Preventing Alzheimer’s Disease?

I’ve been asked to comment on this article: Astaxanthin: A Rising Star in Alzheimer’s Prevention. I am happy to do so.

Whenever I see an article like this one, that touts a new “cure”(or in this case, a new preventative) for Alzheimer’s disease, my first reaction is always distrust. There are entirely too many people out there trying to make a buck by preying on the hopes of those caring for a loved one with Alzheimer’s or on the fears of those desperate to avoid the disorder.

I cannot judge Dr. Mercola’s motivation, but I do note that his site sells the products he espouses.

My second reaction is to check the information out.

This particular article makes so many claims, it will take some time to go through them all, but I think it may be worthwhile to do so.

The first two paragraphs of the article are absolutely 100% accurate.

There is no reference cited for the projection in paragraph three that Alzheimer’s will increase in prevalence from the current one in eight persons age 65 and over, to a state where one in four Americans will be affected. It is unclear whether we are now talking about one in four Americans age 65 and over, or just one in four Americans.

But put aside for the moment the fact that we don’t know exactly to whom the “one in four” refers. Whatever group is meant, this is a major increase.

But you have to wonder… How much of the increase is due simply to the increase in elderly people in the population? We are, thanks to our current excellent health care system, living longer, healthier lives than ever before. It was not that long ago that few adults lived long enough for the neurodegenerative diseases associated with aging to show themselves. One reason the incidence of Alzheimer’s is going up is that we are doing a better job of not dying from other causes. Scary as this projection is, it is unsubstantiated (no reference) and may be misrepresented… or not (we can’t tell since the wording is imprecise). So one probably should not give it much weight.

The fourth paragraph is accurate, but fails to mention that there is no way to objectively determine whether any particular regimen prevents Alzheimer’s, since we don’t really know what causes it and we cannot predict who is going to get it.

There are a few families in which Alzheimer’s is hereditary and caused by specific gene defects. (Don’t worry. If you were in one of these families, you’d know it—researchers would be knocking at your door.) People from these families are not included in clinical trials, since they would skew the data. Familial Alzheimer’s, as it is called, accounts for approximately 10% of all cases.  The other 90% of Alzheimer’s cases are sporadic, meaning the disease occurs for no apparent reason.

The next two paragraphs continue to imply that there is a known regimen that will decrease your risk of getting Alzheimer’s. But there isn’t. We do, however, know a few things about brain health and some of the suggestions later in the article are based on that information.

So thus far, the article is reasonably accurate, but does make some implications that could be misleading. Next time we’ll begin analyzing the specific recommendations one by one.

Until then…



About All Those Scientific Terms…

Sorry, folks. There aren’t many cute/funny diagrams to illustrate these terms. And my graphic arts skills don’t stretch that far.

It’s been brought to my attention that the scientific terms are beginning to pile up a bit and get in the way of understanding the concepts I am trying to share. (Thanks, Jlynn.) So today let’s try to clear away some of the clutter.

There are two ways to go with scientific terms. You can tell yourself they are only names—just monikers attached to bits of matter—which is essentially true. Or you can try to understand where they came from.

Understanding the origin of a name is only useful if it helps you connect the name and the thing being named. So let me take a shot at helping with that.


Amyloid is a generic term referring to clumps of insoluble protein. You can have amyloid deposition in many disorders, as well as a result of repeated medical procedures like kidney dialysis. The specific protein clumping up and getting deposited varies from disorder to disorder.

All amyloids share certain traits. Most important is insolubility. They are tremendously hard to dissolve, which is the reason deposits build up. The reason they are insoluble has to do with their abnormal 3-D shape, called the beta-pleated-sheet conformation. To a chemist, those italicized words carry meaning and significance. To you and me, all they need to say is insoluble protein.

The name of the specific protein in the amyloid deposits of Alzheimer’s disease is beta-amyloid protein (a.k.a. beta amyloid, nicknamed Aβ for short). There is a long (and boring) story about how that name came to be, but suffice it so say that after much initial disagreement, beta-amyloid is the name that was finally generally agreed upon.


APP stands for amyloid precursor protein (or amyloid protein precursor—depending on whose paper you are reading). This is a big protein (in the neighborhood of 700 amino acid subunits long).

The much smaller (40-42 amino acid subunits) beta-amyloid protein (a.k.a. Aβ) is a small piece snipped out of APP by the secretases discussed last time.


These are the enzymes that act like scissors to cut APP.

