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Just How Worthless Are the Standard Alzheimer’s Models?

As mentioned yesterday, Alzheimer’s therapies have, for the most part, been a cliff over which people push bales of money. There are plenty of good reasons for this: we don’t really know what the cause of Alzheimer’s is, when you get down to it, and we’re the only animal that we know of that gets it. Mouse models of the disease would be extremely useful – you wouldn’t even have to know what the problem was to do some sort of phenotypic screen – but the transgenic mice used for these experiments clearly don’t recapitulate the human disease. The hope for the last 25 years or so has been that they’d be close enough to get somewhere, but look where we are.

A team from several Japanese universities has some suggestions about what might be going wrong in that part of the field. In 2014  a paper from these groups described a new model that knocked-in mutant forms of amyloid precursor protein (APP), as seen in some of the human early-onset forms of the disease. (That’s as opposed to overexpression of APP and/or presenilin proteins themselves). This new paper says that the pathology seen in the previous rodents is not actually due to the amyloid protein that they’ve been engineered to overexpress.

One of the supposed markers of amyloid toxicity is the production of the p25 protein, an activator of the CDK5 enzyme. There was a lot of interest a few years ago about reports of this in human brain tissue, post-mortem, but the field has been rather confused since then, with some labs saying that this was indeed a good market in both mouse models and humans, and others unable to reproduce the effects. p25 is elevated, though, in the APP-overexpressing mice, which has kept interest alive in the connection between the two. It appears, though, that the p25 in these mice is a function of membrane disruption caused by the protein overexpression. The single-APP-knock-in mice, they report, have tons of amyloid, but no p25 to speak of.

In fact, they say, most of the phenotypes that you see in the APP/presenilin-overexpressing mouse model are probably artifacts. As you would figure, some others in the field are not taking that suggestion very well – here’s an excellent roundup from Alzforum on the situation as it stands now. The Japanese single-knock-in mice were very difficult to generate, are much in demand, and haven’t quite been around long enough to see what happens to them as they age. They might be just what the field has been looking for, or they might turn out to be another dead end. But either way, they seem to be pointing out serious problems with the previous standard mouse models, which would call into question the relevance of hundreds (thousands?) of previous papers using them.

85 comments on “Just How Worthless Are the Standard Alzheimer’s Models?”

  1. bank says:

    Mouse models based on APP are even worse than is described in these papers, and none of them actually experience loss of neurons, which is a defining feature of AD in humans.

    A recent editorial stated this rather bluntly: “we expect that virtually all existing [mouse] models would be classified as ‘not’ AD, since the combination of human-like patterns of neuritic plaques and neurofibrillary tangles distribution does not exist in any published mouse model.”

  2. Mouseymousey says:

    What about the Degu?

  3. dearieme says:

    “we’re the only animal that we know of that gets it”: that’s odd if we are “the third chimpanzee”. In fact, it’s so odd that it must be a clue. What else is odd about us as chimps?

    1. immunology says:

      our immune response to inflammation and/or infection perhaps? there’s a number of examples where viral infections that are pathologically lethal to human are benign in chimp. i doubt mouse models could be engineered to realistically mimic the human immune system. thoughts?

    2. Daniel Barkalow says:

      The other sorts of chimp typically die in their 30s. It might be that they get Alzheimer’s exactly like us, except that very few of them manage to live long enough, and we’re not monitoring a large elderly population of them like we are of humans. They’re also not going to be a useful model if it takes decades to show any effects.

  4. bhip says:

    Other than models of infectious disease & (too a certain degree) blood pressure), don’t all animal models basically suck? Cancer models-bad. Multiple sclerosis-bad. Arthritis-pretty bad. Pain-bad. Depression-really bad.
    If your compound works in an animal model, it’s comfort food.
    The interesting thing is that activity of your compound/hypothesis in an animal model really has no predictive value for human disease but lack of activity kills programs before clinical testing.

    1. In Vivo Veritas says:

      I’d argue that met disease/glucose homeostasis has some fairly (not perfectly) translatable models.

    2. johnnyboy says:

      There is no such thing as a good animal model for a human disease. However there are adequate animal models for human disease processes, which is how you should use models. Not as a predictor of response in humans, but as a way to understand specific components of the disease process. Which works well when you understand the processes behind the human disease, but not so much when you don’t (ie. in AD, for instance).

  5. Curious Wavefunction says:

    As George Whitesides once mentioned in one of his talks, “Whatever else you think about me I am not a large, hairless, mouse.”

  6. haw says:

    I had been wondering this for a while – great to see this come out and applaud them for looking into it instead of applying for another grant.

    If the theory is wrong, these knock ins are worse than worthless. I could never get over that fact.

  7. Lane Simonian says:

    There are at least two problems with mice models of Alzheimer’s disease. One some mice strains are resistant to excitotoxicity which is likely a major factor in Alzheimer’s disease. Second mutations in amyloid precursor proteins, the c-terminal fragment of the amyloid precursor protein, and amyloid oligomers all increase oxidative stress via g protein signalling, but they are only one source for this oxidative stress. Other sources include the ApoE4 gene, various environmental toxins, and pyschological stress. Or to put it another way, most mice are exposed to a single factor that causes oxidative stress whereas humans are exposed to multiple factors. The level of oxidative stress in humans is thus much greater than in mice.

    The following diagram provides the likely key to understanding Alzheimer’s disease (missing is the role of receptor tyrosine kinases in Alzheimer’s disease).

    Protein kinase C leads to the secretion of the amyloid precursor protein, caspase 3 leads to the first cut in the amyloid precursor protein by increasing BACE1, intracellular calcium release/calpains result in the second cut in the c terminal fragment of the amyloid precursor protein via the gamma secretase, intracellular calcium release/calpains lead to tau hyperphosphorylation as a result of the conversion of p35 to p25 and Ckd5 deregulation, oxidation leads to the release of copper and zinc which results in the aggregation of amyloid monomers into amyloid oligomers, the peroxynitrite-mediated nitration of oligomers leads to the formation of amyloid plaques and to the nitration of tau (the nitration of the phosphatidyinositol 3-kinase also leads to the hyperphosphorylation of tau).

    The rest I am going to do through a series of quotes (again referring to the diagram helps for a visual learner such as myself). ONOO- is peroxynitrite and GSH is glutathione.

