111 years of study of the Alzheimer plaque still got it wrong (until now)

The senile plaque of Alzheimer’s disease has been known for 111 years  which is when Alzheimer’s first patient died and he studied her brain. For the past 60 or so years, we’ve studied it using every technique at our disposal.  We know its chemistry fairly  well, and understand many of the mutations that cause the familial forms of Alzheimer’s disease.

However, we’ve still been interpreting its structure incorrectly until this month.  In addition to the amorphous gunk of the plaque, electron microscopy has described swollen ‘dystrophic neurites’ in and surrounding the plaque.  The semantics of neurites implies a small nerve process which led us all down the garden path to assume that they are dendrites (which are usually smaller than axons).  Wrong, wrong, wrong, they are axons as a recent paper proves conclusively [ Nature vol. 612 pp. 328 – 337 ’22 ].

It took a lot of technology to reach this point.  First was development of the 5XFAD mouse which gets plaques galore, because it contains 5 mutations spread over two proteins, the amyloid precursor (APP) protein from whence the aBeta peptide of the senile plaque and PSEN1 a protein which helps to process APP into aBeta.  Second was the ability to observe dendrites and axons in the living (mouse) brain for long periods using specialized microscopic techniques and a variety of dyes and fluorescent proteins.  They allow us to watch action potentials pass along axons without sticking an electrode into them (by measuring rapid changes in local calcium concentration).

Each senile plaque contained hundreds of axons with focal swellings (the dystrophic neurites).  Most were present for months, but some disappeared without axon loss.  When an action potential got to a focal swelling (also known as a spheroid) it slowed down (the swelling acts as a sink for the current  due to its ability to store ions  (higher capacitance).  Random slowing of nerve conduction is murder for information processing.  It’s old technology but just think of what happens when you play  of  a 33 rpm record at 78 rpms.  It’ s also why the random demyelination (which changes action potential velocity)  of nerve fibers in MS raises hob with information transmission hence neurologic function.

Why did electron microscopy miss this?  Because it is just a two dimensional (very thin) slice of dead brain.

The paper has a lot more about what’s in the swelling — large endolysosomal vesicles, and a possible way to treat Alzheimer’s — genetic ablation of phospholipase D3 (PLD3) was able to reduce the average size of the dystrophic neurities and improve axon conduction.

It’s actually a hopeful paper, because we’ve been assuming that the dystrophic neurites were either dead, severed  or nonfunctional, and here they are intact and conducting nerve impulses.

Like all great scientific papers, it raises more questions than it answers.  Is the swelling due to extracellular aBeta?  Is the swelling an attempt to internalize aBeta and destroy it?  Is there a way to inhibit PLD3 ?   Genetic ablation of a gene in a living human is at or beyond our current technology.

Why trying to remove aBeta was plausible

The recent collapse of the latest attempt to remove the main constituent of the Alzheimer plaque, the aBeta peptide (gantenerumab from Roche) is just the latest in a long sad story.

Monoclonal after monoclonal antibody targeting aBeta has failed.  It certainly is time to move on and try new approaches.

The companies pursuing monoclonals were not stupid.  Their approach was (but no longer is) quite reasonable in view of the clinical and experimental evidence implicating the aBeta peptide as causative of Alzheimer’s  Before moving on, here are some of the reasons why.

First (and probably the best) is the mutation that protects against Alzheimer’s disease.  As most of you know, the aBeta peptide (39 to 42 amino acids) is part of a much larger protein the Amyloid Precursor Protein (APP) which contains 639 to 770  amino acids.  This means that enzymes must  cut it out.  Such enzymes (called proteases) are finicky, cutting only between certain amino acids.  In what follows A673T stands for the 673rd position which normally has amino acid Alanine (A) there.  Instead there is amino acid Threonine (T).   The enzyme cleaving at 673  is Beta Secretase 1 (BACE1).

       [ Nature vol. 487 pp. 153 ’12 ] A mutation in APP protects against Alzheimer’s disease.   First the genome sequence APP of 1,795 Icelanders  were studied to look for low frequency variants.  They found a mutation A673T adjacent to the site that is cleaved by beta secretase 1 (BACE1) which doesn’t vary — it’s gamma secretase which cleaves at variable sites leading to Abeta40, Abeta42 formation.  The mutation is at position 2 in Abeta.  The mutation results in a 40% reduction in the formation of amyloidogenic peptides  in vitro (293T cells transfected with variant and normal APP). Amazingly, a different variant at 673 (A673V — V stands for the amino acid Valine) — increases Abeta formation.    Because BACE1 can’t cleave APP containing the A673T mutation, alternative processing of APP at another site the alpha site (which is within aBeta preventing formation of the full 39 – 43 amino acid peptide).

