it. If you can’t manage that the webs are full of fora where emotion and prejudice are happily embraced. But this is not that place.

    2. Sawyer says:

      None of the therapies you mentioned were Vitamin E. That’s what this post was about. Did you actually read it?

      And please stop employing the infamous argument ad Vioxx. At this point I think one of the SBM contributors could write an entire post titled “Here’s When it’s Relevant to Mention Vioxx”. I have seen it brought up dozens of times in the comments, and ever single time it is being used incorrectly.

      Vioxx is interesting story. It has very little to do with Alzheimers research. This is what’s called a non-sequitur. So are all the other points you brought up. Non sequiturs = bad. We don’t take too kindly to them ’round these parts.

    3. Andrey Pavlov says:

      I find the Vioxx story very interesting. I have read Eric Topol’s newest book and looked over the literature on it and see it as purely a political move. The reality is that Vioxx was pulled because Topol pushed hard and proved that it increase the RR of heart disease. A signal that would be undetectable in clinical trials. Vioxx is actually an example of the system working (almost) correctly. The reality is that Vioxx increases the likelihood of heart attack/disease around 1.38 if I am remembering correctly off the top of my head. However the most prescribed NSAID in the world – and still FDA approved and on the market – is diclofenac which has a RR of around 1.55 or so. So why aren’t we pulling that? Because no champion has come out to do so.

      When I said “almost” I meant that Vioxx should NOT have been pulled. It is an excellent drug that is somewhere on the lower middle end of the spectrum of increase cardiac risk for NSAIDs. However, to my knowledge, there is no data to tell us which is worse – the heart problems or the stomach problems. Because while COX-2 selective inhibitors increase heart risks, they decrease gastrointestinal risks, including bleeding. Now, I’d rather have an upset stomach than a heart attack, but the reality is that GI bleeding can be extremely serious and directly lead to death or indirectly lead to chronically poor health and significantly increase morbidity and induce earlier death than otherwise. In certain populations, Vioxx would be the better drug to give.

      Plus, we still have other COX-2 inhibitors out there which still have elevated cardiac risks. All in all it just didn’t make sense to me that Vioxx was pulled and diclofenac (which is a strong and cheap NSAID, but with more side effects as early generations of drugs tend to be) is still around.

      So I think it is absolutely incorrect to think of Vioxx as a failure of “Big Pharma” or some kind of malicious plot or anything of the sort.

    4. Coco says:

      Could it be that without the immense financial incentive of testing some new medication, few physicians have any interest in testing for nutrition and vitamin based cures, even though many studies suggest both the mechanism and offer a cure.

      Well gee, let’s think for half a second about who might have an immense financial incentive to study non-pharmaceutical “cures” (LOL at word choice there) for enormously expensive, progressive illnesses. Hmmmm. Oh wait, THE VERY INSTITUTION THAT CONDUCTED THIS STUDY. If the VA system could jam some dark chocolate and vitamin E down the throats of veterans with AD living in VA facilities and save themselves the cost of the incredibly intensive care they get now, believe me they would. The VA runs the biggest managed healthcare program in a country with among the highest medical costs in the world. They have every incentive to pursue less expensive treatment modalities for diseases that drain the system of resources, especially diseases like AD that disproportionately affect veterans.

      And I’d love to see these studies with plausible mechanisms of action by which vitamins will “cure” AD.

      1. MadisonMD says:

        Yes, Coco… I found it odd too that Mr. Wilcox would complain that physicians would not test a vitamin based cure, when this very blog post is about a physician-led study to do just that!

        Where do these people come from?

    5. Megan says:

      I disagree with your statement that most psychiatrists don’t check for nutritional deficiencies. I work in geropsych, and every single one of our psychiatrists orders labs to check for b12 & folate levels. They don’t indiscriminately order supplements for everyone with a hint of cognitive decline though, since in most cases, it’s not going to help.

      1. Andrey Pavlov says:

        Indeed. In fact “reversible causes of dementia in the elderly” is tested on our medical boards… the ones for ALL physicians, not just psychiatrists.

    6. Chris says:

      Ah, Mr. Willcox, you have come by again to grace us with another flyby stroke of gibberish. You should try coming back to provide citations, or just to actually read the above article.

  2. Frederick says:

    Good article!
    That is still a good news, at least it is a direction were to look, maybe in the end it will be worthless, but maybe it will have positive effect. It is always good to see that researcher keep on trying thing, that is how new tech and treatment are born.

    Cerebral degenerative disease are, for me, the worst. Not that cancer is easy one, but at least for a lot of cancer type, we have weapons to fight it. My mother die in 2009 of respiratory and heart problem due to her Amyotrophic lateral sclerosis.

    in 1999 she was diagnose with MS and she was lucky to had a mild form of MS, she was on a new drug ( don’t remember the name of it) she was receiving once a month, it was doing good thing of her random pain and all symptoms of the MS. But since 2007 she was having problem talking and swallowing. Her Neurologist put that on MS, but after couple of months of it going one, he decide to go futher and he was stunt to see she also had ALS, 2 neuro-degenerative disease in one person that was a first for him. I start to read on the subject and ALS in a death sentence in a vast majority of case. there is nothing to do except helping to live with the symptoms. She die on the November 1 2009.

    She was jumping on any hope on new treatment, So i can’t blame people for jumping on that sort of bandwagon. But we always have to be careful with those new bandwagon, because a lot turn to be just false hope, that some will exploit to make money .

    1. BillyJoe says:

      If you look up the prevalence of these two degenerative diseases, MS and ALS, you will find that it is almost guaranteed that there will be people with two, and even three, neuro -degenerative diseases.
      P(ms) x P(als) x population > 1.

      1. Frederick says:

        Well that not a good news, i meant that it was rare.

        But her MS was child play compare to what ALS does.

  3. stanmrak says:

    Natural vitamin E (as found in food) is not a single compound, but is composed of four different tocopherols and tocotrienols: alpha, beta, gamma and delta. Cheap vitamin E supplements, synthetic or natural, give you only the most-widely known alpha tocopherol and no tocotrienols. If you use this type, you won’t be getting the full range of benefits that vitamin E offers. Cheap and synthetic vitamin E, without the full complement of supportive nutrients, is the type used in these studies — something that generally is not mentioned in the summary.
    In addition, vitamin E needs other antioxidants including vitamin C, glutathione, lipoic acid and the mineral selenium to be most effective. The fact that vitamin E is so dependent on these other antioxidants means that you won’t get the full benefits of vitamin E unless you’re also getting enough of these other nutrients. I’m certain that these researchers didn’t account for this and didn’t measure levels of these nutrients as well. This is why the validity of these studies is suspect.

    1. Harriet Hall says:

      “vitamin E needs other antioxidants including vitamin C, glutathione, lipoic acid and the mineral selenium to be most effective”

      citation needed. Also need to specify effective “for what.”

      1. stanmrak says:

        This information isn’t exactly a secret. Try Google.

        1. Harriet Hall says:

          Cop-out.
          I asked you for citations because I hadn’t seen any credible evidence to support your assertions.
          Also, you never even specified what you are claiming vitamin E works for.

        2. Chris says:

          “Try Google.” is the lamest excuse ever to refuse to support your claims with actual evidence. If you make a claim, you need to provide the verifiable evidence for that claim. End of story.

          Though you seem to be full of evasion. First evidence for your claims, and then evidence you have any education. Why is that?

        3. MadisonMD says:

          “Try Google”– frickin hilarious.

          Stan– Don’t you know a good marketers sell people things they need?* You seem doomed to scrape the bottom of the marketing barrel trying to sell crap by giving away free BS.