    “Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.”

    TNF-alpha induces peroxynitrite-mediated depletion of lung endothelial glutathione via protein kinase C.

    “The hippocampi – the brain centres for learning and memory – are one of the earliest regions to be sabotaged by Alzheimer’s pathology. Our data revealed that GSH levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI.”

    “We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.”

    [Clinical trials with over-the-counter supplements have concentrated either on
    items which suppress inflammation, or on antioxidants which scavenge oxygen
    derived free radicals. Most of these items have proved to be worthless in the
    treatment of Alzheimer’s disease. Similarly most drugs used to treat Alzheimer’s
    disease do little to slow the deterioration, but instead offer a mild temporary
    symptom relief. However, evidence has been accumulating that the primary driver
    of Alzheimer’s disease is a nitrogen derived free radical called peroxynitrite,
    which may mediate both amyloid and tau accumulation as well as their toxicity.
    Excellent results have been obtained with peroxynitrite scavengers, with
    reversals of Alzheimer’s disease in human clinical trials being repeatedly
    demonstrated. IMHO, the only thing which may be preventing the abolition of
    Alzheimer’s disease is the mental inertia of scientists, as well as the
    bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money
    into repeatedly testing discredited interventions, while ignoring successful
    ones. Common sense is anything but…]

    As a result of nitro-oxidative stress, the synthesis and release of neurotransmitters (via damage to g protein-coupled receptors) needed for the retrieval of short-term memory, sleep, mood, social recognition, and alertness are severely hampered, neurotransmissions are impeded due to the hyperphosphorylation and nitration of tau, the flow of blood in the brain is decreased and the transport of glucose is inhibited leading to delusions, where g protein signalling remains high (APoE4 and psychological stress for instance) neuropsychiatric problems can arise, the regeneration of neurons in the hippocampus is prevented, and in combination with caspase-3 neurons die.

    In the end it is not a difficult disease to understand and effectively treat (although it took me twelve years, but then again I am not that smart)

    1. Mark Thorson says:

      So why are all of the mutations which cause early-onset AD mutations which affect amyloid processing? We don’t see any that affect oxidative stress or peroxynitrite, even though such mutations exist (for example, mutations which impair production of tetrahydrobiopterin)? And most studies show no risk increase or a protective effect from smoking, which strongly increases peroxynitrite. The notion that peroxynitrite causes AD is trivially dismissable. You are a crank for ignoring all of that.

      1. Lane Simonian says:

        But the mutations that lead to early onset Alzheimer’s disease do cause oxidative stress.

        Early onset Alzheimer’s disease and oxidative stress.

        “Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer’s disease and the association between some of these mutations with both oxidative damage and the development of the pathology.”

        Peroxynitrite also causes the destruction tetrahydrobiopterin

        Peroxynitrite Induces Destruction of the Tetrahydrobiopterin and Heme in Endothelial Nitric Oxide Synthase: Transition from Reversible to Irreversible Enzyme Inhibition

        At least you are trying new arguments against this hypothesis, I appreciate that.

        One last point, canine cognitive dysfunction which is one of the best early models for Alzheimer’s disease can be treated with certain antioxidants.

        Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction.

        “The canine represent a higher animal model to study the earliest declines in the cognitive continuum that includes age associated memory impairments (AAMI) and mild cognitive impairment (MCI) observed in human aging. Thus, studies in the canine model suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements, supporting the need for further human studies.”

        Look at the chart, the quotes, the clinical trials, the studies–all of it adds up. Or we can spend another decade working on tau antibodies, amyloid antibodies, and g protein- coupled receptor agonists and antagonists for the treatment of Alzheimer’s disease.

      2. Lane Simonian says:

        One more:

        Neurochem Res. 2007 Apr-May;32(4-5):751-6. Epub 2006 Dec 27.
        Tetrahydrobiopterin availability in Parkinson’s and Alzheimer’s disease; potential pathogenic mechanisms.
        Foxton RH1, Land JM, Heales SJ.
        Author information
        Within the central nervous system, tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis. In addition, BH4 is now established to be an essential cofactor for all isoforms of nitric oxide synthase (NOS). Inborn errors of metabolism affecting BH4 availability are well documented and the clinical presentation can be attributed to a paucity of dopamine, serotonin, and nitric oxide (NO) generation. In this article, we have focussed upon the sensitivity of BH4 to oxidative catabolism and the observation that when BH4 is limiting some cellular sources of NOS may generate superoxide whilst other BH4 saturated NOS enzymes may be generating NO. Such a scenario could favor peroxynitrite generation. If peroxynitrite is not scavenged, e.g., by antioxidants such as reduced glutathione, irreversible damage to critical cellular enzymes could ensue. Such targets include components of the mitochondrial electron transport chain, alpha ketoglutarate dehydrogenase and possibly pyruvate dehydrogenase. Such a cascade of events is hypothesized, in this article, to occur in neurodegenerative conditions such as Parkinson’s and Alzheimer’s disease.

        One person said that I am a crank, but the scientists I cite are not. I can live with that.

      3. Lane Simonian says:

        Yet more:

        “Nitric oxide synthase inhibitors and the peroxynitrite scavenger uric acid blocked the apoptosis-enhancing action of PS-1 mutations. The data suggest pivotal roles for superoxide production and resulting peroxynitrite formation in the pathogenic mechanism of PS-1 mutations.”

        “In parallel, caspase-3 activity was markedly elevated in APPsw PC12 [double Swedish mutation] after stimulation with hydrogen peroxide for 6 hr, whereas caspase-1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (±)-α-tocopherol. The protective potency of (±)-α-tocopherol was even greater than that of caspase-3 inhibitors. Our findings further emphasize the role of mutations in the amyloid precursor protein in apoptotic cell death and may provide the fundamental basis for further efforts to elucidate the underlying processes caused by FAD-related mutations.”

        “Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP [ct terminal fragment of the amyloid precursor protein] may participate in Alzheimer’s pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.”

        In both early onset and late onset Alzheimer’s disease, oxidative damage precedes amyloid formation. The c-terminal fragment of the amyloid precursor proteins and amyloid oligomers add to that damage through amplifying g protein signalling, but they only add to the oxidative damage produced by other stressors. Without the formation of peroxynitrite, there is no c-terminal fragment of the amyloid precursor protein and amyloid oligomers to begin with.