So if you can’t make the full aBeta peptide you don’t get Alzheimer’s (or have less chance of getting it).

Then there are the mutations in the part of APP which code for the aBeta peptide which increase the risk of Alzheimer’s.  They cause the different familial Alzheimer’s disease.   Now that we know the actual structure of the aBeta amyloid fiber, we can understand how they cause Alzheimer’s disease.  This is more strong evidence that the aBeta peptide is involved in the causation of Alzheimer’s disease.

You’ll need some protein chemistry chops to understand the following

Recall that in amyloid fibrils the peptide backbone is flat as a flounder (well in a box 4.8 Angstroms high) with the amino acid side chains confined to this plane.  The backbone winds around in this plane like a snake.  The area in the leftmost loop is particularly crowded with bulky side chains of glutamic acid (single letter E) at position 22 and aspartic acid (single letter D) at position 23 crowding each other.  If that wasn’t enough, at the physiologic pH of 7 both acids are ionized, hence negatively charged.  Putting two negative charges next to each other costs energy and makes the sheet making up the fibril less stable.

The marvelous paper (the source for much of this) Cell vol. 184 pp. 4857 – 4873 ’21 notes that there are 3 types of amyloid — pathological, artificial, and functional, and that the pathological amyloids are the most stable. The most stable amyloids are the pathological ones.  Why this should be so will be the subject of a future post, but accept it as fact for now

In 2007 there were 7 mutations associated with familial Alzheimer’s disease (10 years later there were 11). Here are 5 of them.

Glutamic Acid at 22 to Glycine (Arctic)

Glutamic Acid at 22 to Glutamine (Dutch)

Glutamic Acid at 22 to Lysine (Italian)

Aspartic Acid at 23 to Asparagine (Iowa)

Alanine at 21 to Glycine (Flemish)

All of them lower the energy of the amyloid fiber.

Here’s why

Glutamic Acid at 22 to Glycine (Arctic) — glycine is the smallest amino acid (side chain hydrogen) so this relieves crowding.  It also removes a negatively charged amino acid next to the aspartic acid.  Both lower the energy

Glutamic Acid at 22 to Glutamine (Dutch) — really no change in crowding, but it removes a negative charge next to the negatively charged Aspartic acid

Glutamic Acid at 22 to Lysine (Italian)– no change in crowding, but the lysine is positively charged at physiologic pH, so we have a positive charge next to the negatively charged Aspartic acid, lowering the energy

Aspartic Acid at 23 to Asparagine (Iowa) –really no change in crowding, but it removes a negative charge next to the negatively charged Glutamic acid next door

Alanine at 21 to Glycine (Flemish) — no change in charge, but a reduction in crowding as alanine has a methyl group and glycine a hydrogen.

As a chemist, I find this immensely satisfying.  The structure explains why the mutations in the 42 amino acid aBeta peptide are where they are, and the chemistry explains why the mutations are what they are.

It’s time to look elsewhere.  The best this class of drug (monoclonal antibodies against aBeta) offers is lecanemab which slows the rate of decline by a measly 27%.   This is very small beer

While big pharma was far from stupid to intensively (and expensively) to give the monoclonals the old college try in the past (for the reasons cited above), they would be incredibly stupid to continue this line of attack.

Technology marches on — or does it?

Technology marches on — perhaps.  But it certainly did in the following Alzheimer’s research [ Neuron vol. 104 pp. 256 – 270 ’19 ] .  The work used (1) CRISPR (2) iPSCs (3) transcriptomics (4) translatomics to study Alzheimer’s.  Almost none of this would have been possible 10 years ago.

Presently over 200 mutations are known in (1) the amyloid precursor protein — APP (2) presenilin1 (3) presenilin2.  The presenilins are components of the gamma secretase complex which cleaves APP on the way to the way to the major components of the senile plaque, Abeta40 and Abeta42.

There’s a lot of nomenclature, so here’s a brief review.  The amyloid precursor protein (APP) comes in 3 isoforms containing 770, 751 and 695 amino acids.  APP is embedded in the plasma membrane with most of the amino acids extracellular.  The crucial enzyme for breaking APP down is gamma secretase, which cleaves APP inside the membrane.  Gamma secretase is made of 4 proteins, 2 of which are the presenilins.  Cleavage results in a small carboxy terminal fragment (which the paper calls beta-CTF) and a large amino terminal fragment. If beta secretase (another enzyme) cleaves the amino terminal fragment Abeta40 and Abeta42 are formed.  If alpha secretase (a third enzyme) cleaves the amino terminal fragment — Abeta42 is not formed.   Got all that?