          *”Try Google” if you don’t believe me.

    2. Sawyer says:

      You’ve set up a win-win situation for supplement manufacturers. Big surprise.

      Any study testing a single variable gets to be ignored whenever convenient because it didn’t measure the complex interactions. Of course a positive study looking at a single variable is still trumpeted as a success, meriting “further research”.

      Any study that tests multiple supplements will (by definition) be harder to perform and draw definitive conclusions from. This allows vitamin cheerleaders to again promote any positive study as being more “comprehensive”, even when the positive results are a consequence of weak methodology and researcher DOF. You also get to dismiss any comprehensive study of supplements that comes back with null results, because there will always be some inherent limitations to the methods you can nitpick at.

      All four scenarios (positive/negative, single variable/multiple) are touted as evidence that everyone needs to be taking supplements. Clearly a robust scientific conclusion and not just an idiotic marketing tactic.

      I also see some interesting parallels between insisting top notch vitamin E is better than generics and drug companies insisting their brand name is better than the generics. There could be some real science there, but I don’t know how anyone critical of pharmaceuticals can ignore the similarity .

      1. WilliamLawrenceUtridge says:

        Also see Stan’s comment below, which nicely insulates him from ever having to change his mind further. Any dissenting information can be easily discounted by claiming “bias”. Basically a perfect storm from ever having to truly think about whether anything he says is factually accurate or note.

    3. windriven says:

      “If you use this type, you won’t be getting the full range of benefits that vitamin E offers.”

      Citations regarding differential benefits of different tocopherols or citations supporting the benefit of having all four. If all four, what is the appropriate balance, with citations, of course.

      Talk is cheap, stan. You’ve been around here long enough to know the drill.

      1. stanmrak says:

        Citations are worthless if you don’t know their validity, as is clearly the case here. One could cite this study here as “evidence” to prove a point, but this study is rubbish and isn’t even worth writing about. Anyone who knows the least little bit of nutrition would realize this immediately.

        1. jt512 says:

          Some of us here have advanced degrees in medicine, biostatistics, epidemiology, and/or nutrition, and have spent time in grad school learning how to assess the validity of the literature. Some of us even do this for a living. What are your qualifications for assessing the validity of the literature, and why should we believe your claims when you are either unwilling or unable to provide citations to the literature that you claim they are based on?

          1. Chris says:

            He probably thinks engineers are educated wrong, and would prefer to drive over a bridge or fly in an airplane designed by a graduate of the University of Google. Because papers in engineering journals on Young’s modulus, Poisson’s ratio, dynamic analysis, material science, metal fatigue, etc are all rubbish. :-/

    4. Chris says:

      So what kind of training do you need to be a Antiaging Nutrition and Disease Prevention Expert? So does that require a college degree, or just reading some books in the self-help section of the bookstore?

      Stan, what are your credentials? Do not evade this question again.

      1. stanmrak says:

        I have a brain that is capable of learning on its own and find mentors who know something about nutrition to learn from, unlike the ‘experts’ here who know next to nothing about nutrition, but rely on scientific papers that they don’t even have the capacity to evaluate accurately.

        If you can’t see how this vitamin E study is completely worthless and a waste of time, you really don’t know even the basics of nutritional science.

        1. Chris says:

          Oooh, just like Meryl Dorey.

          You are very evasive about your credentials. Do you even have any? Did you finish high school?

        2. WilliamLawrenceUtridge says:

          If you can’t see how this vitamin E study is completely worthless and a waste of time, you really don’t know even the basics of nutritional science.

          Wow, that’s a really handy excuse to use to avoid actually justifying any of your statements. There are two ways of seeing this – you’re super educated and it’s so obvious to you, you can’t be bothered to write out an explanation (fun fact – people who really have expertise can quickly and easily summarize why they think what they do, often in ways readily understandable to nonexperts). The other explanation is, you don’t have any justification for your beliefs and you’re trying to conceal the fact.

          But I guess your background in marketing has taught you that how you say something is more important than the substance of what you say. And you’re sticking to your strengths – vague pronouncements designed to spread fear, uncertainty and doubt rather than anything complex.

          1. MadisonMD says:

            Welcome back, WLU. I liked this one:

            brain that is capable of learning on its own

            See– no factual input needed. Pure imagination.

            But I guess your background in marketing has taught you that how you say something is more important than the substance of what you say.

            Exactly. This brain churns out effluvia so patently false, that Stan will unfortunately remain a marketing bottom-feeder for the top 1% in gullibility. Can this brain of his ever imagine that a good marketer sells people things that they need?

      2. windriven says:

        Chris asked:
        “Stan, what are your credentials?”

        stan responded to Dr. Hall above:
        “This information isn’t exactly a secret. Try Google.”

        I’m guessing that stan has a PhBS from the University of Google. What interests me is that he is quite selective about studies that he accepts and studies that he doesn’t. His primary criterion appears to be ‘does the study support or contradict my stance.’ Sadly, he claims those that support his stance.

        In response to you stan said:
        “One could cite this study here as “evidence” to prove a point, but this study is rubbish and isn’t even worth writing about.”

        This is not entirely different from what Dr. Hall wrote in the blog, though rather more elegantly and with a good deal more critical analysis than our friend stan.

        If I can summarize stan’s argument (?) I think it goes something like this:
        - Scientists are full of crap
        - Nutritionists allied with the supplements industry excepted
        - The study under consideration is full of crap because it used the wrong flavor of tocopherol
        - Moreover the magic doesn’t happen even with all the right flavors of tocopherols because one also needs Se, C, and sometimes y
        - The study that stan wants hasn’t been conducted, therefore studies that have been run but don’t address what stan wants are crap.
        - Google is the best source of information about nutrition and supplements.

        That about right?

        1. stanmrak says:

          Maybe you should go back to school and learn how reading comprehension. You scored a big ZERO here.

          I didn’t say scientists are full of crap. I said that they can’t always tell the valid studies from the fraudulent ones, unless they are already an expert in the subject. This study is so worthless, it doesn’t merit any further mention.

          I never mentioned nutritionists allied with the supplements industry. I don’t know any.

          tocopherols and tocotrionols are not ‘flavors’ of vitamin E, and yes, you do need these other supporting nutrients for vitamin E to work effectively. vitamins do not work in a vacuum. That’s Nutrition 101.

          You can learn about everything with Google. You’re not reading Google’s information! Isn’t all scienctific data now on the internet? PLOS is found through google.

          I didn’t cherry-pick any studies — or even mention one. This is a lesson in futility. For every peer-reviewed study you find to support your argument, you can find one that refutes it.

          Jeff came up with a couple of supporting pieces of data. I’m not going to be bothered with debunkers and naysayers.

        2. Frederick says:

          What amaze me about people like him ( he will reply to my comment but i don’t really care) ir is how they always know better than everybody. Those studies are made by neurologist, chemist, biochemist. people with decade of work, 1 or even 2-3 PHD long experience and knowledge. BUT they don’t know that vitamin E is bla bla bla. But he know. And than after that he say all people here ( except for him of course) know nothing. Also that using a proven credible source to back up you knowledge is not important.
          So i mean, Who is this guy to be so much better than all those person put together.

          Impressive… not

          I admire patience of people with type like this, but this is good, we can’t bring them to rational thinking, But we can help others NOT to fall in their BS.

          1. WilliamLawrenceUtridge says:

            It’s extraordinarily instructive to compare Stan’s proclaimations from on high to comments by Angora Rabbit, who appears to be a genuine researcher on nutrition.

