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Does Glucophage Make Alzheimer’s Worse?

Metformin, now there’s a drug story for you. It’s a startlingly small molecule, the sort of thing that chemists look and and say “That’s a real drug?” It kicked around in the literature and the labs in the 1960s, was marketed in Europe in the 1980s but was shopped around in the US for quite a while, partly because a lot of people had just that reaction. (It didn’t help that a couple of other drugs in the same structural class turned out to cause lactic acidosis and had to be pulled from use). Bristol-Myers Squibb finally took metformin up, though, and did extremely well with it in the end under the brand name Glucophage. It’s now generic, and continues to be widely prescribed for Type II diabetes.
But for many years, no one had a clue how it worked. It not only went all the way through clinical trials and FDA approval without a mechanism, it was nearly to the end of its patent lifetime before a plausible mechanism became clear. It’s now generally accepted that metformin is an activator (somehow, maybe through another enzyme called LKB1) of adenosine monophosphate kinase (AMPK), and that many (most?) of its effects are probably driven through that pathway. AMPK’s a central player in a lot of metabolic processes, so this proposal is certainly plausible.
But never think that you completely understand these things (and, as a corollary, never trust anyone who tries to convince you that they do). A new paper in PNAS advances the potentially alarming hypothesis that metformin may actually exacerbate the pathology of Alzheimer’s disease. This hasn’t been proven in humans yet, but the evidence that the authors present makes a strong case that someone should check this out quickly.
There’s a strong connection between insulin, diabetes, and brain function. Actually, there are a lot of strong connections, and we definitely haven’t figured them all out yet. Some of them make immediate sense – the brain pretty much has to run on glucose, as opposed to the rest of the body, which can largely switch to fatty acids as an energy source if need be. So blood sugar regulation is a very large concern up there in the skull. But insulin has many, many more effects than its instant actions on glucose uptake. It’s also tied into powerful growth factor pathways, cell development, lifespan, and other things, so its interactions with brain function are surely rather tangled.
And there’s some sort of connection between diabetes and Alzheimer’s. Type II diabetes is considered to be a risk factor for AD, and there’s some evidence that insulin can improve cognition in patients with the disease. There’s also some evidence that the marketed PPAR-gamma drugs (the thiazolidinediones rosiglitazone and pioglitazone) have some benefit for patients with early-stage Alzheimer’s. (Nothing, as far as I’m aware, is of much benefit for people with late-stage Alzheimer’s). Just in the past month, more work has appeared in this area. The authors of this latest paper wanted to take a look at metformin from this angle, since it’s so widely used in the older diabetic population.
What came out was a surprise. In cell culture, metformin seems to increase the amount of beta-amyloid generated by neurons. If you buy into the beta-amyloid hypothesis of Alzheimer’s, that’s very bad news indeed. (And even people that don’t think that amyloid is the proximate cause of the disease don’t think it’s good for you.) It seems to be doing this by upregulating beta-secretase (BACE), one of the key enzymes involved in producing beta-amyloid from the larger amyloid precursor protein (APP). And that upregulation seems to be driven by AMPK, but independent of glucose and insulin effects.
The paper takes this pretty thoroughly through cell culture models, and at the end all the way to live rats. They showed small but significant increases in beta-secretase activity in rat brain after six days of metformin treatment. And the authors conclude that:

Our finding that metformin increases A-beta generation and secretion raises the concern of potential side-effects, of accelerating AD clinical manifestation in patients with type 2 diabetes, especially in the aged population. This concern needs to be addressed by direct testing of the drug in animal models, in conjunction with learning, memory and behavioral tests.

Unfortunately, I think they’re quite right. Update – in response to questions, it appears that metformin may well cross into the brain, presumably at least partly by some sort of active transport. There’s some evidence both ways, but it’s certainly possible that relevant levels make it in. With any luck, this will be found not to translate to humans, or not with any real clinical effect, but someone’s going to have to make sure of that. For those of us back in the early stages of drug discovery, the lesson is (once again): never, never think we completely understand what a drug is doing. We don’t.