Where do CRISPR and iPSCs come in?  iPSC stands for induced pluripotent stem cells, which can be made from cells in your skin (but not easily).  Subsequently adding the appropriate witches brew can cause them to differentiate into a variety of cells — cortical neurons in this case.

CRISPR was then used to introduce mutations characteristic of familial Alzheimer’s disease into either APP or presenilin1.  Some 16 cell lines each containing a different familial Alzheimer disease mutation were formed.

Then the iPSCs were differentiated into cortical neurons, and the mRNAs (transcriptomics) and proteins made from them (translatomics) were studied.

Certainly a technological tour de force.

What did they find?  Well for the APP and the presenilin1 mutations had effects on Abeta peptide production (but they differered).  Both however increased the accumulation of beta-CTF.  This could be ‘rescued’ by inhibition of beta-secretase — but unfortunately clinical trials have not shown beta-secretase inhibitors to be helpful.

What did increased beta-CTF actually do — there was enlargement of early endosomes in all the cell lines.   How this produces Alzheimer’s disease is anyone’s guess.

Also quite interesting, is the fact that translatomics and transcriptomics of all 16 cell lines showed ‘dysregulation’ of genes which have been associated with Alzheimer’s disease risk — these include APOE, CLU and SORL1.

Certainly a masterpiece of technological virtuosity.

So technology gives us bigger and better results

Or does it?

There was a very interesting paper on the effect of sleep on cerebrospinal fluid and blood flow in the brain [ Science vol. 366 pp. 372 – 373 ’19 ] It contained the following statement –”

During slow wave sleep, the cerebral blood flow is reduced by 25%, which lowers cerebral blood volume  by ~10%.  The reference for this statement was work done in 1991.

I thought this was a bit outre, so I wrote one of the authors.

Dr. X “Isn’t there something more current (and presumably more accurate) than reference #3 on cerebral blood flow in sleep?  If there isn’t, the work should be repeated”

I got the following back “The old studies are very precise, more precise than current studies.”

Go figure.

Why drug development is hard #31: retroviruses at the synapse

What if I told you that a very important neuronal synaptic protein Arc (Arg3.1) is acting like like a virus, sending copies of itself (and its messenger RNA) across the synapse?  Would a team of shrinks, who’ve never examined me, tell you that I was crazy and unfit to blog?  Well there is very good evidence that exactly this occurs in one situation and probably many more [ Cell vol. 172 pp. 8 – 10, 262 – 274, 275 – 288 ’18] — http://www.cell.com/cell/fulltext/S0092-8674(17)31509-X.

Arc stands for Activity Regulated Cytoskeleton associated protein.  It’s messenger RNA (mRNA) is transcribed from the gene in response to neuronal activity.  More importantly, the mRNA for  Arc is rapidly distributed to active synapses through the cell body and dendrites, where it is translated into protein. It is locally and rapidly stimulated during the induction of long term depression and plays a critical role in removing a class of glutamic acid receptors (AMPA receptors) from the synapse.  To whet the interest of drug developers, Arc regulates the activity dependent cleavage of the Amyloid Precursor Protein (APP) and beta amyloid production by its interaction with presenilin

Several posts could easily be filled with what Arc does, but that’s not what is so amazing about these papers.  Parts of the Arc protein arose from one of the many transcriptionally dead retroviruses found in our genome.  Our species literally wouldn’t exist without other retroviral gifts.  For instance syncytin1 is a protein expressed a high levels in the placenta.  It is produced from the envelope gene of an endogenous retrovirus (HERV-W) which has undergon inactivating mutations in its other major genes (gag and pol).  Mutant mice in which the gene has been knocked out die in utero due to failure of placenta formation.

Part of the arc gene arose from the Gag gene (Group specific antigen gene) of a retrovirus.  Recall most viruses have proteins coating their genetic material when they’re on the move (e. g. a capsid).  In the case of retroviruses, the genetic material is RNA rather than DNA.  Well the gag elements of the Arc protein form a capsid containing the mRNA for Arc (just like a virus).  In some way or other the capsid containing mRNA gets outside the neuron at the nerve muscle junction and gets into muscle.  The evidence is good that this happens, but in a system somewhat removed from us — the fruitfly (Drosophila).  Fruitfly neuromuscular junctions lacking this mechanism are weaker.