            Stan always comments on funding, motivation and vague statements about how you can’t trust anyone (except him, and presumably the person selling him his vitamin supplement).

            Angora Rabbit will specifically comment on how the molecular pathways discussed in the article are problematic because of competing agonist/antagonist responses or some concrete aspect of physiology.

            Which is to say – guest post! Guest post!

        3. windriven says:

          “Maybe you should go back to school and learn how reading comprehension. ”

          Ummm, I don’t want to be a dick or anything but I’m guessing that the problem with the sentence above doesn’t have anything to do with my reading comprehension. But I take stan advise, go back skool. Me read good sometime.

          stan:
          “I’m certain that these researchers didn’t account for this and didn’t measure levels of these nutrients as well. ”

          windriven:
          [stan suggests] “Scientists are full of crap”

          stan, the researchers are scientists working on possible clinical benefits of alpha tocopherol in populations with AD. I’d be willing to bet that they are conversant in the forms (sorry you don’t like ‘flavors’, lighten the hell up) of tocopherols. So I’d say my translation is pretty accurate.

          “You can learn about everything with Google.”
          Google is a garbage heap. Yes, there are all sorts of goodies to be found there. But one has to pick through an enormous amount of detritus to get to it. Google is great for discount light fixtures and finding just where the Turks and Caicos are anyway. For technical information I’d rather look first at Pubmed, PLOS, etc.

    5. WilliamLawrenceUtridge says:

      Sounds like a great reason to get your vitamins from food, as is recommended by every health authority, everywhere, rather than from a pill.

      Way to go Stan, you’re finally beginning to grasp medicine – patients should take care of themselves as best they can through preventive health interventions like a proper, adequate, high-nutrient-density diet and exercise, and vaccinations.

  4. Jt512 says:

    Although the trial was preregistered, the trial’s registration record shows that the primary outcome measure, the ADCS/ADL scale, was not declared until November 1, 2013, which would likely have been after the results of the study were known. Of the five outcome measures reported, only the ADCS/ADL had a statistically significant treatment effect (compared with placebo) (P=.03).

    The reported p-values were adjusted for multiple treatments, but not for multiple outcomes. This seems a reasonable approach if their primary endpoint was predetermined, but not if it was chosen because it was the one that was significant. If that were the case, then the authors would have had five ways to declare success—one for each outcome measure—a multiple comparisons issue that they did not adjust for; or, in the language that has recently become popular, an opportunity to exercise researcher degrees of freedom in a hunt for significance.

    1. MadisonMD says:

      jt512:
      I too was looking closely at the statistical design of the trial. Unfortunately JAMA apparently does not require the protocol to be posted as a supplement (NEJM does).

      The reported p-values were adjusted for multiple treatments, but not for multiple outcomes.

      I’m able to find a record from December 2005 declaring the primary outcome. So I don’t think they had multiple outcomes.

      What bothers me more is the trial design. I’m very surprised they did not use a 2×2 design, which would be typical to minimize the sample size and maximize the power. In this design they would have compared all Vit E patients (regardless of memantine) verses all VitE placebo. It would have been a negative trial. The only reason not to do this is to suspect some complex interaction, which the authors admit in discussion that they have no ideas about.

      Related to this, they see no benefit when Vit E is given with memantine, which is surprising if Vit E is truly effective.

      1. jt512 says:

        I’m able to find a record from December 2005 declaring the primary outcome.

        You’re right! I was looking at the same material, but somehow missed that.

        So I don’t think they had multiple outcomes.

        They did have multiple outcomes, as do most trials. In addition to the primary outcome, they had four secondary outcomes, which they did not adjust their p-values for. I previously wrote that that would be ok if they had decided on their primary outcome in advance (which you correctly pointed out they had); however, thinking about a little more, I’m not so sure.

        The problem is subtle and unobvious in the current paper, because things came out just right: the primary outcome was the only significant one. But what if things had gone differently, say, the primary outcome had been non-significant, but one of the secondary outcomes had been significant. What would the authors have concluded? I suspect that they would have concluded that the benefit of the treatment for the secondary outcome was real. If so, then they indeed had a multiple comparisons problem that they did not adjust for (recall, they adjusted for multiple treatments, but not multiple outcomes). The fact that only the primary outcome was significant doesn’t eliminate the problem because the results, in principle, could have gone another way.

        Of course, it is possible that if only a secondary outcome had been significant, the authors would have considered the finding exploratory and state that it is subject to confirmation in an independent trial, but how often do we see authors do that?

        What bothers me more is the trial design. I’m very surprised they did not use a 2×2 design, which would be typical to minimize the sample size and maximize the power. In this design they would have compared all Vit E patients (regardless of memantine) verses all VitE placebo. It would have been a negative trial. The only reason not to do this is to suspect some complex interaction, which the authors admit in discussion that they have no ideas about.

        The study was a 2×2 factorial design. Had there been no interaction between vitamin E and memantine, they could have compared all vitamin E recipients with all non-vitamin E recipients, as you suggest; however, there was a significant interaction, and so the effect of vitamin E alone had to be determine by comparison with the all-placebo group.

        Related to this, they see no benefit when Vit E is given with memantine, which is surprising if Vit E is truly effective.

        Yes. The authors admit that the effect of vitamin E alone, but not in combination with memantine, is paradoxical, and they can’t explain it. This unexpected interaction casts a degree of doubt on the positive finding for vitamin E.

        Furthermore, the finding for vitamin E alone is not very impressive. Berger and Sellke (1987) showed that a p-value of .03 can increase our confidence in the alternative hypothesis by at most a factor of 3.5. In other words, if before the study we believed there is a 50–50 chance that the alternative hypothesis is true (ie, odds of 1:1), observing a p-value of .03 can at most raise the odds to 3.5:1. Thus a p-value of .03 can never indicate strong evidence for an effect. Berger and Sellke derived their findings using unadjusted p-values, whereas in the present study the p-values were at least partially adjusted for multiple comparisons. To be honest, I’m not sure how such adjustment would affect the weight of the evidence that a p-value indicates, but in any event, we should bear in mind that p-values of this magnitude are not particularly persuasive. Given that, together with a possible residual multiple comparison problem, and an unexplained inconsistency between the vitamin-E-only effect and the vitamin-E-plus-memantine effect, I would say that the evidence from the study for a benefit from vitamin E is weak.

        1. MadisonMD says:

          jt512:
          I remain equally skeptical about the outcome. However, the statistical design was a bit different than the typical 2×2 analysis… and I don’t really see any sleight of hand in the analysis (not having access to the protocol).

          The primary endpoint involved pairwise comparisons of each of the 4 arms. This involved 6 comparisons, so an alpha=0.0083 was allocated to each for a total alpha=0.05. If any of them were statistically different, they would have concluded a difference between 2 of the arms and it would have met the primary endpoint.

          A typical 2×2 statistical design trial have made only two comparisons: One between all patients who had VitE and those that had VitE-placebo and a second between all patients who had memantine and those who had memantine-placebo. It would actually have required fewer patients.

          The problem is subtle and unobvious in the current paper, because things came out just right: the primary outcome was the only significant one. But what if things had gone differently, say, the primary outcome had been non-significant, but one of the secondary outcomes had been significant. What would the authors have concluded? I suspect that they would have concluded that the benefit of the treatment for the secondary outcome was real. If so, then they indeed had a multiple comparisons problem that they did not adjust for (recall, they adjusted for multiple treatments, but not multiple outcomes). The fact that only the primary outcome was significant doesn’t eliminate the problem because the results, in principle, could have gone another way.