Alpha secretase cuts right in the middle of the Aβ part of APP. Any APP molecule that is cut by alpha secretase has had its Aβ portion cut in two, so if half of the APP molecules in a brain are cut by alpha secretase, the potential for Aβ production has been cut in half.

On the opposite side of the coin, beta and gamma secretase work together to free the Aβ section from the big old APP molecule. Beta secretase cuts one end free, and gamma secretase cuts at the other end, releasing Aβ. You only need to stop one of this pair from working to decrease Aβ production.

Together, these three enzymes are called secretases because the protein pieces they cut free are released outside the cell (that is, they are secreted— 😉 .   We scientists usually go for the obvious when naming things.)


I’m afraid I can’t be much help with these…

When drug names look like catalog numbers, that is pretty much what they are—someone is testing a bunch of similar compounds and has numbered them. There is no good way to recall these except to have a good memory. Personally, I don’t try to keep them straight in my brain; I just look them up when I need them.

Chemical names of drugs are sometimes used. These carry useful information only if you are chemist enough to understand them… usually I am not that much of a chemist. I treat these the same as the catalog-type names.

Brand names of drugs are assigned by the companies selling them. While these do sometimes carry meaning, more often they are just made up by some marketing guru employed by the pharmaceutical company.  If you are an Alzheimer’s caregiver, you probably recognize these more readily than I do. Some of the more common I carry in my brain. But even with those, I look them up to be sure I have it straight when writing about them.

Did that help?

I hope so. Next time we’ll get back in sequence and talk about drugs being developed to prevent aggregation and/or promote the breakdown and removal of beta amyloid deposits.

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Reducing Beta-Amyloid in Alzheimer’s Disease Brain, part 1

Last week I wrote about beta-amyloid protein, one of the two proteins (the other is tau)that is misfolded in Alzheimer’s disease. “Misfolded” refers to the fact that in Alzheimer’s disease, these two proteins are found in abnormal 3-D forms that are related to the dysfunction and death of brain cells.

Alpha, beta, and gamma secretase process APP

This week’s post is about the specific enzymes that act like scissors, cutting beta amyloid out of the larger APP protein molecule from which it is released. Those enzymes are named alpha, beta, and gamma secretase. The diagram shows where each of those enzymes cuts the APP molecule.

As you can see, beta and gamma secretase produce the protein fragment we call beta-amyloid and alpha secretase cuts right through the middle of the beta-amyloid segment, thus stopping beta-amyloid formation.

Developing drugs to target beta secretase

The first step in producing beta-amyloid—both the harmless Aβ40 and the Aβ42 that clumps up in insoluble deposits around brain neurons—is the cut made by beta secretase just outside of the membrane. (The aqua rectangle in the diagram represents a portion of cell membrane.)

Much effort has been expended to produce drugs that will stop beta secretase from making that initial cut. This is not a simple matter because APP is not the only protein that beta secretase cuts. In fact, beta secretase is involved in the processing of many proteins, some of which are important to neuronal function. Stopping the cutting, or cleavage, of APP without interfering with the cleavage of other proteins is difficult. Making the problem harder is the fact that most good of beta secretase will not travel through the blood brain barrier, a glial cell construction that determines which molecules from blood are allowed to enter the brain.

Some drugs for type 2 diabetes inhibit beta secretase

The good news is that some oral drugs used to control type 2 diabetes are inhibitors of beta secretase. Those are Rosiglitazone and Pioglitazone. Both of these enter the bloodstream, but Rosiglitazone might not be able to get into brain—it may not cross the human blood brain barrier. Pioglitazone can enter brain.

Although approved for use in type 2 diabetes, these drugs have not been approved for use in Alzheimer’s. Both were being tested on persons with Alzheimer’s disease, but no positive results have been reported. Recently, the FDA warned that cardiac risks were associated with Rosiglitazone use, and since it wasn’t helping brain function, studies on Rosiglitazone were discontinued.

Pioglitazone is still being tested on Alzheimer’s patients in phase two clinical trials. A new drug, CTS-21166, is being tested in healthy non-demented volunteers (phase 1 clinical trials). In these volunteers CTS-21166 reduces the amount of beta amyloid found blood plasma, without significant negative side-effects.

Developing drugs to target gamma secretase

Gamma secretase makes the final cut that releases beta amyloid from the APP molecule. Inhibiting the function of gamma secretase is problematic because most inhibitors won’t cross the blood brain barrier to enter brain, and because some very important proteins (in addition to APP) rely on processing by gamma secretase to make them fully functional. One of those proteins, called Notch, is so important that removing it from mice is lethal. For this reason, many laboratories are working to find drugs that will modulate or control the activity of gamma secretase, without shutting it down completely. The best of these drugs inhibit gamma secretase cleavage of APP with little or no reduction in cleavage of Notch.