24 comments on “Does Glucophage Make Alzheimer’s Worse?”

  1. processchemist says:

    Ah, metformin… studying a scaled up synthesis, a chemist I know collapsed while filtering in a buchner half a Kg of product (He woke up ok without consequences – I always tell this story to young people unwilling to use a mask to work with powders of APIs).
    The PNAS story is interesting but: does metformin cross the BB barrier (I know nothing about it)?

  2. CF says:

    The outstanding Alzhiemer’s research published this year is very exciting. The PrP/a-beta article in Nature this week, and the APP/DR6 article last week are well worth reading.
    As an aside I think PNAS should institute a policy that any articles which mention marketed products should be open access upon publication.

  3. Jesse says:

    Metformin may not be permeable to BBB by passive diffusion, as you look at its structure. It still can pass across BBB by uptake transporters (OCTs specifically).

  4. CMC Guy says:

    So has the first Lawsuit been filed yet claiming metaformin increased AD? Because it is a generic who gets sued and likewise who would be responsible for conducting the studies mentioned?

  5. retread says:

    Derek: “There’s a strong connection between insulin, diabetes, and brain function.”
    Quite true. There are also strong connections between just about any significant illness and brain function — hypertension, kidney disease, liver disease, lung disease — you name it. Having any one of them makes it harder for your brain to function. All of them produce some degree of cognitive difficulty on their own, and if you have another problem going on in your brain (incipient Alzheimer’s, mild cognitive impairment, previous head injury, previous stroke), they will add to (or worse multiply) the existing problems.
    #2 “The outstanding Alzhiemer’s research published this year is very exciting.” Hopefully, it will lead to something. However, I’ve been hearing this sort of thing for 40 years now and we still don’t have anything useful for Alzheimer’s despite rather breathless propaganda to the contrary.
    I’m the one who had to listen to this stuff when desperate families of patients brought it in, try the latest nostrum (assuming it wasn’t actually harmful) and watch it fail, so excuse the cynicism. However, you are the people who (hopefully) will eventually produce something helpful, so be excited and keep on working. It is a fit use of your intelligence, even if you fail, as so many have before you.

  6. Rev. Howard Furst says:

    The authors make a big deal about insulin ameliorating the negative effects of metformin, though they don’t adequately address the little issue that insulin access to the brain is limited by the blood-brain barrier, whereas metformin does get into the brain. The effects of insulin on metformin-induced changes in beta-amyloid processing in vivo are most likely mediated by peripheral effects of the insulin. Likewise, Actos and Avandia are tissue-selective insulin sensitizers that probably have no direct effect on neuronal glucose utilization, so their possible effects on Alzheimer’s would also haveto be peripheral, most likely vascular.

  7. john fitzgibbon says:

    So given the recent literature links between type II diabetes/insulin sensitivity in the body and Alzheimers and the fact that lifestyle can significantly alter insulin sensitivity should we not start pushing different diets (low carb/low glycemic) and lifestyles as way to slow/prevent this disease.

  8. Ben says:

    Derek, I think you’re neglecting the obvious conclusion here — diabetes cures Alzheimers…
    In all seriousness, until I see a convincing mechanism of action for metformin, I think a lot of the discussion around linking AMPK to BACE is speculative goal-chasing where scientists look for exactly what they’re looking for. This isn’t to say the work isn’t good, but before I’m willing to buy this conclusion, I’d like to see a credible MOA.

  9. K says:

    Just to through another one in the mix…
    I heard a talk once where the presenter said that patients on metformin showed a 40%* lower incidence of cancer.
    *My memory of the precise percentage may have faded over time, but the figure was rather remarkable, even if 40% is wrong.

  10. Gretchen says:

    1. Although fatty acids don’t cross the BBB, ketones do, and the brain can run on 50% to 75% ketones when it has to, as with a low-carb diet, after a short period of adaptation.
    2. Not a lot of insulin crosses the BBB. exogenous insulin seems to help with AD only when given intranasally.