          I don’t follow you here. They did, after all select a primary outcome at the outset. Sure, if the primary was negative, they might have put some spin playing up the secondary outcome– almost requisite to get a study published. However, it would be fairly transparent that that’s what they had done. If so, we would understand that there was a higher than 5% of false positive outcome. In support of your argument, we could point out that the negative secondary outcomes fail to provide concordant support of the primary.

          I agree with your Bayesian analysis and conclusion– I do think the adjusted p=0.03 is what you would use here and the effect on posterior probability is modest at best (weak if you additionally consider that VitE+memantine didn’t seem to be useful).

          1. jt512 says:

            A typical 2×2 statistical design trial have made only two comparisons: One between all patients who had VitE and those that had VitE-placebo and a second between all patients who had memantine and those who had memantine-placebo. It would actually have required fewer patients.

            The results of such an analysis would have been invalid in this case, due to the interaction between treatments, so it’s a good thing that they designed and analyzed the trial the way they did.

            1. MadisonMD says:

              They found an apparent interaction (think it’s real?)… but a 2×2 factorial design is valid if you don’t have reason to suspect one at the outset.

              1. jt512 says:

                We need to get our terminology correct once and for all. The present study is a standard 2 × 2 factorial design: subjects were randomized to two levels of each of two treatments. The study would be a 2 × 2 factorial regardless of whether the authors only analyzed the main effects or whether they did what they did, namely, analyze the simple effects (ie, a pairwise comparison of the four groups).

                Now that we’ve hopefully got the terminology straight, we can discuss why a main-effects analysis would have been invalid in the present study, and why the only valid analysis would be the simple-effects analysis that the investigators performed. The reason is that a main-effects analysis is invalid in the presence of a strong interaction between the treatments, as was found in the present data. The main effect for vitamin E (all vit. E recipients, vs all non-vit-E recipients), if calculated, would have averaged over the interaction, resulting in an estimated effect size that is wrong for both groups (ie, vit-E-only and vit-E-plus-memantine).

                You ask if the observed interaction is real? I don’t know, and it doesn’t matter. Even if it was just a fluke—a result of random error—it’s there in the data, contaminating the main effects., Thus, you have no choice but to abandon your main-effects analysis and analyze the simple effects instead.

              2. MadisonMD says:

                We seem to be going in circles so I’ll not restate the above… After all, I mostly agree with you … except my understanding is with a clinical trial you should, in general, plan on what analysis you will do before you look at the results.

              3. jt512 says:

                [M]y understanding is with a clinical trial you should, in general, plan on what analysis you will do before you look at the results.

                Yes, you should have an analysis plan in advance; but, when you have a two-factor study, the analysis plan should specify what analysis you will do to check for an interaction, and what analysis you will do if there if there is an interaction and if there is not.

              4. MadisonMD says:

                Ah, yes… agreed jt512.

  5. Jeff says:

    Mixed tocopherols or tocotrienols would be a better choice for a trial involving Alzheimer’s patients. There is evidence high dose alpha-tocopherol reduces blood levels of gamma-tocopherol:

    http://www.ncbi.nlm.nih.gov/pubmed/20373187

    1. windriven says:

      In my estimation (admittedly unwilling to part with $46 to read the whole thing) it is pretty thin gruel.

      “may have important biological effects.”
      “may be offset by deleterious changes in the bioavailability”
      “This might account…”

      Lots of maybes, not so much on a chain of evidence that demonstrates a clear link. For a simple start, is there any evidence that those who consume diets rich in soybean oil or other potent sources of gamma tocopherol display slower progression of cognitive diseases?

      1. Jeff says:

        There is some epidemiological evidence for mixed tocopherols and tocotrienols:

        http://www.sciencedaily.com/releases/2010/07/100707102439.htm

        1. windriven says:

          Yes, it is an interesting story. But there is very little detail.

          “After adjusting for various confounders, the risk was reduced by 45-54%, depending on the vitamin E component.”

          I focused on the ‘depending on the vitamin E component’ because it wasn’t broken out. There was no discussion of differential levels either in total or by component. Hard to tell much from that.

          These are interesting bits of information. But not, I think, nearly enough to base therapies on.

  6. Andrey Pavlov says:

    jt512 makes excellent points. The discord between the memantine + vit E and each alone is indeed puzzling. At first blush seeing results like this gives me the gestalt that the result is more likely to be due to significance hunting rather than an actual effect. Possibly not, but I certainly would not be jumping on the Vit E bandwagon. In the right circumstance I may well recommend it for a patient of mine – that circumstance being continued progression despite maximal therapy and no contraindications for use of Vit E (including cost; I actually had elderly neighbors growing up whom I did a lot of work around the house for where the wife developed severe Alzheimers and out of desperation, the husband essentially spent every penny he could on ANY treatment he could find. Granted, Vit E is relatively cheap, but it would at least be at the back of my mind) . This would be a case where I would be OK with “why not give it a try.” I see little overall downside, a little bit of evidence to possibly support its use, and low cost. I would carefully hedge my words and make it clear that this is, in fact, a mostly evidence free last stab at something with low likelihood of help but low likelihood of harm as well.

    Also, while not addressing sales of Vit E, you can look at Google Trends and see that the search term for “Vitamin E” has spiked already (and look at other spikes relative to news items about Vit E over the past few years. It can also be segregated into “Vitamin E” as a medical treatment and that essentially mirrors the previous graph of trends.

    1. BillyJoe says:

      “I would be OK with “why not give it a try.””

      I’d have to disagree.
      I’m never ok with “why not give it a try”.
      I never give anything “a try”.
      I will consider using something if there is sufficient evidence of effectiveness.

      The chance of anything working for which there is no evidence of effectiveness is too low to warrant the time and money spent, especially when you will never know whether it worked or not and, therefore, whether you should “try” it again. Anecdotes and all that.

      Plausibility might increase the chance of it working but most plausible treatments do not pan out when put to clinical trail.

      In short, I think “why not give it a try” is a cop out.
      And it’s contaminated by being a favoured mantra of CAM believers and practitioners…
      SBM: there is no evidence that noni juice works. CAM: have you tried it?

      1. Andrey Pavlov says:

        @BJ:

        That is where science and clinical medicine part ways. I am also describing a very specific, very “end of the line” scenario. Believe me BJ, I know very well the jargon and pitch of CAM (in case you didn’t know I am NYBGRUS).

        But in the world of clinical medicine, when everything with a good support base has been tried and a patient is desperate and deteriorating we can – and should – make individual exceptions to our rule. We do order unnecessary xrays because the mental stress and anguish on the patient is a negative that outweighs the negatives of the xray and the benefit of removing that mental anguish makes it a good risk:benefit. The same in this case with the vitamin E. I would not try something highly implausible, with evidence against it, or that could be potentially harmful. In this case, with the right subpopulation in the right clinical context, this paltry level of evidence will suffice to justify its use. Now that IS a clinical judgement, but the reality is at some point we work our way down the line until the paltriest of evidence is indeed sufficient.

        What we absolutely should NOT do is jump on a bandwagon and start recommending to all patients, say anything except how highly unlikely it is to work but with SOME evidence it MAY work but we shall never now, or ascribe improvements to the VItE.

        I know that some patients/people will take this as a sign of physician endorsement, which is why I think it is very important to approach the topic properly and provide true informed consent on the matter and be unabashed in any statements made about it. But the reality is we are still dealing with people and their families and, if done properly, that effect will be minimized (but never eliminated). The benefit to the right patient/family does, IMO, outweigh the potential negatives of the “just try it” attitude.