Drugs that target gamma secretase, without stopping Notch processing

Several such drugs are in clinical trials now. Phase one testing (on healthy non-demented volunteers) is being performed on Begacestat and PF-3084014. Both these drugs reduced concentrations of beta-amyloid in blood plasma, but not in cerebrospinal fluid (indicating they may not be crossing the blood brain barrier). Another drug, CHF-5074, has no effect on Notch processing at all and reduces brain Aβ while improving behavioral performance in animals. This drug is also being tested in phase 1 trials. No results are available yet.

In testing on Alzheimer’s individuals (phase 2 and phase 3 trials). A drug called BMS-708163 decreased beta-amyloid in cerebrospinal fluid. Another drug, tarenflurbil, was tested but had no positive effects. Tarenflurbil’s failure to perform may have been due to confounding factors in the study, and it will probably be re-tested.

Finally, a simple sugar (monosaccharide), NIC5-15, is being tested. This sugar is safe, but whether it is effective in reducing beta-amyloid production remains to be seen.

Reducing beta-amyloid by stimulating alpha secretase

A large number of drugs are known that stimulate alpha secretase activity. Since alpha secretase chops APP in the middle of the region that would become beta-amyloid, stimulating alpha secretase activity should decrease Aβ formation. These drugs are entering phase 1 clinical trials; no results are available yet.

Next time…

It should be possible to decrease beta amyloid production by using the kinds of drugs discussed today. But equally important is preventing beta amyloid from clumping and forming deposits in brain. Next time, we’ll look at drugs that prevent aggregation and/or promote the breakdown and removal of beta amyloid deposits.

Information about specific drugs is from the review Alzheimer’s disease: clinical trials and drug development, by Francesca Mangialasche, Alina Solomon, Bengt Winblad, Patrizia Mecocci, and Miia Kivipelto (Lancet Neurol 2010; 9: 702–16).

The misfolded proteins of Alzheimer’s Disease: Beta-Amyloid

In Alzheimer’s disease there are problems in passing messages from neuron to neuron (impaired synaptic transmission), problems caused by a lack of energy molecules in the neurons (mitochondrial dysfunction), and problems caused by misfolded proteins which cannot be degraded by the cell, and so build up in the brain, forming abnormal protein deposits. The misfolded proteins of Alzheimer’s disease—proteins that adopt three-dimensional shapes that are dysfunctional—are beta-amyloid and tau.

Misfolded beta-amyloid protein, the primary component of the senile plaques of Alzheimer’s disease, is the topic of today’s post.

Two kinds of beta-amyloid protein

Beta-amyloid protein is found in both normal brain and Alzheimer brain. There are two primary varieties of this small protein. The most common form, only forty amino acid subunits long, is called Aβ 40. Ninety percent of all beta-amyloid is Aβ 40.

The second variety, which makes up only ten percent of the beta-amyloid in normal brain, is forty-two amino acid subunits long and is called Aβ 42. For some reason those two extra amino acid subunits cause Aβ 42 to be prone to adopting a three-dimensional shape called the beta-pleated sheet conformation. Beta-pleated sheet proteins tend to clump together into insoluble aggregates which brain cells are unable to efficiently degrade. These aggregates form in the spaces outside brain cells, and are called senile plaques.

Changes in the ratio of Aβ 42 to Aβ 40

Many tests have shown that in Alzheimer’s disease the ratio of Aβ 42 to Aβ 40 is increased, making it easier for senile plaques to form. There are three ways this could happen:

1) the brain could be producing more Aβ 42,

2) the brain could be producing less Aβ 40,

or 3) the degradation of Aβ 42 could be impaired.

(If you are thinking, “Wait a minute! Couldn’t the degradation of Aβ 40 be increased?” you are correct. But this is not a likely cause since Aβ 40 is normally degraded very effectively anyhow.)

Approaches to drug discovery concentrate on these (first) three possibilities.

Why all three?

Not every case of Alzheimer’s dementia is caused by the exact same problem(s). In fact, it seems more likely that Alzheimer’s is caused by combinations of problems, and can develop from different combinations in different people. Thus it makes sense for the researchers fighting this terrible disorder to investigate all the roads that may lead to useful treatments.