  11. Dick G says:

    So do we substitute a new FDA approved branded drug for Metformin only to find out, ten years from now, that it also leads to Alzheimers. Sadly both Diabetes(type2) and Alzheimers are preventable. Both result from a combination of genetic type, diets high in processed grains and modern vegetable oils (omega 6’s). Yet the ADA and mainstream nutrition still are strong proponents of low fat high grain diets and they still encourage the substitution of polyunsaturates for saturated fats. Morbidity will not decrease unless we return to more traditional foods. The historical record of modern disease should be proof that the western diet and not saturated fats are the enemy.

  12. Matteblacke says:

    Dick G:
    Apologies for my slowness (possibly metformin related, who knows), but please remind me again how genetic type is a preventable cause of type 2 diabetes and Alzheimers?
    I agree with you, in that it is difficult to conclusively prove a MOA for a side-effect when the drug itself has an (as yet) unproven mode of action.

  13. Not to clutter up a scientific discussion with anecdote, but this post reminds me of a clinical scenario written by a fellow medical blogger in which Alzheimer’s like dementia in an elderly patient was reversed upon discontinuation of her metformin.

  14. kevin horgan says:

    Andrew Morris in Dundee has studied the relationship between cancer and metformin – apparently there is a ~ 40% reduction – the Scottish health system is structured to facilitate epidemiologic studies. Time to look at incidence of Dementia.

  15. kevin horgan says:

    Andrew Morris in Dundee has studied the relationship between cancer and metformin – apparently there is a ~ 40% reduction – the Scottish health system is structured to facilitate epidemiologic studies. Time to look at incidence of Dementia.

  16. Dick G says:

    Mattleback, The APOE4 allele is a widly recognized risk factor for the development of Alzheimer’s. The incidence of Type II Diabetes is much more prevelant on some etnic types which suggests a genetic link. As for “genetic type is a preventable cause of type 2 diabetes and Alzheimers” these are your words.

  17. Stephanie says:

    You previously visited AMPK and the brain with the AMPK suppressors and appetite suppressants Rimonabant and Taranabant.
    Now you’re saying metformin, an AMPK activator, may contribute to Alzheimer’s.
    A new study links AMPK to brain development:
    Enzyme Is Essential Contributor to Brain Growth
    When scientists at Washington University School of Medicine in St. Louis selectively disabled the enzyme AMP-activated protein kinase (AMPK) in mouse embryos, overall brain size was reduced by 50 percent, the cerebrum and cerebellum were shrunken, and the mice died within three weeks of birth.
    We clearly more research on AMPK’s effect on the brain.

  18. Stephanie says:

    This just gets stranger and stranger.
    Found this in today’s news about AMPK
    Anti-Psychotics and Weight Gain
    Written by Shamir Benji on March 8, 2009 – 6:48pm
    A few recent animal studies have shown that anti-psychotic drugs can increase the activity of an enzyme known as the appetite-regulating enzyme commonly known as AMPK. Further, all anti-psychotics also limit the ability of insulin to work; the resulting insulin resistance has also been associated with weight gain.
    So what are the treatment options for these individuals?
    To begin with, all individuals who take anti-psychotics should be encouraged to eat healthy and enter into an exercise program. A decrease in calorie consumption is important.
    A single study from China showed the anti-diabetic drug, metformin, did reverse the weight gain induced by anti-psychotics. These effects were observed in diabetics who were on anti-psychotic drugs. Metformin should not be taken by individuals with normal blood sugar because this can lead to a severe lowering of blood sugars that can be life threatening. This may not be of great importance in China, but in North America, prescribing a diabetic drug to a non-diabetic is one “great method” of generating a medical malpractice claim.

  19. Caleb Murdock says:

    Taking Avandia for just two weeks gave me permanent tinnitus, and I suspect from my research that it was my brain which was affected and not my ears. If that’s the case, then Avandia can get into the brain. My tinnitus now gets worse or better depending on how high my blood sugar is. There is so much that we don’t know about the drugs that we use.