        Put more specifically, if I had a patient that had failed all other treatments and the family was disappointed but obviously content with having reached the limits of good solid medical science, I would never even suggest it. If I had the same patient but she and the family were immensely distraught and seemed to me desperate enough to try anything, I would rather have them try this than some other true quackery and use it as an opportunity to clearly explain how we were dredging the very bottom of the medical barrel here. That, IMO, will provide a deeper and better patient-doctor relationship and would likely prime them to be ready to have this be the “last” intervention. If not, and they keep coming back for more and more woo-y stuff and crying “but you were willing to try THAT with very little evidence!” then it is also likely that no action or inaction on my part would have changed the outcome. If a NEW patient, naive to treatment, came and asked about VitE supplementation I would advise against it, citing the lack of evidence and reason to support it, and say that we could save it as a truly last resort. Once again, priming the patient for the long-haul reality of a progressively degenerative disease.

        Remember that real medicine is and absolutely should be very firmly rooted in science but it itself cannot BE science. There’s still a human element in it that complicates things and makes it messy at the fringes.

        1. BillyJoe says:

          Well, what do you know? I thought you posted here as nybgrus as well!

          You were speaking as a doctor dealing with a range of patients, whilst I was talking as if I were one of those patients – and only figuratively, since I am not a patient or, at least have been so only three times in my entire life.

          So what I said was from my point of view as a potential patient. I would not give anything a “try”. And I am using the word “try” in the sense that CAM uses that word. But I might consider “using” something that was either plausible or had an evidence base, preferably both, depending on the severity of my condition, the degree of plausibility and the amount of evidence. For example, I would not consider using prayer – even on my deathbed |:

          Anyway, we are probably on roundabout the same page.

          1. Andrey Pavlov says:

            I used to post here as NYBGRUS. After I authored a couple posts here I decided to just drop the ‘nym. I don’t need protection from anonymity (which isn’t really much protection anyways) since I stand by what I say and make sure I would have no problem with any of my superiors reading what I have written. Over at Neurologica, when I do comment, I still use NYBGRUS since it auto logs me in as that and is just easier.

            I understand where you are coming from and as a physician would try and clue in to your predilections. I think you are likely looking at my use of the word “try” from the CAM perspective. As MadisonMD pointed out, we do “try” a lot of things in medicine since we do not know what individual responses will be. Even in the ICU I would “try” a lot of things to determine what is going on. Let’s “try” a 500cc bolus since I can’t decide if my patient’s low BP is due to intravascular volume depletion or pump failure. Let’s “try” memantine since you have what appears to be Alzheimers and it has some evidence that it may help slow progression and we have no better options. Let’s “try” VitE since you’ve failed other therapies and we are down to the last option that isn’t just a blind shot in the dark.

            That’s what I mean by “try” in this context, if that makes sense.

      2. MadisonMD says:

        BJ:
        I am very sympathetic to what you’re saying here– and I think Andrey is sympathetic as well. Perhaps “just try it” may sound a bit slapdash… but I mostly agree with Andrey.
        There always has to be some threshold of certainty to act–it’s never 100%. It’s judgement how much certainty you require. What do you do when you have a progressive and deadly disease, few effective therapies, and a low-toxicity drug. The drug showed a beneficial effect in a RCT. There are uncertainties, but you are nevertheless–say 70%?– convinced that it can slow the decline of the disease by about 20%. Do you act? I think most physicians would act.
        Interesting thought experiment: would a drug be approved by FDA based on these data for Vitamin E? I think not– it would require a validation study.

  7. Coco says:

    Another unanswered question, at least to my mind, is how generalizable a veteran population with suspected AD is to a non-veteran population. Setting aside demographic factors, veterans are more likely than non-veterans to develop dementia, including AD type. Moreover, dementia in veterans appears to be correlated with factors, such as head trauma and PTSD, that are not as common in the non-veteran population. If there is a causal connection there (i.e. head trauma causes AD in some individuals) then it is also possible that the response to treatment could be different depending on the underlying cause.

    I’m sure there are studies out there comparing these populations (veterans and non-veterans with suspected AD) , I guess I’m just curious about the implications of these differences on results like these.

    1. windriven says:

      @Coco

      “veterans are more likely than non-veterans to develop dementia”

      Interesting. Do you have a citation for that? Does that hold across generations or is it particularly associated with veterans of a particular military era? The US was not much at war from 1953 when Korea wound down till the mid 60s when Vietnam really heated up. I’d also be interested to know if there is a correlation between branch of service and RR for AD. Coast Guard v. USMC for instance.

      1. Frederick says:

        It also seem that people in sport who suffer many concussion have more risk of having a neurological degenerative disease,

        it seem that head concussion can play a role.
        ( a dailymail.co.uk article nt the greatest source i know :-) )
        http://www.dailymail.co.uk/health/article-1304054/Lou-Gehrig-disease-Bumps-head-kill-sportsmen-soldiers-years-later.html

        Having seen first hand the effect of ALS, each time i hear a young sportsman have multiple concussion, it always make me sad, because each time it increase the risk.

        1. MadisonMD says:

          It also seem that people in sport who suffer many concussion have more risk of having a neurological degenerative disease

          But this mechanism is distinct from Alzheimers… unless the idea is that these veterans are being diagnosed erroneously.

  8. incorrect says:

    “We know of no treatment that will delay, prevent or cure Alzheimer’s disease, or that affects the underlying disease process.”

    This is incorrect. There is a very large amount of data linking specific dietary profiles with dementia in later life; much of this data is on middle-aged or younger adults, which is the timepoint at which we need to modify diet. If you are waiting for an RCT to prove this, don’t hold your breath. There is some RCT data that antihypertensive medications prevent dementia, but I consider this weaker than the lifestyle epidemiology on alcohol, smoking, obesity, metabolic syndrome and dietary patterning.

    1. Harriet Hall says:

      See http://www.nih.gov/news/health/apr2010/od-28.htm

      “Many preventive measures for cognitive decline and for preventing Alzheimer’s disease—mental stimulation, exercise, and a variety of dietary supplements—have been studied over the years. However, an independent panel convened this week by the National Institutes of Health determined that the value of these strategies for delaying the onset and/or reducing the severity of decline or disease hasn’t been demonstrated in rigorous studies.”

    2. David Weinberg says:

      @incorrect

      Epidemiologic data have proven to be very unreliable in predicting the effects of supplements. There were very strong epidemiologic data supporting protective effects of omega 3 fatty acids in prevention of cardiovascular disease, but a powerful clinical trial said otherwise.

      nejm.org.proxy.lib.mcw.edu/doi/full/10.1056/NEJMoa1205409

      There is a similar story for macular degeneration.

      http://jama.jamanetwork.com/article.aspx?

      Even worse, sometimes clinical trials have shown a paradoxical effect, where promising supplements, supported be epidemiologic data were shown to be harmful as in: beta-carotene and lung cancer:

      http://ajcn.nutrition.org/content/69/6/1345s.full

      Or vitamin E for cardiovascular disease:

      http://annals.org/article.aspx?articleid=718049

      So, no matter how strong the epidemiologic evidence for diet and Alzheimers risk reduction, no definitive conclusions should be drawn short of a clinical trial

    3. WilliamLawrenceUtridge says:

      The sad truth is, by the time an individual is old enough that they need the benefits of a youth spent eating a proper diet and getting enough exercise, generally neither of these activities will be of help as treatment. People should be eating real food and exercising for the myriad benefits it offers, not to avoid a specific disease.

      And people need to stop pretending you can make up for a lifetime of poor diet and exercise through a year of fruit smoothies and multivitamins. The damage is done, it’s rather unlikely you can undo it with food.