  8. anon says:

    The standard models are pretty worthless. A recently-reported model from the Lasmezas group at Scripps Florida is based on prion-induced protein misfolding & plaque formation. It may have some relevance if plaque neurotoxicities have common mechanisms for neuronal lethality. Here’s a blog post on it:

    1. Paul M Plotsky says:

      The Octodon degus, a small Chilean rodent exhibits a naturally occurring syndrome that looks a lot like Alzheimer’s disease both from a cognitive/behavioral perspective and from an anatomical/cellular level. Since this is naturally occurring, it provides a real chance to look at the whole process of development of Alzheimer’s like symptoms and pathology. I view this as very positive since we really do not know the cause of this disease. Right now our models rely on inducing one feature of the disease into mice transgenically and following the animals’ progress, but we don’t really know if this is the cause of the disease.

      Granted, using the degu as a model will be both slow and expensive. These animals are more rat than mouse sized. They also live anywhere between 3-10 years, although in the lab it seems like 3-4 years is average. They don’t typically develop cognitive pathology until they are 2-3 years old, but far more research needs to be done to pinpoint markers. It is also not clear what percentage of the animals exhibit this pathology. It may require the capture and domestication of individuals from the wild population. So much room for interesting and, perhaps, vital research, but so little time and money devoted to it. A real missed opportunity.

      Unfortunately, very few groups have looked at this model.

  9. steve says:

    I think that it’s obvious that mice are not susceptible to Alzheimer’s. Mickey is almost 100 years old, more than 50X the normal mouse lifespan, and he’s as sharp as a tack. (Not so sure about Minnie, however….).

  10. dave w says:

    I wonder if there’s some sort of “information-science” (vs. “neurochemical”) effect underlying age-related memory decline, something equivalent to using up the address space in a computer storage and hitting a “memory full” condition: if new experiences aren’t sufficiently distinctive from previous ones, it causes a problem with remembering them individually? (perhaps observable biological anomalies – amyloid plaques/tangles/peroxynitrites?/etc. are some sort of manifestation resulting from this, rather than the “upstream” cause?)

    (This is definitely a “long-shot” speculation, I admit…)

    1. Mark Thorson says:

      If that were the case, there should be a positive correlation between education level and prevalence of dementia. Studies show either a negative correlation or no significant correlation.

    2. Lane Simonian says:

      More likely, the problem is that memories cannot be retrieved due to a shortage of acetylcholine (as a result of damage done to choline transport systems, the choline acetyltransferase enzyme, and to muscarinic acetylcholine receptors). It is somewhat akin to being in a library without call numbers: the books are still there (short-term memories), but there is no way to retrieve them without the call number (the recall mechanism).

    3. NJBiologist says:

      Dave W–The concept you’re describing can be demonstrated in a lab setting. Cognitive psychologists call it “proactive interference”–defined as the ability of a presentation to reduce future learning. Since the usual cognitive psych subject is an undergrad looking for a little beer money, substantial pathology is probably not required–but pathology might enhance proactive interference.

  11. steve says:

    Just saw the comments about degus (I was too busy before writing my hysterical post about Mickey Mouse). I hadn’t heard of these animals before so I looked them up. They have a mutated insulin that only has 1-10% of the activity of other insulins and so are very susceptible to diabetes. Insulin is a highly evolutionarily conserved protein so this is very unusual. This is not my field but I wonder if degus are more susceptible to Alzheimer’s due to difference in glucose metabolism. It might be interesting to make transgenic mice or rats with degu insulin to see if they end up with similar phenotypes.

    1. Dr CNS says:


      Degus don’t get Alzheimer’s, ADHD or separation anxiety (wiki dixit).
      They may show some phenotypes that we interpret as paralleling those in AD or another human disease.
      However, at the molecular level, they may or may not originate from the same mechanism(s).

      AD, like other CNS diseases, is poorly understood. How can one build a preclinical model and expect to be helpful at predicting efficacy reversing something that is not understood?

      In the gone by years of “me-too” drugs, we used the concept of predictive validity. If a clinically efficacious drug for disease XYZ turned your mice pink, then a new drug that also turned the mice pink was expected to be efficacious later on in the clinic. That concept was helpful to get some new drugs approved, including a few in this decade.

      These days “me-too” drugs are no longer pursued, and we work on novel mechanisms without precedents for clinical efficacy. We also lack a causative understanding of these diseases. However, we can establish a correlation with a quantifiable molecular entity (gene, protein, metabolite, etc.) and generate a biological hypothesis – then we work to generate support for it – or we disprove it. We do this using “mechanistic” models. They can tell us things are going as expected (or not) based on our working hypothesis, but they cannot predict the drug will have clinical efficacy.

      If we do this in an animal species, we need to be aware of the multiple layers of differentiation that make a rat a rat, and you and me, you and me. These are not just at the molecular level, but also in terms of species having different physiology.

      By working in preclinical species, are we not multiplying the problem we are trying to solve in human, and adding risk by not being aware of these differences?
      And are we really enabling drug discovery with any “actionable intelligence” to help us mitigate somewhat the risk of running a billion dollar clinical program?

  12. steve says:

    Again, not my field but it seems on the surface degus sure seem to be close enough for modeling purposes. Rodents don’t get human diabetes either (no amyloid) but they’ve certainly been clinically predictive for diabetes drugs. No model is perfect but you need to start somewhere.

    Curr Alzheimer Res. 2015;12(4):314-22.
    Natural AD-Like Neuropathology in Octodon degus: Impaired Burrowing and Neuroinflammation.
    Deacon RM, Altimiras FJ, Bazan-Leon EA, Pyarasani RD, Nachtigall FM, Santos LS, Tsolaki AG, Pednekar L, Kishore U, Biekofsky RR, Vasquez RA, Cogram P1.
    Author information
    Alzheimer’s disease (AD) is the most common cause of dementia, affecting more than 36 million people worldwide. Octodon degus, a South American rodent, has been found to spontaneously develop neuropathological signs of AD, including amyloid-β (Aβ) and tau deposits, as well as a decline in cognition with age. Firstly, the present work introduces a novel behavioral assessment for O. degus – the burrowing test – which appears to be a useful tool for detecting neurodegeneration in the O. degus model for AD. Such characterization has potentially wide-ranging implications, because many of these changes in species-typical behaviors are reminiscent of the impairments in activities of daily living (ADL), so characteristic of human AD. Furthermore, the present work characterizes the AD-like neuropathology in O. degus from a gene expression point of view, revealing a number of previously unreported AD biomarkers, which are found in human AD: amyloid precursor protein (APP), apolipoprotein E (ApoE), oxidative stress-related genes from the NFE2L2 and PPAR pathway, as well as pro-inflammatory cytokines and complement proteins, in agreement with the known link between neurodegeneration and neuroinflammation. In summary, the present results confirm a natural neuropathology in O. degus with similar characteristics to AD at behavioral, cellular and molecular levels. These characteristics put O. degus in a singular position as a natural rodent model for research into AD pathogenesis and therapeutics against AD.