Production of Aβ 40 and Aβ 42

Beta-amyloid is a short portion of a much longer precursor protein. The precursor is simply called Amyloid Precursor Protein, or APP. It is much easier to show you how beta-amyloid is produced than to tell you. So please look carefully at the diagram below.The aqua colored rectangle represents a section of cell membrane. APP is an integral membrane protein–meaning that it runs through the membrane from one side to the other. Alpha, beta, and gamma secretase are three of the enzymes that process APP. Specifically, they cut through the APP amino acid subunit string at the points shown by the white arrows.

You will notice that alpha secretase cuts right through the middle of Aβ, destroying both the 40 and 42 forms.

Beta and Gamma secretase produce Aβ. First the beta secretase cuts the right end, and then the gamma secretase cuts the left end, freeing the Aβ.

Each of those secretases is a target for drug development. More on that next week.

By the way, what I have been sharing here is common knowledge in the field of Alzheimer’s research. To list all the people who contributed to building the knowledge we have up to this point would require, quite literally, volumes. However, if you want a reference or two to peruse, and you have access to a medical library, I would be happy to search a few down for you. Just tell me what particular portion of this information you want to pursue. Also, much of the early research on Alzheimer’s is now open access and can be read by anyone via the internet.

Stay in touch.


Developing new drugs for Alzheimer’s Disease: Targeting misfolded proteins

The search for new drugs

When scientists search for new drugs, they begin by looking at the disease or disorder in question. If the cause of a disorder is known, research focuses on attempting to eliminate it. But if that doesn’t work, or if a scientist is studying a disease like Alzheimer’s, where the cause is not known, then she begins to look at the major problems or symptoms of the disease. Three of the major problems in Alzheimer’s disease are 1) synapses that don’t work properly, 2) neurons that lack the energy they need to function, and 3) misfolding of specific proteins.

Two weeks ago, I wrote about the synapses and drugs that directly affect synaptic transmission. To see that post, click here. Last week, the topic was the energy deficit in Alzheimer neurons, and the search for drugs that enhance mitochondrial function. You can read about that here.

Today, I want to begin talking about the misfolded proteins of Alzheimer’s disease. It’s a complicated topic, so we’re going to approach it bit by bit. First, we need some background information:

For proteins, folding properly is a big deal

When your cells make proteins, they connect protein subunits (called amino acids) together like beads on a string. There are twenty common subunits, each with a different 3-D shape. The subunits used and the order in which they are strung determines many of the traits of the protein made.

Now this is the part that is important to understand… The function of a protein depends on its three-dimensional shape.

When proteins are being made, there is an entire class of helper proteins (called chaperones) who have the important job of making sure the new proteins get folded into their proper functional shapes. (Yes, “who.” I fully intend to talk about proteins as if they were people. Grammarians will just have to deal with it.)

But proteins don’t always stay neatly folded. Changes in temperature, changes in acidity, even interactions with other molecules can cause proteins to change their shape.

If a protein unfolds completely and stays that way, it is essentially dead and cannot perform its function in the cell. (This is, quite literally, what happens when you cook an egg. Egg white is a protein called ovalbumin, and when it is unfolded, it goes from being clear and runny to being white and stiff.) Though we eat and digest many denatured proteins, allowing the subunits they are made of to be recycled, within the cell, proteins that are even partially unfolded are essentially useless.

Normally, unfolded or misfolded proteins are degraded and destroyed by the clean-up organelles of the cell.

In Alzheimer’s disease, misfolded proteins persist

However, in Alzheimer’s disease, beta-amyloid protein and the protein tau adopt abnormal misfolded shapes, and the cell is unable to degrade them properly.  Beta-amyloid is the main component of the senile plaques found in Alzheimer brain. Tau protein produces tangles inside the neurons.

Both beta-amyloid protein and tau protein are targeted by drug developers. In future posts, I’ll write about the approaches being used to fight their deposition in brain.

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If you’d prefer some lighter reading, try my Transitions blog.

Wishing you the best,


New Drugs for Alzheimer’s: The Energy Connection

Last Friday, I discussed drugs that treat the synaptic dysfunction of Alzheimer’s Disease (AD). This week we will look at drugs that aim to safeguard brain neurons by protecting their energy supply. These drugs affect the function of organelles within the cell called mitochondria.

If you remember mitochondria from past Biology classes, the phrase “powerhouse of the cell” may come to mind. The function of mitochondria is to produce ATP molecules, which the cell uses as a form of stored energy.