  9. goodnightirene says:

    iPad is useless for commenting. The “undo” key is really a delete key.

    Oh well, it was hardly profound.

  10. Vicki says:

    You are the debunker and the naysayer, relative to this post, the study discussed–which you seem to be attacking because while it says vitamin E can be helpful, which you also say, it isn’t going beyond the data to also recommend three other supplements–and Science-Based Medicine, which is not your blog. There are people who get to decide what the topics are here, and you’re not one of them. (Nor am I, but I’m not spewing random comments and demanding the last word.)

    1. MadisonMD says:

      WAZZAT YOU SAY VICKI?

  11. “We know of no treatment that will delay, prevent or cure Alzheimer’s disease, or that affects the underlying disease process.”

    Are you sure about that? What kind of significant results do you need in order to consider something useful for treating Alzheimer’s? There are a series of nootropic GABA derivatives (called racetams) that are somewhat speculative, but some studies show improvements in the underlying neuro degenerative causes.

    1. MadisonMD says:

      “We know of no treatment that will delay, prevent or cure Alzheimer’s disease, or that affects the underlying disease process”

      Are you sure about that? What kind of significant results do you need in order to consider something useful for treating Alzheimer’s?

      There is a difference between being useful for treating and delay, prevent or cure. I don’t think you would have an argument that some drugs available today are modestly useful for treating advanced Alzheimers.

  12. Hi, longtime SBM reader, first time writing.

    My Grandmother was diagnosed with Breast Cancer about a month ago. My grandparents have been caught in the woo-web, and are convinced that a trip to the Gerson Clinic in Mexico would solve the problem.

    At a cost of $22,000, plus flights, plus health insurance, plus living costs.

    My grandparents don’t put a lot of stock in doctors, believe in “divine healing” (then why bother with expensive enemas?), and are currently trying to get a loan.

    I don’t know how to handle this…

    1. MadisonMD says:

      @Austin

      This is too bad. It’s much more benign and less expensive to get anastrozole and, if not metastatic, lumpectomy perhaps without radiation.

      BTW– the above citations show effect of different treatments on hundreds or thousands of patients with breast cancer with 10-20 years of follow up. The Tijuana folks have a few case reports and awfully failed trials of Gerson therapy in incurable pancreatic cancer and laetrile in incurable cancer of all types. You can show this to your grandparents, but I’m not sure they will listen– it’s human nature to believe what you wish to be true.

      Some people have to learn the hard way, but it does disgust me that charlatans are taking advantage of the gullible.

      Good luck to you and family.

  13. Dr Robert peers says:

    Hey you dudes, listen to this…did you know that refined seed oils are low in vitamin e, and four European studies have linked these common vegetable oils with cognitive decline and doubling of alzheimer risk?…the trick is that vitamin e protects polyunsaturated fatty acids, in cell membranes, against self catalysing per oxidative chain reactions…next trick is that brain cell membranes have the richest concentrations of long chain omega six and omega three fatty acids in the body…making neuronal synapses the biggest sitting duck for lipid per oxidation, when the diet includes vitamin e depleted polyunsaturated seed oils…this per oxidation is now known to cause beta amyloid accumulation, by inhibiting amyloid degrading enzymes and other clearance mechanisms like proteostasis and blood brain barrier clearance…so there is the true role of vit e in this disease…it won’t do much to stop rampant lipid per oxidation in established disease, due to severe lipid per oxidation being due to beta amyloid itself, at that late stage…however, dudes eating refined seed oils for many years, but who happen to take vit e, may never develop the disease…as for the claim that no current treatment reverses the disease, how about myo inositol, a seed sugar that rapidly improved language and orientation, in a small trial in 1996?…I identified this molecule as a common ingredient of the diets of centenarians, back in 2005, the same year that it was shown to inhibit the pro ageing igf signal pathway, suppression of which turns on ancient cytoprotective genes, esp for protein damage control…proteostasis…so there, nobody who avoids refined seed oils gets the disease, while those in its early stages, given inositol powder, should enjoy initial improvement, that may well persist in the long term…proof that this anti ageing pathway suppresses alzheimer pathology was provided in 2009, by salk researcher Andy dillin, who dampened the igf pathway genetically, and saw major improvements in brain pathology and cognition, in his transgenic alzheimer mice….interestingly, high inositol diet, like the Mediterranean diet, is known to partly prevent Alzheimer’s…and can delay death in diagnosed cases, by up to four years…good, but suggests that to actually block progression, inositol rich diet will need boosting with powder supplement

    1. windriven says:

      Any citations for all these claims … Dude?

      1. Dr Robert Peers says:

        Hi windriven

        It should be obvious to even the most casual observer, that I must be familiar with the alzheimer literature, to make the claims that you refer to…so are you suggesting that I have a mere speculative hypothesis…as Harriet hall insists…or do you see an inductive hypothesis..unknown to dr hall..emerging from the mass of data I have collected, since 1990, on this disease?…so, if you think I am just guessing, and have no citations, have a nice day…but if you are sincerely interested in seeing my extensive reference collection, just drop me an e mail…I am happy to share these groundbreaking discoveries on Alzheimer’s and anti ageing with private individuals, but due to repeated offensive dismissals of my hypothesis over the years, by researchers untrained in scientific induction..and by nutritionally unaware dismissive medicals like dr hall…I have no intention of publishing these conclusions, except in rural health journals…I was raised in a farming community, and was a solo country doctor at one stage, and my focus is now on rural health…only…my e mail is drrobertpeersATmeDOTcom..dude

        1. windriven says:

          @Dr. Peers

          “so, if you think I am just guessing, and have no citations, have a nice day”

          Not at all, I just think it would be sporting of you to share the goddamned things with us so we don’t have to guess. I for one don’t know you from Adam’s house cat. You could be batcrap crazy or you could have the one true ticket to nirvana. How the hell are we supposed to know based on your stream of consciousness comment?

          1. Dr Robert Peers says:

            Hello again dude…you are welcome to e mail me, for those priceless citations…nobody else on this blog seems at all interested, except dr Harriet hall, who is happy..as any non nutritional medico would be…to dismiss my work as just a hypothesis, without asking me to belly up to her bar with stout citations, as she says…I have suggested to her that she study the difference between a speculative and an inductive hypothesis…something you don’t learn at medical school…she has issued a lone genius alert about me, but nobody seems interested in this charge..in any case, I have done my homework, on both Alzheimer’s and anti ageing, so I have no need of criticism, when praise is quite enough…dr hall is welcome to her opinion, based as usual on her skills at snap judgment, and is not likely to ever find out if my hypothesis is correct, since I shall not be publishing it, for the reasons I have given you

            1. windriven says:

              @Dr. Peers

              I would indeed have you forward me the links but the reality is that I am neither physician nor pharmacologist. I own a couple of medical device companies. My interest in this forum is primarily on the intersection between medicine and public policy.

              So unpublished work that has not been peer reviewed would be beyond my competence to judge. We can none of us rely entirely on our own analyses – there is too much information and too many limits on individual competence across the landscape of scientific inquiry. So we rely on others where they do have specific competence.

              I would echo Dr. Pavlov in encouraging you to publish so that your peers can evaluate your work and hopefully bring it to a larger audience.

        2. Harriet Hall says:

          “I have no intention of publishing these conclusions”

          You say you have found the cause of Alzheimer’s and an effective treatment for it, but you are not willing to publish and share it with the world because people have treated you dismissively? That says a lot about you.