Well that’s pretty far from us.  However one of the papers (275 – 288) showed that the Arc protein and its mRNA was found in extracellular vesicles released from mouse neurons cultured from their cerebral cortex.  Could viral-like particles be crossing the synapses in our brains (which are already pretty chockfull of stuff — see https://luysii.wordpress.com/2017/11/15/the-bouillabaisse-of-the-synaptic-cleft/).  It’s very early times (in fact the Cell issue came out 3 days ago) but people are sure to look.  There are at least 100 Gag derived genes in the human genome (Campillos, M., Doerks, T., Shah, P.K., and Bork, P. (2006). Computational characterization of multiple Gag-like human proteins. Trends Genet. 22, 585–589.).

Remarkable.  Remember CRISPR was hiding in plain sight for half a century.  We have a lot to learn.  No wonder drugs have unexpected side effects.

Progress has been slow but not for want of trying

Progress in the sense of therapy for Alzheimer’s disease and Glioblastoma multiforme is essentially nonexistent, and we could use better therapy for Parkinsonism. This doesn’t mean that researchers have given up. Far from it. Three papers all in last week’s issue of PNAS came up with new understanding and possibly new therapeutic approaches for all three.

You’ll need some serious molecular biological and cell physiological chops to get through the following.

l. Glioblastoma multiforme — they aren’t living much longer than they were when I started pracice 45 years ago (about 2 years — although of course there are exceptions).

The human ZBTB family of genes consists of 49 members coding for transcription factors. BCL6 is also known as ZBTB27 and is a master regulator of lymph node germinal responses. To execute its transcriptional activity, BCL6 requires homodimerization and formation of a complex with a variety of cofactors including BCL6 corerpressor (BCoR), nuclear receptor corepressor 1 (NCoR) and Silencing Mediator of Retinoic acid and Thyroid hormone receptor (SMRT). BCL6 inhibitors block the interaction between BCL6 and its friends, selectively killing BCL6 addicted cancer cells.

The present paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 3981 – 3986 ’17 ] shows that BCL6 is required for glioblastoma cell viability. One transcriptional target of BCL6 is AXL, a tyrosine kinase. Depletion of AXL also decreases proliferation of glioblastoma cells in vitro and in vivo (in a mouse model of course).

So here are two new lines of attack on a very bad disease.

2. Alzheimer’s disease — the best we can do is slow it down, certainly not improve mental function and not keep mental function from getting worse. ErbB2 is a member of the Epidermal Growth Factor Receptor (EGFR) family. It is tightly associated with neuritic plaques in Alzheimer’s. Ras GTPase activation mediates EGF induced stimulation of gamma secretase to increase the nuclear function of the amyloid precursor protein (APP) intracellular domain (AICD). ErbB2 suppresses the autophagic destruction of AICD, physically dissociating Beclin1 vrom the VPS34/VPS15 complex independently of its kinase activity.

So the following paper [ Proc. Natl. Acad. Sci. vol. 114 pp. E3129 – E3138 ’17 ] Used a compound downregulating ErbB2 function (CL-387,785) in mouse models of Alzheimer’s (which have notoriously NOT led to useful therapy). Levels of AICD declined along with beta amyloid, and the animals appeared smarter (but how smart can a mouse be?).

3.Parkinson’s disease — here we really thought we had a cure back in 1972 when L-DOPA was first released for use in the USA. Some patients looked so good that it was impossible to tell if they had the disease. Unfortunately, the basic problem (death of dopaminergic neurons) continued despite L-DOPA pills supplying what they no longer could.

Nurr1 is a protein which causes the development of dopamine neurons in the embryo. Expression of Nurr1 continues throughout life. Nurr1 appears to be a constitutively active nuclear hormone receptor. Why? Because the place where ligands (such as thyroid hormone, steroid hormones) bind to the protein is closed. A few mutations in the Nurr1 gene have been associated with familial parkinsonism.

Nurr1 functions by forming a heterodimer with the Retinoid X Receptor alpha (RXRalpha), another nuclear hormone receptor, but one which does have an open binding pocket. A compound called BRF110 was shown by the following paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 3795 – 3797, 3999 – 4004 ’17 ] to bind to the ligand pocked of RXRalpha increasing its activity. The net effect is to enhance expression of dopamine neuron specific genes.

