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Unpleasant Alzheimer’s News

Here are a couple of new developments in Alzheimer’s and dementia – nothing encouraging, unfortunately. A new paper in JAMA Internal Medicine, from a team that’s looked at multiyear patient records, suggests that there’s a dose-response relationship between use of strong anticholinergic drugs and later development of dementia and Alzheimer’s. These compounds include tricyclic antidepressants, first-generation antihistamines (chlorpheniramine, etc.) , and muscarinic antagonists given for bladder control, and you also have pure muscarinic compounds like hyoscine/scopolamine that are given in a number of indications. The results here look pretty solid, as far as I can tell – increased use of cholinergic antagonists seems to be a risk factor, and the risk goes up with dose. That’s not very welcome news, given the number of older patients who are taking one or more drugs in these classes. This is another one to add to the “environmental insult” part of the ledger on slow-developing CNS problems, which is getting to be a thicker stack of evidence than I would have once thought.

Now, just why such exposure should lead to a higher rate of dementia is a good question. It’s certainly true that cholinergic neurons take a beating in Alzheimer’s pathology. There are five types of muscarinic receptors, though, and they can’t all be the same here, mechanistically (that said, many compounds are rather unselective among them). For a while in the 1990s, companies were actually working on m2 antagonists as a possible mechanism for potentiating cholinergic signaling in Alzheimer’s (I was involved in some of that), but they were trying to be as selective as possible, just for the normal gamut of side effects.

In another area, there’s been another report on the “transmissible Alzheimer’s” front. Swiss pathologists have examined brain tissue from several people who died of Creuzfeld-Jacob disease, as in the earlier report in this area. These patients had contracted C-J from surgical grafts of dura mater (the previous report was from people who’d been exposed from human-derived growth hormone treatment). But these patients, in addition to the prion damage from the disease itself, also (as in the previous work) showed amyloid plaques in the brain and in vascular tissue, and they were quite young to have developed them. Control samples from people who’d died of sporadic Creuzfeld-Jacob (not associated with transfer of tissue) showed no such findings.

This paper is completely consistent, then, with the earlier paper’s hypothesis that surgery might transfer “seeds” of pathological amyloid protein, that over the years spread into plaques. That still doesn’t mean that Alzheimer’s is transmissible under ordinary circumstances – you could hardly duplicate the experience of having someone else’s amyloid protein inserted directly into your central nervous system, I’d think. But it does mean that surgical procedures (and surgical instruments) used in brain operations are worth considering closely. And it adds another piece to the amyloid puzzle.

22 comments on “Unpleasant Alzheimer’s News”

  1. Miles says:

    Deeply scary and thought provoking…..Derek, you are a gentleman and a scholar.

    1. fred gaskin says:

      Consider Yvette Sheline’s work on antidepressants and CSF AB production, Hippocampal Volume, Cognitive Function, especially in the elderly.

  2. petros says:

    Don’t forget all the programmes that were (and are) pursuing M1 agonists for this indication.

  3. Lane Simonian says:

    Certainly anticholinergic drugs can contribute to memory loss but a wider consideration of potential mechanisms is needed. Scopolamine, for instance, inhibits neuroprotective phosphatidylinositol 3-kinase/Akt pathway, Biphosphonate drugs such as Fosamax, also inhibit this pathway. One should also be leary of drugs whose overdose or perhaps chronic use increase peroxynitrite formation (acetaminophen, for instance).

    Good job of working on that stack of “environmental insult”. It will keep getting bigger.

    The second story seems alarming, but in the end should not be of concern. The assumption is that amyloid plaques cause Alzheimer’s disease and recent studies indicate that in certain situations the plaque is transmissible. However, the plaque is likely neuroprotective because it inhibits the formation of hydrogen peroxide which may be at the heart of prion diseases.

    Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia.

    Copper-dependent generation of hydrogen peroxide from the toxic prion protein fragment PrP106-126.

    Accumulation of prion protein in the brain that is not associated with transmissible disease.

    The likely problem in prion disease is that the infection spreads so quickly that not enough amyloid forms to inhibit the formation of hydrogen peroxide. Under slower stimuli of oxidative stress, more widespread amyloid plaques form as is the case in Alzheimer’s disease. The idea that amyloid plaques can be “seeded” is no proof at all that Alzheimer’s is an infectious disease.