          Science has learned from long, hard experience that even the best, most reasonable-sounding, intuitively obvious inductive hypotheses can be wrong and must be subjected to proper testing.

          1. Andrey Pavlov says:

            I’ll go one further and say that if he really does have some significant breakthrough that his inaction is criminally negligent and ethically abhorrent.

            In the meantime, I’ve single handedly dismantled the Standard Model of physics if only someone will listen. But I won’t publish my findings. I need people to just listen to me and accept what a brilliant genius I am.

          2. MadisonMD says:

            Seems like Dr. Peers could get published. Medical Hypotheses has published stuff that is less inductive, certainly. I don’t think I’d be so harsh as to call non-publishing criminal or unethical–especially when it has not been received with gratis when attempts at publicizing were made.

            Editors might frown on a stream-of-consciousness style of text. It works for James Joyce, and perhaps is all right for literary magazines, but not so much scientific magazines. Personally, I find the stream-of-consciousness writing very difficult to follow– whether Joyce or Peers. Of course, Dr. Peers might simply use the breezy “dude” stream-of-consciousness style for blog comments. The manuscripts might be better.

            In any case, I agree with Harriet that an inductive hypothesis needs to be tested experimentally before changing the practice of medicine.
            Such testing is not unique to Medicine. For example, Einstein’s General Relativity is about an inductive a model as you could achieve, but many scientists–appropriately– reserved judgement until a prediction uniquely made by the model was observed: light bent by gravity was detected by Eddington and others during a solar eclipse in 1919.

            So the watershed finding that could propel Dr. Peers to fame and acceptance is a unexpected prediction from the model that is demonstrated to be true.

            Believe me Dr. Peers (if you are reading this), reviewers and scientists don’t favor my scientific ideas favorably either. But if I back them up with data that cannot be easily explained in another way, most come around.

            1. Harriet Hall says:

              “I don’t think I’d be so harsh as to call non-publishing criminal or unethical”

              What would you have called it if the discovery of penicillin had not been published? If knowledge of the effectiveness of smallpox vaccine or polio vaccine had not been shared with the public?

              Think of the untold suffering that could be prevented and the lives that might be saved by disclosing the cause and treatment of Alzheimer’s.

              1. MadisonMD says:

                Dr. Hall:
                I was sloppy in what I wrote. I meant to be it clear that I was speaking specifically to Dr. Peer’s case. Yes I fully agree that it would be criminal if penicillin or vaccines were withheld and not published. If Dr. Peers definitely had such a knowledge and, moreover, had convincing evidence that it is true, I expect that you and the other scientists would have reacted differently.
                So this–albeit preliminary– vetting convinces me that he is not a moral monster. Nevertheless, I’d encourage him to publish if he has the ability to put it in the proper format.

              2. Andrey Pavlov says:

                Yes, that was my point – he is claiming knowledge of significant breakthroughs to shift the paradigm of Alzheimer’s research but has also stated that he has no desire to publish it. Assuming the former true then my assessment stands. Of course, I do not think it likely to be true, but if he genuinely does then it is inconsistent with an ethical person to intentionally withhold that information from peer review.

    2. Harriet Hall says:

      In an e-mail, Dr. Robert told me he has identified “the main cause of AD and an anti-aging molecule that may arrest disease progression.”

      Lone genius alert: He is claiming to have done something the entire scientific medical establishment has been unable to do: find the main cause of AD and a way to arrest the disease. What hubris!

      He only has a hypothesis that has not been tested. The health effects of a Mediterranean diet can’t be attributed to any single component, and cherry-picked studies (mostly in animals) that tend to support the hypothesis are not enough. I would be delighted if his hypothesis pans out, but I must withhold judgment for the time being.

      1. Dr Robert Peers says:

        Hi Harriet

        Thank you for your detailed analysis of my hypothesis, and for your helpful comments

        Have a nice day!

        Ps..the Andy dillin anti ageing alzheimer mouse study, that you say I cherry picked..do you know any similar studies, perhaps with negative conclusions, that I have deliberately ignored?…has now led to the discovery, at Hebrew university in Jerusalem, of a drug that suppresses the same pro growth, pro ageing igf signal pathway, designed specifically to induce the expression of anti ageing protein chaperones and heat shock proteins, that dillin showed were able to reverse both alzheimer pathology and cognitive defects, in his transgenic alzheimer mice…should sell well…my point is that myo inositol suppresses exactly the same pathway…with similar anti cancer and antI alzheimer effects…I suggest you study the anti ageing literature, and also learn the difference between a speculative and an inductive hypothesis, as I employ only the traditional inductive method pioneered by Gilbert, Newton and bacon.

  14. Angora Rabbit says:

    This is for Stan:
    I commend you for working to self-educate yourself on issues of nutrition. Unfortunately, the risk one runs with a Google education is that it does not enable a person to see where their gaps in learning and information are.Information and Knowledge are NOT the same thing. When you post about the VE form used, I’m sorry to say that this gap appears. What you say reflects our thinking perhaps 15yrs ago. It does not take into account the discovery of Tocopherol Transfer Protein (TTP), which explained a lot and changed everything.

    For many vitamins and minerals, organisms have evolved machinery to enhance micronutrient utilization and bioactivity. For years we thought that lipoproteins were that system for VE. We now know that system is TTP, made by the liver to deliver postprandial VE to tissues around the body.

    Now here’s the thing. As you say, there are six major VE forms, three tocopherols and three tocotrienols. But what TTP revealed is that ONLY alpha-tocopherol is the VE form that the body prefers to use, because only alpha-Tocopherol has 100% binding affinity for TTP. b-Toco has 38%, and the rest bind weakly from there. So in fact, the authors WERE using the best bioactive form that is naturally preferred by humans. Once this was discovered, clinical trials of VE shifted to alpha-Toco because it is the best form for the body.

    The other 5 isoforms are not retained by the body, nor are they appreciably stored in the liver, and their half-life in humans is very short. In fact, the liver prefers to degrade and dispose of tocotrienols over tocopherols, indicating that those forms are not preferred by the body – indeed, the body prefers to get rid of them!

    And before you start complaining that they used an unnatural form, apparently Google U also failed to reveal that alpha-tocopherol is enantiomeric (look up the word on Wiki). There are 8 stereoisomers of aTE and only the 2R-stereoisomers are maintained by humans (RRR, RSR, RRS, RSS); the S-enantiomers have short halflives in consequence (SRR, SSR, SRS, SSS).

    In other words, the authors chose exactly the right form of VE (no surprise). They picked the form with the strongest potency and bioactivity in humans, and, sadly, the results were not what some had hoped. But the data are what they are.

    Stan, I have said this to you before, and I’ll say it again. I strongly encourage you to get a real education about nutrition. A good starting point would be a textbook that covers the principles of Physiology, so that you understand better concepts like bioavailability, homeostasis, and regulation that are key to understanding nutrient roles and DRIs. And then get yourself a really good nutrition textbook (Whitney/Rolfes is a nice start). I understand these can be easily searched for on Google.

    1. Sawyer says:

      Oh come on AngoraRabbit, we all know the concept of enantiomers is a Big Pharma conspiracy! And racemic mixtures are an invention of white supremacists. Nature would never create such dastardly compounds.

    2. MadisonMD says:

      Thank you, Angora. This was very informative.

      It’s plain that Stan is not really interested in an education on nutrition. He’s interested in marketing his wares.

    3. Andrey Pavlov says:

      @angora rabbit:

      You evoke strong feeling of nerd crush in me. Thanks for taking the time to comment!