    1. Diver dude says:

      I fear that, for human CNS diseases at least, “close enough for modelling purposes” means “a complete waste of time and money”.

      Accepting “in homo, veritas” a better approach might be to take the entire established pharmacopeia and try each one in AD sufferers. At least you would be working in the right species and, who knows?, you might get lucky. Its not as if we have the foggiest idea how most of our drugs actually work anyway.

      We’ve got to do something with all the Zuckerberg money and this seems at least as realistic a proposition as any.

    2. Dr CNS says:

      yes, you need to start somewhere.
      However, some “somewhere” have more merit than others.

      Let’s see… mouse, rat, marmoset, macaque, pigeon, zebra fish, fly… now degu.
      It looks like we will cure AD and PD in all other species before we do it in human…

      1. steve says:

        As we have for a number of diseases. The idea that you can just do research in humans and that there is no value in animal models belies the history of drug development. Most of our medicine has come from animal models. The issue is making them better, not throwing up our hands and saying we have to do all drug development in people – that is, quite simply, impossible. How do you propose to screen drug candidates on people?

        1. Anon says:

          “How do you propose to screen drug candidates on people?”

          That’s what we are effectively doing anyway, given that the mouse models are rubbish. Except that we may be throwing out drugs that could actually work in humans just because they didn’t work in the mouse models!

        2. Dr CNS says:

          We can test drug candidates in human the same way we are doing it now.

          Yes, for some diseases preclinical models may be helpful.
          For CNS diseases it is quite clear than these animal models don’t tell you anything of value in terms of predicting clinical efficacy.
          Of course, there are still a number of (mechanistic) preclinical in vivo studies that may provide some useful information – just not predicting clinical efficacy. For example PK, PK/PD relationships, toxicology, to name a few.

          Why spend money, time and credibility doing something that does not add any value?

          1. steve says:

            Simply because older mouse models weren’t clinically predictive doesn’t mean that every possible animal model is worthless. If you read the review I cited on degus the similarities with human disease are quite striking. There’s a big difference between engineering a mouse to develop a disease based on a theory and finding a similar disease developing in an animal spontaneously. Degu is a naturally occurring model and to presume a priori that it isn’t capable of teaching anything is to simply close your eyes to the history of drug discovery. You may want to conduct experiments in humans but I doubt that many others would want you experimenting on their loved ones without any preclinical data whatsoever to back up your ideas.

          2. Janex says:

            Because at this point we don’t actually know if it will add value or not. It’s a poorly understood degus disease that may or may not share some of the same disease processes as Alz. But unless we actually do the experiment, we’ll never find out.

            And Alz gets all the publicity but it’s not the only neurodegenerative disease out there. Since there are a lot of things that we can do in animals to identify mechanisms that we could never ethically attempt in humans, this model could let us understand something new about how neurodegeneration works.

            If you just make the assumption that it won’t add value and never do the experiment to find out, than you have a 100% chance of it not adding value.

        3. Diver dude says:

          I’m not thinking of new drugs, I’m suggesting testing as many already approved drugs on AD sufferers as possible. And we are effectively already doing it. AD sufferers rarely only have AD. They will be receiving multiple meds for multiple indications. So lets start to look at the whole population of AD sufferers and see if there is any relation between the rate of decline of cognitive abilities and the meds they are taking. Yes, you’ll have to do it with the entire AD population of the world to get the sample size, but Mark Zuckerberg seems interested, so why not see if Facebook is in a position to help?

          1. loupgarous says:

            Actually, that would be a case where Microsoft and Facebook MIGHT know what they’re doing – if either one (or both collaboratively) were to set a large clinical database studying both co-morbidity and effects of therapy for co-morbid conditions on targeted diseases.

            Let’s say (for example) we want to look at ibuprofen’s effect on AD. As anon says, we’ve already got millions of AD sufferers co-morbid with RA or osteoarthritis, so they’re taking ibuprofen and all sorts of other NSAIDs for that. The data are already there waiting to be mined. It’d be a case where MS and Zuckerberg could do more than write big checks.

          2. janex says:

            The raw data exists in Europe’s National Health archives. There have been several Big Data studies to come out of various European countries using those archives and both Microsoft and Facebook have the clout to set up a collaboration to get access.

          3. NotThatSimple says:

            The only problem is that the data you’re referring to is uncontrolled, and it seems to be surprisingly difficult to get reliable interpretations from uncontrolled data. Just look at the history of nutrition and nutritional supplements.

  13. Lane Simonian says:

    This one is for Bank.

    Neuronal Apoptosis by Apolipoprotein E4 through Low-Density
    Lipoprotein Receptor-Related Protein and Heterotrimeric GTPases

    We thus conclude that one of the neurotoxic mechanisms triggered by ApoE4 is to activate a cell type-specific apoptogenic program involving LRP and the Gi
    class of GTPases and that the apoE4 gene may play a direct role in the pathogenesis of AD and other forms of dementia.

  14. Wallace Grommet says:

    Lane, in your AD pathway model, I noted the copper/zinc role coming into play about midway through the disease progression. The harmful effect of these metals is troubling, particularly for those of us who drank water for decades from water systems made of copper. Do you have a perspective on the risk of AD vis a vis long term exposure to molecular copper in drinking water? And are there mitigating factors that weigh upon the incidence within that population of copper tainted water consumers? My interest is vocational, as I do a bit of water supply piping, and have copper pipes in my home.