  4. Mimac says:

    Well, any news if agonists are beneficial?

    Cochrane Database Syst Rev. 2001;(2):CD001749. Efficacy and safety of nicotine on Alzheimer’s disease patients. López-Arrieta JM, Rodríguez JL, Sanz F.

    REVIEWER’S CONCLUSIONS: This review is not able to provide any evidence that nicotine is a useful treatment for Alzheimer’s disease.

  5. Lane Simonian says:

    A little bit of agonism of acetylcholine receptors may be a good thing, but too much actually increases your risk for Alzheimer’s disease.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098701/

    Too much stimulation of acetylcholine and other g protein-coupled receptors leads to oxidation which in turn disables these receptors. Oxidation/nitration also inhibits the transport of choline and the activity of choline acetyltransferase. Then the appropriate antioxidant has to be used to try to reverse part of this damage.

    1. Harrison says:

      I think it is difficult to make a definitive link between excessive nicotine and Alzheimer’s disease based on smoking studies, given all the toxic substances in cigarette smoke. In addition, nicotinic acetylcholine receptors are ion channels, not GPCRs. Muscarinic receptors are GPCRs. M1 agonists have been around for decades and about a dozen have been in clinical trials, most famously Xanomeline by Lilly. Nobody could ever dose high enough to get efficacy without causing some nasty GI side-effects.

      1. Lane Simonian says:

        You are right, there are a number of compounds in cigarettes that can contribute to oxidative stress and nicotinic acetylcholine receptors are not g protein-coupled receptors. However, it is possible that nicotinic acetylcholine receptors still activate g proteins.

        http://onlinelibrary.wiley.com/doi/10.1002/bies.201300082/abstract

        If true, it provides a mechanism by which nicotine could add to oxidative stress and potentially one among several ways in which moderate to heavy cigarette smoking can contribute to Alzheimer’s disease.

        As an aside, my math problem was 2 +2= _. Maybe this is a good omen.

        1. Lane Simonian says:

          This study indicates that one of the mechanisms by which nicotine contributes to tau hyperphosphorylation is through the activation of the p38-mitogen-activated protein kinase.

          http://www.pnas.org/content/102/8/3046.full

          P38 mapk via peroxynitrite also leads to tau hyperphosphorylation by inhibiting the phosphotadiylinositol 3-kinase/Akt pathway and the subsequent activation of GSK-3. This also leads to the nitration of tau which may be one of the critical events in Alzheimer’s disease:

          FASEB J. 2006 Jul;20(9):1431-42.
          Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.
          Zhang YJ1, Xu YF, Liu YH, Yin J, Li HL, Wang Q, Wang JZ.

          These results provide the first in vivo evidence showing that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. Our findings reveal a common upstream stimulator and a potential therapeutic target for Alzheimer-like neurodegeneration.

          High quality evidence against the oxidative stress hypothesis for Alzheimer’s disease is welcomed but it has to be more than contradictory studies.

      2. Mark Thorson says:

        Lane linked to a speculative review article, not a meta-analysis. Smoking is inversely associated with Alzheimer’s Disease, and this is a robust result.

        http://www.ncbi.nlm.nih.gov/pubmed/1833354

        Because smokers are chronically exposed to peroxynitrite, this blows Lane’s pet theory out of the water.

        1. Lane Simonian says:

          A counter meta-analysis study on the relationship between smoking and Alzheimer’s disease.

          http://www.ncbi.nlm.nih.gov/pubmed/20110594

          1. Lane Simonian says:

            Perhaps, it is helpful to go through the process by which I came to my “pet hypothesis”. I started studying Alzheimer’s disease twelve years ago because my aunt and cousin were in the late stages of the disease and my mother was in the early stage of the disease. I started by looking at some of the major hypotheses for the disease: diabetes, high cholesterol, amyloid, etc. and what I found is that not everyone with Alzheimer’s disease had these. At best they could only be contributing factors. The one common element was that everyone with Alzheimer’s disease had calcium dysregulation. Then I went back and tried to identify the pathways that lead to caclium dysregulation. Part of that dysregulation was due to overactivation of inositol 1,4,5 triphosphate receptors. That is what leads to the second cut in the amyloid precursor protein mutation (gamma secretase).

            http://www.ncbi.nlm.nih.gov/pmc/articles/PMC43811/

            So I thought this was it. But then I found a chart linking phospholipase C to protein kinase C to p38 mapk to peroxynitrite. And eventually traced the intermediate link to NMDA receptor activation and the influx of calcium.