More to the point MPP+ is a toxin pretty selective for dopamine neurons (it kills them). BRF110 helps survival against MPP+ (but only if given before toxin administration). This wouldn’t be so bad because something is causing dopamine neurons to die (perhaps its a toxin), so BRF110 may fight the decline in dopamine neuron numbers, rather than treating the symptoms of dopamine deficiency.

So there you have it 3 possible new approaches to therapy for 3 bad disease all in one weeks issue of PNAS. Not easy reading, perhaps, but this is where therapy is going to come from (hopefully soon).

Will flickering light treat Alzheimer’s disease ?

Big pharma has spent zillions trying to rid the brain of senile plaques, to no avail. A recent paper shows that light flickering at 40 cycles/second (40 Hertz) can do it — this is not a misprint [ Nature vol. 540 pp. 207 – 208, 230 – 235 ’16 ]. As most know the main component of the senile plaque of Alzheimer’s disease is a fragment (called the aBeta peptide) of the amyloid precursor protein (APP).

The most interesting part of the paper showed that just an hour or so of light flickering at 40 Hertz temporarily reduced the amount of Abeta peptide in visual cortex of aged mice. Nothing invasive about that.

Should we try this in people? How harmful could it be? Unfortunately the visual cortex is relatively unaffected in Alzheimer’s disease — the disease starts deep inside the head in the medial temporal lobe, particularly the hippocampus — the link shows just how deep it is -https://en.wikipedia.org/wiki/Hippocampus#/media/File:MRI_Location_Hippocampus_up..png

You might be able to do this through the squamous portion of the temporal bone which is just in front of and above the ear. It’s very thin, and ultrasound probes placed here can ‘see’ blood flowing in arteries in this region. Another way to do it might be a light source placed in the mouth.

The technical aspects of the paper are fascinating and will be described later.

First, what could go wrong?

The work shows that the flickering light activates the scavenger cells of the brain (microglia) and then eat the extracellular plaques. However that may not be a good thing as microglia could attack normal cells. In particular they are important in the remodeling of the dendritic tree (notably dendritic spines) that occurs during experience and learning.

Second, why wouldn’t it work? So much has been spent on trying to remove abeta, that serious doubt exists as to whether excessive extracellular Abeta causes Alzheimer’s and even if it does, would removing it be helpful.

Now for some fascinating detail on the paper (for the cognoscenti)

They used a mouse model of Alzheimer’s disease (the 5XFAD mouse). This poor creature has 3 different mutations associated with Alzheimer’s disease in the amyloid precursor protein (APP) — these are the Swedish (K670B), Florida (I716V) and London (V717I). If that wasn’t enough there are two Alzheimer associated mutations in one of the enzymes that processes the APP into Abeta (M146L, L286V) — using the single letter amino acid code –http://www.biochem.ucl.ac.uk/bsm/dbbrowser/c32/aacode.html.hy1. Then the whole mess is put under control of a promoter particularly active in mice (the Thy1 promoter). This results in high expression of the two mutant proteins.

So the poor mice get lots of senile plaques (particularly in the hippocampus) at an early age.

The first experiment was even more complicated, as a way was found to put channelrhodopsin into a set of hippocampal interneurons (this is optogenetics and hardly simple). Exposing the channel to light causes it to open the membrane to depolarize and the neuron to fire. Then fiberoptics were used to stimulate these neurons at 40 Hertz and the effects on the plaques were noted. Clearly a lot of work and the authors (and grad students) deserve our thanks.

Light at 8 Hertz did nothing to the plaques. I couldn’t find what other stimulation frequencies were used (assuming they were tried).

It would be wonderful if something so simple could help these people.

For other ideas about Alzheimer’s using physics rather than chemistry please see — https://luysii.wordpress.com/2014/11/30/could-alzheimers-disease-be-a-problem-in-physics-rather-than-chemistry/

Could Gemfibrozil (Lopid) be used to slow down (or even treat) Alzheimer’s disease?

Is a treatment of Alzheimer’s disease at hand with a drug in clinical use for nearly 40 years? A paper in this week’s PNAS implies that it might (vol. 112 pp. 8445 – 8450 ’15 7 July ’15). First a lot more background than I usually provide, because some family members of the afflicted read everything they can get their hands on, and few of them have medical or biochemical training. The cognoscenti can skip past this to the text marked ***

One of the two pathologic hallmarks of Alzheimer’s disease is the senile plaque (the other is the neurofibrillary tangle). The major component of the plaque is a fragment of a protein called APP (Amyloid Precursor Protein). Normally it sits in the cellular membrane of nerve cells (neurons) with part sticking outside the cell and another part sticking inside. The protein as made by the cell contains anywhere from 563 to 770 amino acids linked together in a long chain. The fragment destined to make up the senile plaque (called the Abeta peptide) is much smaller (39 to 42 amino acids) and is found in the parts of APP embedded in the membrane and sticking outside the cell.