    1. Lane Simonian says:

      My sister asked me this question recently as she had plumbers replace some iron pipes with copper ones. Unfortunately, I don’t know the answer to this question as I am not sure what levels of copper exposure might increase the risk for Alzheimer’s disease. Copper and zinc are eventually entombed in amyloid plaques so the damage they do by increasing hydrogen peroxide levels and the formation of amyloid oligomers are probably an early aspect of neurotoxicity in Alzheimer’s disease. Certain dietary antioxidants (such as ferulic acid, curcumin, and rosmarinic acid) are metal chelators so that might help mitigate the problem.

      1. Wallace Grommet says:
        What about these types of chemicals as Pero scavengers?

        1. Lane Simonian says:

          Ebselen has its limitations as an antioxidant but this is likely the right approach.

  15. Anon says:

    Old people provide a great model for AD, and they are cheaer and more available now than all the transgenic mice in the world.

  16. Anon says:

    Testing in animal models is useful only if the models are predictive. But it is not obligatory, so why do it if they are not predictive?

  17. Patrick Star says:

    So, maybe this has been raised before, or maybe I’m stupid for asking it, but:
    Can’t it simply be the case that AD isn’t one disease, but rather has many fundamentally different causes? So all the classical AD symptoms are a common endpoint of several otherwise unrelated neurodegenerative processes, not symptoms of one specific disease?
    (Possibly these in turn are damaging on their own, thus accounting for eg. the AD prevalence in Down syndrome)

    1. Mark Thorson says:

      Down’s is caused by triplication of chromosome 21. The gene for the amyloid precursor protein is on chromosome 21, so this is often cited as support for the amyloid cascade hypothesis. All of the other mutations associated with early onset AD affect amyloid processing.

      1. Mark Thorson says:

        And just to complete the point, let’s say there are causes upstream of amyloid which cause AD. Why don’t we see an association between mutations that affect those upstream processes and AD? Just to pull an example out of thin air, there are mutations which affect production of peroxynitrite. Are any of them associated with early-onset AD? Nope. If there are upstream causes of AD, we would expect to see them in these mutations.

        1. Lane Simonian says:

          Now we are getting somewhere. Peroxynitrite is the upstream cause of amyloid production in the mutations that lead to early onset Alzheimer’s disease. Here is how those mutation lead to peroxynitrite formation.

          Wild-Type But Not FAD Mutant Presenilin-1 Prevents
          Neuronal Degeneration by Promoting Phosphatidylinositol
          3-Kinase Neuroprotective Signaling

          “Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.”

          When you cut off the PI3k/Akt signalling pathway, the main alternative is the phospholipase C/protein kinase C/NMDA receptor/peroxynitrite/caspase 3 pathway.

          “Presenilin-2 Mutations Modulate Amplitude and Kinetics of
          Inositol 1,4,5-Trisphosphate mediated Calcium Signals*”

          This increases intracellular calcium release which increases gamma secretase activity (the second cut in the amyloid precursor protein) and hyperphosphorylation of tau (via Cdk 5 dysregulation) but it also leads to increased protein kinase C activity and peroxynitrite formation.

          “APP695 is a transmembrane precursor of Abeta amyloid. In familial Alzheimer’s disease (FAD), three mutations V642I/F/G were discovered in APP695, which has been suggested by multiple studies to be a cell surface signaling receptor. We previously reported that normal APP695 encodes a potential GO-linked receptor with ligand-regulated function and that expression of the three FAD mutants (FAD-APPs), not normal APP, induces cellular outputs by GO-dependent mechanisms. This suggests that FAD-APPs are constitutively active GO-linked receptors.”

          Increased g protein signalling either through g protein-coupled receptors or through other mechanisms increases protein kinase C activity, NMDA receptor activity, and peroxynitrite formation.

          So all the mutations linked to amyloid formation in Alzheimer’s disease lead to peroxynitrite formation first. Add to that peroxynitrite scavengers inhibit the damage done by these mutations. Whether it is early Alzheimer’s disease or late Alzheimer’s disease, the pathway leading to neuronal cell death and cognitive dysfunction are the same; the only difference are the triggers for the disease.

          1. Mark Thorson says:

            You freakin’ crank. That’s a mouse study. Mice don’t get AD. Nearly every study shows that smoking (which provides heavy exposure to peroxynitrite) is either neutral or protective against AD. If peroxynitrite caused AD, smoking would be a major risk factor for AD. It is not. You are wallowing in cognitive bias.

      2. Patrick Star says:

        Yes, and my (somewhat unclear) point related to this was that these might be neurotoxic on their own without them being the root cause of late-onset AD.
        Late-onset AD: Multiple neurodegenerative diseases => Amyloid accumulation => More neurotoxicity
        Downs AD: Amyloid accumulation (over long time) => Neurotoxicity (perhaps exacerbated by other Downs pathology?)

    2. loupgarous says:

      It’s not an unintelligent question to ask. When I was a kid, some researchers were dead certain that cancer was a metabolic disease, which was caused by cellular hypoxia, excess cortisol, and high blood sugar. Well, the signalling in some cancer cell lines may be connected to one or more of those clinical variables. But not every one, and some cell lines have entirely different signalling mechanisms.

      So it’s not a bad question to have in the back of your head if you’re paying for Alzheimer’s disease research (and one hopes that this is on Mr. Zuckerberg’s short list of underfunded research paths).

      Sure, pluck the low-hanging fruit, because the answer may well be among the obvious paths. But if you’ve got money to spend on what’s not being funded now, why not evaluate drugs which seem to work in the human model in Degus? (Or mice, for that matter.) Once you get an animal model that does track well with drugs known to have some efficacy in humans, you’re perhaps at a better starting point than you were.

      Of course, toxicology’s a different matter. No one knew to sacrifice expectant laboratory animals in the early tox studies for thalidomide to look for signs of fetal resorption in the uterus, to cite one pitfall in comparative toxicology (if that’s not a “thing,” it should be).

      But a relatively inexpensive resolution in evaluating Degu as a model for efficacy of drugs for AD is to take senescent Degu and try the stuff we know works (at least somewhat) in humans. If the results there are promising, that might be a sign we can try looking at candidate drugs in the Degu, then try them in humans (and tox studies permitting, try the stuff that doesn’t work in Degus, but ought to work in humans – because all models break down at some point).

      1. Dr CNS says:


        Been there, done that. If anything, we have learned that “disease models” dont exist.