            That is when (three years into the research) I began to look for every causal link I could find between peroxynitrite and Alzheimer’s disease. First causes: everything from certain fungi, to high glucose levels, to moderate to heavy smoking, to BMAA, to DDT increase the production of peroxynitrite. Then the consequences; the receptors, enzymes, and transport systems oxidated or nitrated by peroxynitrite affect the release and synthesis of neurotransmitters involved in short-term memory, sleep, mood, social recognition, and alertness, reduce the flow of blood and the amount of glucose in the brain, prevent the regeneration of neurons in the brain, and kill neurons in the brain. Then I finally looked at treatments that seemed to have worked in clinical trials and they all involved peroxynitrite scavengers: eugenol in rosemary and geraniol in lemon essential oils via aromatherapy, and ferulic acid, syringic acid, vanillic acid, p-coumaric acid, and maltol in Korean red ginseng and heat processed ginseng.

            I understand that there is a fine line between cherry-picking and building evidence for a hypothesis. And not every new study fits comfortably into this hypothesis, but it often fits somewhere.

            I am not a genius scientist; I am just an historian who fit one study after another bit by bit to come to what appears to be a sustainable hypothesis (and to give credit where credit is due long before I knew it there have been scientists advocating this hypothesis for Alzheimer’s disease).

          2. Mark Thorson says:

            The actual paper being here:

            http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906761/

            One of the co-authors, Glantz, is the most militant anti-tobacco activist in academia. Does this paper sound objective to you? How often does a meta-analysis refer to a “secret report” and make allusions to conspiracies which are then used to construct their rejection criteria for studies in the meta-analysis? This is not an ordinary meta-analysis.

            But of course, you must go picking in the cherry orchard, because anything else blows your cherished peroxynitrite theory out of the water.

  6. Bryan says:

    Is it possible that the underlying conditions that require anticholinergic drugs are risk factors for AD,or were the researchers able to control for this?

  7. Chronic chlorpheniramine user says:

    “That’s not very welcome news, given the number of older patients who are taking one or more drugs in these classes.”

    No kidding. Senility was already the thing that scared me most about growing old….

  8. Nile says:

    Every time you read a paper about prions with results from human autopsy, spare a thought for the pathologist.

    After a beer or two, get them talking about things that frighten them – and few things do, their work by definition is up-close and personal with things that kill people – and CJD autopsy is right up there at the top.

    Nothing cleans and ‘sterilises’ the instruments: that which is not dead cannot die. Pathologists, however, can. Move on to stronger drink and they will tell you to your face that there is no minimum infectious dose: if anything can possibly be real in homeopathy, CJD contamination comes the closest.

    Maybe methyl mercury and CF3 are not so bad to work with, after all.

    1. Mark Thorson says:

      That’s why I don’t eat U.S. beef anymore. The USDA had a surveillance project, but when they started finding too many cattle with BSE, they mostly curtailed it. Their behavior is indistinguishable from a cover-up of an epidemic. In a report, their panel of experts said that BSE was now permanently present in U.S. herds. USDA also prohibited Creekstone Farms from testing their cattle for BSE. In Japan, they test all of the cattle for BSE. I miss beef, but I’m making do with chicken and pork. There’s never been a natural case of a transmissable spongiform encephalopathy observed in a pig.

      1. Alastair Donald says:

        There’s never been a natural case of a transmissable spongiform encephalopathy observed in a pig……………….that you have been told or know about!

  9. Thomas says:

    The anticholinergics paper is from a year ago — it got quite a lot of press when it appeared.

  10. Anon says:

    What if it were peroxynitrites after all?

    Cu atsm starts a trial in ALS in April.

    1. C T says:

      Increased peroxynitrites would be the result of increased hydrogen peroxide, and we know the body’s peroxidase activity decreases with age. A connection between peroxynitrites and dementia seems plausible. I find Lane’s mention of rosemary especially intriguing.

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