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.

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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).

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Comments

  • George Dionne  On July 20, 2015 at 11:55 am

    Hope that the disease could be treated somehow better cause I’m iffy about the side effects if using Gemfibrozil. Thanks for the nice update on the disease!

  • Harrison  On July 23, 2015 at 3:26 pm

    The person to contact about this kind of data mining is Rachel Whitmer at Kaiser Permanente. She has the entire California database at her disposal and publishes extensively on it.

    • luysii  On July 23, 2015 at 7:47 pm

      Harrison — Thanks a lot. I’l give it a shot.

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