        If we did what you propose and we found a correlation between dagu and human efficacy for a group of already approved AD drugs youd be establishing predictive validity for said models.
        That would enable you with the prediction of clinical efficacy for drugs working through the same molecular mechanism. The prediction would break down when different mechanisms are acting.

        Presumably we are not interested in those, as we are looking for drugs acting through novel mechanisms, hoping they will show beter impact on disease progression than existing treatments.

        Is replicating failed strategies using a new animal species the best we all can do for AD?

        1. steve says:

          It’s pretty absurd to say that because one animal model wasn’t clinically predictive that we “have learned that disease models don’t exist”. Exploring a new, spontaneous model with robust similarities to human disease is not “replicating failed strategies”, it’s trying something new. Unless you believe that humans were created by divine intervention to have a radically different biology from any other species on earth then it’s pretty hard to state categorically that we can’t possibly learn anything from animal disease models. The history of drug discovery would beg to differ with you.

          1. Mouseymousey says:

            My discussions with biologists about using degu models seemed to hinge on how (not!) easy it would be to derive good data from them: the degus have a neurodegenerative phenotype that, just like AD, has different onset times and can start at different points in brain etc. Studies would take 2-3 years to run and would need probably thousands of the cute (they really are!) little critters to read out data.

            conclusion: It’s not a disease model, it’s a disease. Hence it would be a brilliant model to study, but it’s a bit too brilliant.

            n’est-ce pas?

          2. Unemployed_degu says:

            The EU’s innovative medicines initiative PharmaCog spent a good deal of money on investigating if degus were a good model for AD. In the end, the degu researchers ended up with some funding, but not much else came out of it.

    3. Lane Simonian says:

      There are many causes of Alzheimer disease, but the endpoint is basically the same (one major difference is that when g protein signalling remains high there are neuropsychiatric problems). This is a relatively good analogy.

      “It could be a bit like the Mississippi river,” says Dr Hardy. “You can start in all sorts of places, but eventually you’re going to end up in New Orleans.” If Alzheimer’s is a general response to all sorts of neurological triggers then it may be that the fungal infections found by Dr Carrasco are simply one of a long list of causes.

      In the case of Down syndrome it begins with high levels of myo-inositol due to an extra chromosome containing the sodium/myo-inositol co-transporter (high levels of glucose and high blood pressure due to high sodium levels also lead to high levels of myo-inositol in the brain). Myo-inositol is converted into phosphatidyinositol 4,5 biphosphate which is a substrate for both phosphatidyinositol 3-kinase (leading to a neuroprotective pathway) or phospholipase C (leading to a neurodestructive pathway). In the end too much phospholipase C activity cuts off phosphatidylinositol 3-kinase activity.

      All individuals with Down syndrome end up with the features of Alzheimer’s disease (plaques and tangles) by the age of 40 but not all go on to develop Alzheimer’s disease. And the likely reason for this is that people with Down syndrome have high levels of hydrogen peroxide which is a peroxynitrite scavenger.

      1. Lane Simonian says:

        Correction: “And the likely reason for this is that people with Down syndrome have high levels of hydrogen sulfide which is a peroxynitrite scavenger.”

        1. Wallace Grommet says:

          How is the cytotoxity of hydrogen sulfide offset in your scavenger theory?

          1. Lane Simonian says:

            Unfortunately, it is not. Hydrogen sulfide may delay the onset of Alzheimer’s disease in someone with Down syndrome, but it may be a cause of Down syndrome itself.



  18. Lane Simonian says:

    But that is the point, Mark, in mice “amyloid mutations” produce oxidative stress but not Alzheimer’s disease. So removing amyloid oligomers or inhibiting BACE1 is at best likely to only slow down the progression of Alzheimer’s disease in human beings where the level of oxidative stress is much higher than in mice (the same is also true for many antioxidants).

    I think that you know that the statement that nearly every study shows that smoking is neutral or protective against Alzheimer’s disease is an exaggeration. If you look at the studies from just this year, the trend is toward studies indicating that prolonged moderate to heavy smoking increases the risk for Alzheimer’s disease. You cannot say that all these studies reflect an anti-smoking bias just as I cannot say that every study suggesting the opposite has been promoted by the tobacco industry.

  19. DanielT says:

    I am wondering what you do if there is no animal model for a human disease? Can you just go straight into humans after animal tox studies? If so might it be better to convince the FDA that no animal model exists for Alzheimer’s and just start testing compounds in human patients? Wouldn’t a program of testing thousands of compounds in parallel in phase 1/2a studies over a five year period work?

    1. steve says:

      FDA does not care about efficacy, only safety. You don’t need efficacy data to test a compound in humans. That said, it’s highly unlikely that hospital internal review boards (IRBs) will let their doctors give drug candidates to patients without some preclinical evidence of efficacy or that you could raise funding for such a trial. Lack of an animal model also makes it very difficult to screen drug candidates. If you don’t have an animal model then it’s very unlikely you have a valid in vitro screen. The problem with Alzheimer’s models to date is that they were predicated on a theory of the etiology of Alzheimer’s, namely the beta amyloid hypothesis. If the degu represents a spontaneously occurring disease with a number of close similarities to the human situation then it would make sense to study it from first principles to gain some insight into what is driving the pathology.

      1. Mouseymousey says:

        To summarise Steve’s informed opinion above:

        you (like mouse models of AD) invent ever more cr@p animal models.

        Ethics boards don’t want you to put patients in harm’s way without an idea that the study will lead to some benefit.

      2. DanielT says:

        But if no model exists how are you supposed to be able test a new compound. Could you argue the past the review boards that in the absence of a model the only approach that could work is random screening of many compounds? To use a model that you does not work is equivalent to the drunk searching for his keys under the street light despite him losing them in the dark alley. A random screen will at least involve stumbling around in the dark alley where you at least have a chance of finding the keys.

        1. Dr CNS says:

          how about inventing a flashlight, so you can look in the right place and expect to see better?

  20. Some Dude says:

    “In the end it is not a difficult disease to understand and effectively treat (although it took me twelve years, but then again I am not that smart)”

    Looks like the historians have figured out molecular biology. Time for the biologists to figure out history in return.