ATP stands for adenosine-tri-phosphate—basically an adenine nucleotide with three phosphate groups attached. The phosphate groups are highly positively charged. To push three positive phosphate groups together takes a lot of energy, because objects of the same charge repel one another. So energy is used to form the bonds holding ATP together, and can be released by breaking, or cleaving, the bond holding the third phosphate in place.

When neuronal mitochondria become less effective producers of ATP, neurons don’t have the energy they need for metabolism, repair, and signaling. If mitochondrial function is badly impaired, neurons die.

Looking for drugs that protect organelle function is a new approach to treating Alzheimer’s Disease, but it makes sense. Mitochondria dysfunction occurs early in AD and promotes synaptic damage as well as neurodegeneration. Furthermore, amyloid proteins can interact with the mitochondria to cause even more impairment in the brain.

When researchers began to study mitochondria in AD, they found that some drugs already in use (Donepezil and Memantine) helped preserve mitochondial structure and enhanced mitochondrial function. How much of their effectiveness in AD is due to mitochondrial protection and how much to receptor blockade is not yet clear.

One new drug that enhances mitochondrial function is currently being tested on AD patients. Thus far it appears that this drug, Latrepirdine, is effective and improves overall well-being in people with AD.

Related articles: Alzheimer’s Disease: physical changes in AD brain. Alzheimer’s Disease: biochemical changes in AD brain. Finding new drugs for the AD brain.

Finding new drugs for the Alzheimer’s brain

Some great drugs have been found by accident. We’ve all heard the story of moldy bread leading to the discovery of pennicillin. But usually, drug discovery is an intentional process. So where does a scientist start?

Three Problem Areas In Alzhimer’s Disease

You have to begin by looking at the disorder you hope to treat and asking, “What are the major problems here?” In Alzheimer’s Disease, the three most obvious problems are:  1) Synapses stop working properly. 2) Cells lack energy. 3) Proteins are misfolded.

Today we’ll look at how scientists target synaptic performance.

Synapses Stop Working Properly

A synapse is the point of communication between two neurons. Here is a picture of two neurons grown in the lab. A synapse between them is circled.

It is at the synapse that messages pass from one neuron to the next. Although the messages that  make up our thoughts and perceptions travel through the neuron as electrical impulses, when they reach the point of passage from one neuron to the next (the synaptic cleft) they move across as chemicals, neurotransmitters. Neurotransmitters drift across the synaptic cleft by diffusion.

It’s as if you were to race across town in one speeding car, then stroll leisurely to another, only to get in and take off once again at breakneck speeds. The electrical impulses travel… well, like lightning. But at the synapse, neurotransmitters gently diffuse across. On the far side of the synaptic cleft, the neurotransmitters interact with receptor molecules and the electrical impulses produced by that interaction race off to the next synapse.

The problems with AD that are most approachable in terms of drug development are at the synapse itself, and are involved with the neurotransmitters and their receptor molecules. Here is a screen capture of a diagram of a normal synapse:

You see the vesicles containing neurotransmitter in the axon terminal (left) and the receptor molecules on the dendritic spine (right). What is not shown in this diagram is a mechanism for clearing neurotransmitter out of the cleft. All synapses have some way of doing this, because otherwise the neurotransmitter chemical would just hang around stimulating the receptors and overexciting the next neuron in line. It would be like you turned on the radio and the volume kept automatically increasing. Really annoying if you can hear well, but not such a bad idea if you’re a little deaf.

In AD, where many neurotransmitter levels are decreased, this is not a bad thing. Many drugs being developed for AD are designed to increase the signal sent through the cleft by intentionally blocking the clearance mechanisms in order to make the signals stronger. Blocking clearance has the same effect as increasing the amount of neurotransmitter available.  Rivastigmine (sold as Exelon) and Galantamine (numerous trade names) work this way, by blocking clearance of acetylcholine from the synapse.

Another drug, Memantine (Namenda), blocks NMDA receptors for the neurotransmitter glutamate.  NMDA receptors are one of six varieties of glutamate receptors, and though they are important in normal brain function, if they are overstimulated, they can actually kill neurons. Blocking the NMDA glutamate receptors, while leaving the other glutamate receptors alone, seems to improve function in many Alzheimer patients. The Alzheimer Reading Room recently ran a post on Memantine research.

Many other drugs in development act on synapses is ways similar to these three. Someday, researchers hope to give physicians a broader choice of remedies for synaptic problems than are available now.

Other posts related to this one:             Alzheimer’s disease: biochemical changes in AD brain             Neurons: you know you’ve got them, but what are they really?            Alzheimer’s disease: physical changes in AD brain            Brain Basics: a look at normal brain

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