  20. Pasi Saario says:

    I’m here for the first time. This metformin/AD article brought me here. Few things here I’d like to comment. This research is certainly not a good news for diabetics on metformin.
    You wrote (as many others) that metformin is a AMPK activator. There has been evidence that metformin does also inhibit complex I of the mitochondrial respitatory chain. This may lower ATP-levels and thus activate AMPK.
    I’ve understood that AD is a disease of neuronal hypometabolism and problems are mainly related to glucose/insulin-axis.
    Complex I in mitochondria “burns” glucose derived NAPDH; fats deliver also FADH2 to complex II.
    If metformin “shuts up” complex I in AD brain neurons, which may be functioning not so well in the first place, that may explain at least a part of the adverse effect.
    Metformin may also affect lactate metabolism which is important for neurons.

  21. retread says:

    #20 All dying cells show decreased metabolism. The problem (as it is with every biochemical parameter found in Alzheimer’s disease ) is whether decreased metabolism (which has been well documented, even in preclinical states) is a cause of the disease or an effect of “the’ underlying pathologic process(es).

  22. Karen says:

    This was very very interesting. I googled to see if there was any connection with hypoglycemia and dementia. My Mother seems to get worse when her blood sugar drops. After giving her some karo syrup the next day she does better. Maybe it is not related but seems to help so that is why I googled this subject. I know hypoglycemia is opposite of diabetes,but her levels I am sure are changing everyday. Any input,comments?

  23. Deb says:

    That study is strange in many ways.
    – the metformin doses in this study are about 500 times higher than used for diabetes.
    – insulin hardly crosses the brain barrier
    – other recent work indicate that metformin may PROTECT from AD by inhibiting neurofibrillary tangles:
    All in all, we tend to have overreactions. So far is that metformine reduces overall mortality by close to 40% compared to other standard diabetes II treatments

  24. Lane Simonian says:

    A study like this and the one below help bring it all together.
    J Neurochem. 2011 Aug;118(4):460-74. doi: 10.1111/j.1471-4159.2011.07331.x. Epub 2011 Jun 24.
    AMP-activated protein kinase: a potential player in Alzheimer’s disease.
    Salminen A1, Kaarniranta K, Haapasalo A, Soininen H, Hiltunen M.
    Author information
    AMP-activated protein kinase (AMPK) stimulates energy production via glucose and lipid metabolism, whereas it inhibits energy consuming functions, such as protein and cholesterol synthesis. Increased cytoplasmic AMP and Ca(2+) levels are the major activators of neuronal AMPK signaling. Interestingly, Alzheimer’s disease (AD) is associated with several abnormalities in neuronal energy metabolism, for example, decline in glucose uptake, mitochondrial dysfunctions and defects in cholesterol metabolism, and in addition, with problems in maintaining Ca(2+) homeostasis. Epidemiological studies have also revealed that many metabolic and cardiovascular diseases are risk factors for cognitive impairment and sporadic AD. Emerging studies indicate that AMPK signaling can regulate tau protein phosphorylation and amyloidogenesis, the major hallmarks of AD. AMPK is also a potent activator of autophagic degradation which seems to be suppressed in AD. All these observations imply that AMPK is involved in the pathogenesis of AD. However, the responses of AMPK activation are dependent on stimulation and the extent of activating stress. Evidently, AMPK signaling can repress and delay the appearance of AD pathology but later on, with increasing neuronal stress, it can trigger detrimental effects that augment AD pathogenesis. We will outline the potential role of AMPK function in respect to various aspects affecting AD pathogenesis.
    In the absence of oxidative stress or in the case of mild oxidative stress, AMPK activation leads to the activation of the neuroprotective Akt kinase. But when this kinase is blocked by presenelin gene mutations or inhibited by factors leading to peroxynitrites, AMPK activation leads to the further formation of peroxynitrites, caspase activation, beta secretase activation, and in most cases amyloid. Or in other words metformin’s activation of the AMPK adds to the risk of Alzheimer’s disease in people already experiencing neuronal stress.

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