    1. Lane Simonian says:

      For an example of the latter, see the works of Jared Diamond, although he is certainly not free from criticism either. Maybe history and molecular biology are not that far about. Historians and molecular biologists both put together the factors that lead to a sequence of events. I have simply done what historians do: reviewed many primary sources to tell to try to tell an accurate story. I have enough background in biology to be able to evaluate those studies and to see the relationship between them. Looking at the data through a different lens (whether a molecular biologist doing history or an historian doing molecular biology) may lead to new if not perfect insights.

  21. Ron Louie says:

    anon touts older humans as plentiful and better than animal models, but they aren’t cheap; the consenting process alone, whoowee! But he’s and some other commenters are suggesting something that Cummings in Cleveland and even the Alz Assn has recommended: empiric clinical trials of re-purposed FDA-approved agents. Op-Eds on the subject:

  22. Anon says:

    So sad to read all these comments arguing one opinion on the mechanism of AD against another, based on published research which is 50% non-reproducible rubbish, and 80% irrelevant.

    I think after 20+ years of research on AD, it’s pretty clear that the reductionist approach has not worked, and will not work. Time to think different, and take a completely different approach.

    1. Me says:

      NO!! It’s a binary switch that can be flicked on/off with a small molecule!!!! BLASPHEMY!!!!!!

      1. Lane Simonian says:

        Ah, but with the exception of the binary switch comment, small molecules are likely the key to treating Alzheimer’s disease and the best small molecules for treating the disease are methoxyphenols because of their hydrogen donating capacities. These are likely the only two chemical formulas necessary to understand the treatment of Alzheimer’s disease.

        ONOO- (peroxynitrite) + 2H+ + 2e-=NO2- + H20

        Protein-Tyr-NO2 + H2O –> Protein-Tyr-H + H+ + NO3-

        Tyrosine nitration inhibits neurotransmissions, prevents the regeneration of neurons in the hippocampus, and limits the transport of choline and its conversion to acetylcholine. Cysteine oxidation (which can be partially reversed by hydrogen donation) limits the release of neurotransmitters needed for the retrieval short-term memory, sleep, mood, alertness, and social recognition.

        Panax ginseng serves as a good example of how methoxyphenols may be able to help treat Alzheimer’s disease.

        “To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.” [Ferulic acid and syringic acid are methoxyphenols].

        The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.
        These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

        A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

        One of these days people will stop mocking me for trying to put aspects of this disease together.

    2. pete says:

      @ Anon
      “I think after 20+ years of research on AD, it’s pretty clear that the reductionist approach has not worked, and will not work. Time to think different, and take a completely different approach.”

      ..OK, I’m thinking differently. So what’s the completely different approach ?

      1. Dr CNS says:


        I can assure you there are a few robust ideas to generate novel, reasonable hypotheses and ways to test them.

        Moving that agenda forward is not favored in the currently-preponderant disease narrative, which many see as a fallacy.

        The key? Diversity of thought in your teams – generate a disruptive hypothesis and exlore it. IMHO

  23. Björnur says:


    Mr Lane Simonian are a Alzheimer blogger and stock investor.
    He doesnt like the Amyloidbeta theory, Especially that Toxic Oligomers might be the cause.

    He invested heavily in Anavex and have written “millions” of comments about their tech.

    And got upset when their stock crashed,

    Everything he writes promotes the science behind Anavex and why their clinical mega failure was indeed a succes.

    He wrote this about Aducanumab Nature article.

    His personal agenda is a fruit of recent stock crash and to convince others to invest in Anavex with arguments that the science behind Anavex is the real thing.

    He cant accept the crash of Anavex.


    1. Lane Simonian says:

      I don’t have any money invested in Anavex. I don’t directly invest in stocks at all and I am especially leery of biotech stocks (big risks seeking a windfall).

      I think the mechanism behind Anavex 2-73 is a good one–it limits excitotoxicity by inhibiting the production of neuronal nitric oxide–that should at least slow down the progression of Alzheimer’s disease. It would be helpful to know if it is also a peroxynitrite scavenger. It is too early to deem the drug either a success or a failure.

      The comment that I don’t like the amyloid beta hypothesis is indeed a true statement. I don’t like it when a company like Biogen carried last observed results forward to make it look like their drug was more effective than it actual was. And when people cite the results as a vindication for the amyloid hypothesis it makes me cringe.

      My interest in the disease is first personal and second curiosity. I get paid a small stipend for writing for Seeking Alpha; I receive no other financial compensation for writing about Alzheimer’s disease.

  24. Lane Simonian says:

    I will try to end this on a more positive note. First with the critical quote again:

    We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

    And a mouse study:

    A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

    But rosmarinic acid did not work in humans, because amyloid oligomers are only one source of oxidative stress, so there is less neuronal cell loss in mice than there is in human beings.

    Now if you had the mice smoking, fed them a high carbohydrate, sugar, and salt diet, exposed them to a variety of air pollutants, pesticides, toxic metals, and industrial solvents, and stressed them then they might be a good model for Alzheimer’s disease.

  25. Anon says:

    This topic should be called:

    “Just How Worthless Are All The Opinions On The Mechanism Of Alzheimer’s Disease?

    1. Andre Brandli says:

      Well, human genetics pain a very clear picture. You will succumb to early-onset AD, if you carry mutations in APP, PSEN1 and PSEN2. Furthermore, people with trisomy 21 have three instead of two APP genes and will also develop AD. These are these are the hard facts. This is a good start to understand AD.

    2. Andre Brandli says:

      Well, human genetics paints a very clear picture. You will succumb to early-onset AD, if you carry mutations in APP, PSEN1 or PSEN2. Furthermore, people with trisomy 21 have three instead of two APP genes and will also develop AD. These are the hard facts and this is a good start to understand AD.

      1. Lane Simonian says:

        Facts are sometimes complicated things. In fact, the genetics of Down syndrome and early onset Alzheimer’s disease has led to the misleading conclusion that amyloid is the cause of Alzheimer’s disease.

        Individuals with Down syndrome have an extra copy of the chromosome for the sodium/myo-inositol co-transporter which leads to higher levels of myo-inositol in the brain. High glucose levels and high blood pressure due to high sodium levels also lead to higher levels of myo-inositol in the brain and also increase the risk for Alzheimer’s disease.