No protein lives forever in the cell, and APP is no exception. There are a variety of ways to chop it up, so its amino acids can be used for other things. One such chopper is called ADAM10 (aka Kuzbanian). ADAM10breaks down APP in such a way that Abeta isn’t formed. The paper essentially found that Gemfibrozil (commercial name Lopid) increases the amount of ADAM10 around. If you take a mouse genetically modified so that it will get senile plaques and decrease ADAM10 you get a lot more plaques.

The authors didn’t artificially increase the amount of ADAM10 to see if the animals got fewer plaques (that’s probably their next paper).

So there you have it. Should your loved one get Gemfibrozil? It’s a very long shot and the drug has significant side effects. For just how long a shot and the chain of inferences why this is so look at the text marked @@@@

****

How does Gemfibrozil increase the amount of ADAM10 around? It binds to a protein called PPARalpha which is a type of nuclear hormone receptor. PPARalpha binds to another protein called RXR, and together they turn on the transcription of a variety of genes, most of which are related to lipid metabolism. One of the genes turned on is ADAM10, which really has never been mentioned in the context of lipid metabolism. In any event Gemfibrozil binds to PPARalpha which binds more effectively to RAR which binds more effectively to the promoter of the ADAM10 gene which makes more ADAM10 which chops of APP in such fashion that Abeta isn’t made.

How in the world the authors got to PPARalpha from ADAM10 is unknown — but I’ve written the following to the lead author just before writing this post.

Dr. Pahan;

Great paper. People have been focused on ADAM10 for years. It isn’t clear to me how you were led to PPARgamma from reading your paper. I’m not sure how many people are still on Gemfibrozil. Probably most of them have some form of vascular disease, which increases the risk of dementia of all sorts (including Alzheimer’s). Nonetheless large HMOs have prescription data which can be mined to see if the incidence of Alzheimer’s is less on Gemfibrozil than those taking other lipid lowering agents, or the population at large. One such example (involving another class of drugs) is JAMA Intern Med. 2015;175(3):401-407, where the prescriptions of 3,434 individuals 65 years or older in Group Health, an integrated health care delivery system in Seattle, Washington. I thought the conclusions were totally unwarranted, but it shows what can be done with data already out there. Did you look at other fibrates (such as Atromid)?

Update: 22 July ’15

I received the following back from the author

Dear Dr.

Wonderful suggestion. However, here, we have focused on the basic science part because the NIH supports basic science discovery. It is very difficult to compete for NIH R01 grants using data mining approach.

It is PPARα, but not PPARγ, that is involved in the regulation of ADAM10. We searched ADAM10 gene promoter and found a site where PPAR can bind. Then using knockout cells and ChIP assay, we confirmed the participation of PPARα, the protein that controls fatty acid metabolism in the liver, suggesting that plaque formation is controlled by a lipid-lowering protein. Therefore, many colleagues are sending kudos for this publication.

Thank you.

Kalipada Pahan, Ph.D.

The Floyd A. Davis, M.D., Endowed Chair of Neurology

Professor

Departments of Neurological Sciences, Biochemistry and Pharmacology

So there you have it.  An idea worth pursuing according to Dr. Pahan, but one which he can’t (or won’t).  So, dear reader, take it upon yourself (if you can) to mine the data on people given Gemfibrozil to see if their risk of Alzheimer’s is lower.  I won’t stand in your way or compete with you as I’m a retired clinical neurologist with no academic affiliation. The data is certainly out there, just as it was for the JAMA Intern Med. 2015;175(3):401-407 study.  Bon voyage.

@@@@

There are side effects, one of which is a severe muscle disease, and as a neurologist I saw someone so severely weakened by drugs of this class that they were on a respirator being too weak to breathe (they recovered). The use of Gemfibrozil rests on the assumption that the senile plaque and Abeta peptide are causative of Alzheimer’s. A huge amount of money has been spent and lost on drugs (antibodies mostly) trying to get rid of the plaques. None have helped clinically. It is possible that the plaque is the last gasp of a neuron dying of something else (e.g. a tombstone rather than a smoking gun). It is also possible that the plaque is actually a way the neuron was defending itself against what was trying to kill it (e.g. the plaque as a pile of spent bullets).