    4. Andrés says:

      Angora Rabbit said (my bolds):

      They picked the form with the strongest potency and bioactivity in humans

      From wikipedia (my bolds):

      Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many molecules in the bodies of living beings are enantiomers themselves, there is sometimes a marked difference in the effects of two enantiomers on living beings.

      I have already cited Jensen & Lauridsen (2007) (my bolds):

      Synthetic all-rac-alpha-tocopherol consists of a racemic mixture of all eight possible stereoisomers. Assessing the correct biological activity in form of bioavailability and biopotency has been a great challenge during many years as it is difficult to measure clinical endpoints in larger animals than rats and poultry.

      For humans and other animals, only different biomarkers or surrogate markers of bioactivity have been measured, and due to the lack of good biological markers for bioactivities, bioavailability is often used as one of the surrogate markers for bioactivities with those limitations this must give.

      7/8 of dl-α-tocopherol are xenobiotic substances. You have clearly graded their bioavailability by TTP affinity. The question is if we are certain that enantiomers RSR, RRS, RSS have no deleterious effect in comparison to RRR (d-α-tocopherol aka vitamin E) once arrived at their destination. If there is not any more recent direct information about their bioactivity and safety I will keep avoiding it while possible in favor of d-α-tocopherol as a prudent strategy.

  15. Jeff says:

    @Angora Rabbit: My understanding was that newer, more bioavailable forms of tocotrienols have been developed are starting to be used in clinical trials. Google this phrase to read the pdf file:

    Tocomin SupraBioTocomin SupraBio®: Clinically-Proven
    HEPATOPROTECTIVE Tocotrienol

    1. MadisonMD says:

      Jeff– these marketers are a bunch of hacks. If the title didn’t give it away to you, then how were you not clued in by a photo-shopped liver above outstretched hands?

      If you are fooled this easily, then you should know there are people on the internet who would like to get in touch with you. They put your contact information on a very special list sold to duplicitous natural remedy suppliers.

  16. Angora Rabbit says:

    Hi Jeff,

    A quick Pubmed search indicates just 7 papers using it, and reveals that Tocomin is just α-tocopherols and α,γ,δ-tocotrienols in palm oi). From one paper:
    “It is a reddish vegetable oil suspension of naturally occurring tocotrienols and tocopherols that are extracted and concentrated from palm tree fruit and it contains
    predominantly 10–14% a-tocopherols, 10–14% a-tocotrienols, 20–24% g-tocotrienols, and 3–6% d-tocotrienols by weight.”

    And if it’s reddish it also contains carotenoids and pro-vitamin A. It’s a product of the Malaysians, who are very keen on increasing red palm oil market share. (insert long boring story here) It’s actually more dilute than good ole’ a-tocopherol. So my opinion hasn’t changed. But bless ‘em for actually telling us what’s in it!

    Thanks for bringing it up!

  17. Jeff says:

    MadisonMD: Here’s one study using the SupraBio System:
    http://www.ncbi.nlm.nih.gov/pubmed/24373555

    Here’s another article about tocotrienol absorption:

    http://www.palmoilhealth.org/news/research-news/poor-oral-bioavailability-of-tocotrienols-can-be-overcome-with-tocomin-suprabio/

    Perhaps I should have posted these two links instead of the pdf file.

    1. MadisonMD says:

      Yes– the pubmed link is bit more helpful. Thanks Jeff.

      So this study shows that this product can be useful to treat Non-alcoholic steatohpatitis (NASH). As expected from Angora’s comment, it was supported by the Malaysia Palm Oil Board. It is difficult to verify that the primary endpoint was prespecified, because the clinicaltrials.gov identifier oddly points to a study entitled Neuroprotective and Cardioprotective Effects Of Palm Vitamin E Tocotrienols.

      In any case, we already have a much larger, better designed study to demonstrate that Vitamin E can be used to treat NASH, so these results with Vitamin E in the palm oil product are not very surprising. So, it seems like it could be used for this one specific condition if you are diagnosed with it. But it may cost less to just pick up the generic alpha-tocopherol than to use this branded product.

    2. AngoraRabbit says:

      Jeff, thanks for these. The problem for VE isn’t gut absorption – this is pretty good for most of the isomers simply because they are absorbed along with the fat (still waiting for a gut VE transporter to be discovered, if it should exist). If there is fat in the diet, the VE will be absorbed with it (along w/ the other fat-soluble vitamins). The problem is with retention once absorbed, and no amount of pre-emulsification in the pill is going to help with that.

      I read the corporation link – it’s just marketing spin. Their overarching goal is to promote sales of their product from their extensive palm oil plantations. No different from Big Pharma, in that it’s all about $$.

      Red palm oil is great for preventing vitamin A deficiency in populations with VAD, but there isn’t a lot of money in humanitarian aid or in shifting people to cook with red palm oil, is there? Hence the promotion of product to the moneyed folks.

  18. Harriet Hall says:

    Dr. Robert Peers has apparently stopped posting here and instead is inundating me with e-mails, mostly copies of letters he has sent to other people. Nine so far just this morning. In one of them he says ” I have spent 22 years completely solving the causes of AD, PD, schiz and bipolar. ”

    His statements and actions are those of a crank, not a scientist. If his hypothesis is correct, he is only undermining his cause and delaying its acceptance by his actions. I feel justified in ignoring anything he has to say until he publishes in a peer-reviewed journal.

  19. Carl Fink says:

    Surprised no one pointed this out.

    86% were white, 13% black, and 11% Hispanic.

    That adds to 110% of the participants.

    1. jay says:

      Actually, it adds to 99%, since Hispanic is not a race, but an ethnicity. Hispanics can be white, black or Asian. The missing 1% is indicated as “other” in Table 1.

    2. nancy brownlee says:

      @Carl Fink


      86% were white, 13% black, and 11% Hispanic.

      That adds to 110% of the participants.”

      Hispanic people may be any color in the human spectrum, and may self- identify as a color plus Hispanic ethnicity . I don’t know if this is relevant, in this case.

    3. MadisonMD says:

      Good eye. But, in U.S., hispanic is counted as ethnicity–not a race– and so can fall within black or white race.

      1. Chris says:

        I personally despise questions about being in the Hispanic ethnic group.

        First what does it mean? Does it even include someone from Brazil, Belize, Suriname, Guyana, French Guiana or Trinidad and Tobago? What about Haiti? Jamaica? Or Aruba? Curacao? The Bahamas? What about the families in California who are descended from the >a href=”http://www.zabalavineyards.com/vision.php”>original Spanish colonists?

        Was the independence hero of Chile, Bernardo O’Higgins, Hispanic or Irish? What about the disgraced former president of Peru, Alberto Fujimori?

        I was born in Panama. I lived a third of my youth there and in Venezuela. I can even communicate in Spanish. Why am I not Hispanic, when one of the band parents who was born in Florida a few years after his parents fled Cuba, and does not speak one word of Spanish, considered Hispanic (and yes, I teased him about this when we were chaperones at a band camp)?

        Anyway, it is just one of my annoyance triggers when asked about Hispanic heritage in a phone survey. Especially after reading 1493 by Charles Mann (I learned about the Spanish hierarchy by heritage from the teacher who taught us Venezuelan history and social studies four times a week, she was an awesome storyteller).

      2. Chris says:

        Oh, crud, my moderated comment does not show.

        In short: the definition of “Hispanic” is silly, which one would know if they paid an iota of attention to anything that happens in South America (including the names of “national heroes”), or even realized that Spanish is not the language of Brazil. Only an idiot would think of it as a definitive demographic piece of data.

        By the way, not every one who speaks Spanish is “Mexican.” Just something else that annoys me.

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