        Myo-inositol is converted into phosphatidylinositol 4,5 biphosphate. When acted upon by phosphatidylinositol 3-kinase this leads to the neuroprotective Akt pathway but when acted upon by phospholipase C it leads to a neurodegenerative pathway via protein kinase C, NMDA receptors, peroxynitrite formation, and caspase-3 activity (when the phosphatidylinositol 3-kinase/Akt pathway is cut off by presenilin 1 gene mutation or nitration).

        And here is the second problem created by trisomy 21, it increases DRYK1A which overactivates NMDA receptors leading to increased caspase-3 activity which leads to the BACE1 cut in the amyloid precursor protein. Hydrogen peroxide also activates this kinase in Alzheimer’s patients during the early stages of the disease. The fact that trisomy 21 increases amyloid precursor protein levels is only important in conjunction with the fact that it also increases myo-inositol levels and DRYK1A activity.

        The genetic mutations that lead to increased amyloid levels lead to oxidative stress first and reducing that oxidative stress can help both individuals with early onset and late onset Alzheimer’s disease. To reiterate the studies listed above:

        “Nitric oxide synthase inhibitors and the peroxynitrite scavenger uric acid blocked the apoptosis-enhancing action of PS-1 mutations. The data suggest pivotal roles for superoxide production and resulting peroxynitrite formation in the pathogenic mechanism of PS-1 mutations.”

        “In parallel, caspase-3 activity was markedly elevated in APPsw PC12 [double Swedish mutation] after stimulation with hydrogen peroxide for 6 hr, whereas caspase-1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (±)-α-tocopherol. The protective potency of (±)-α-tocopherol was even greater than that of caspase-3 inhibitors. Our findings further emphasize the role of mutations in the amyloid precursor protein in apoptotic cell death and may provide the fundamental basis for further efforts to elucidate the underlying processes caused by FAD-related mutations.”

        “Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP [ct terminal fragment of the amyloid precursor protein] may participate in Alzheimer’s pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.”

        Far from being worthless, this type of “speculation” may lead to effective treatments for Alzheimer’s disease. The problem is that scientists speculated that amyloid and tau tangles were the cause of Alzheimer’s disease rather than trying to understand what led to amyloid and tau tangles and how upstream oxidants caused many of the problems in Alzheimer’s disease. The evidence-based challenge to the hardened orthodoxy may finally lead to the breaking of the log jam that has prevented progress on this disease for a quarter century.

        1. Andre Brandli says:

          “… the genetics of Down syndrome and early onset Alzheimer’s disease has led to the misleading conclusion that amyloid is the cause of Alzheimer’s disease.”

          Lane, this is insane! If you carry a mutation in APP impairing proper maturation of the APP precursor protein or if you have 3 instead of 2 APP gene copies as in patients with trisomy 21, the following pathological events will unfold in your brain over a period of 40 to 60 years. You’ll be getting premature amyloid plaque deposition (seen already in juveniles), followed by neurofibrillary tangle development and neuroinflammation, then neuronal death sets in, and finally you’ll be presenting with dementia. With regard to trisomy 21, you are right that these patients have other genes located on chromosome 21 in excess. However, there are rare cases of patients with APP gene duplication only, and they also develop early-onset AD. This fact throws your hypothesis of about causative role of the SLC5A3 (SMIt; sodium/myo-inositol co-transporter) in AD over board. If you really want to understand the link between trisomy 21 and AD, you should read the excellent review by Wiseman et al. and go to Figs. 1 & 2 to see the evidence I cited above:
          Wiseman et al. (2015) A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci. 2015 Sep;16(9):564-74.

          In summary, the genetic data is crystal clear. A point mutation in a APP gene is sufficient to trigger early onset AD. No need to invent other causes or crazy hypotheses. Any treatment options for early-onset AD (and probably also the non-hereditary forms of AD) will have to focus on preventing amyloid plaque formation as the pathological event that will trigger the downstream events leading to dementia.

  26. Lane Simonian says:

    This is a good nuanced article (figure 3 was helpful as well). Also the evidence that APP gene mutations only are a cause of early onset Alzheimer’s disease is important. I was wrong on this one: the amyloid precursor protein itself increases g protein signalling and thus more amyloid precursor proteins would trigger Alzheimer’s disease.

    Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o)

    “This suggests that APP is a receptor coupled to G(o) and that abnormal APP-G(o) signalling is involved in the Alzheimer’s disease process.”

    Let me provide some evidence that SMIt and DYRK1a would further increase the risk for Alzheimer’s disease.

    “Role of increased cerebral myo-inositol in the dementia of Down syndrome.”

    “Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease.”

    “Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models.”

    Genetic evidence cannot be used to prove that amyloid causes Alzheimer’s disease, in part because those same genes also lead to oxidative stress. Amyloid may contribute to the disease (via increasing oxidative stress and perhaps through cerebral amyloid angiopathy), but if nitro-oxidative damage to the brain is not also addressed, then at best amyloid antibodies can only slow down the disease.

    1. Andre Brandli says:

      Good that you liked the article. I and probably most experts will agree that misprocessing of APP (either due to point mutations in the APP or by mutations in PSEN1 or PSEN2, components of gamma-secretase) are the cause of hereditary early-onset AD. There are definitely lots of open questions to what happens down-stream, once amyloid placques start to be deposited in the patient’s brain. So there is room for lots of crazy speculations. Importantly, any proposed targets or mechanisms have to subjected to rigorous testing. So if you have an idea, go ahead and raise the money to test your idea rigorously. Otherwise, we will go on and on to discuss the same propositions.

      Regarding your last point: “… best amyloid antibodies can only slow down the disease.” Nobody has claimed that they will cure AD with anti-amyloid antibodies. Personally, I would like to see all amyloid-clearing antibodies to be tested in patients, which were diagnosed with hereditary early-onset AD. These patients develop dementia rapidly and they might benefit most from a drug that slows disease progression.

  27. Lane Simonian says:

    I agree with all of this. I am in the process of trying to raise $125,000 to test the use of heat processed ginseng and direct inhalation aromatherapy (clove, bay laurel, lavender, and sweet orange) for the treatment of Alzheimer’s disease (placebo-controlled, randomized, double-blinded). Then, I will be able to match the results with earlier clinical trials and the hypothesis or I will need to significantly alter the hypothesis.

    1. Andre Brandli says:

      Excellent! That’s now constructive. Wishing you good luck!

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