Alzheimer’s treatment completes Phase I trial

woman walking beneath ancient oaksA new potential treatment for Alzheimer’s disease recently completed a Phase I clinical trial—a study designed to determine if the treatment was safe for Alzheimer’s disease patients

The Phase I trial
Phase I studies are performed on a relatively small number of volunteers—ten in this instance—for the primary purpose of establishing the safety of a treatment method before proceeding to larger trials designed to determine if the treatment is effective.
There is a lot of red tape to get through before this (or any) Phase I trial is allowed to begin. Multiple review boards check the proposal, informed consent must be obtained from the volunteers, and the design of the experiment is scrutinized to ensure that it will produce a clear answer to a single question: Is this treatment safe?
This particular Phase I study used CERE-110, a gene therapy construct owned by Sangamo Biosciences, and a stereotaxic delivery method unusual in human trials. Results were reported in, *A phase 1 study of stereotaxic gene delivery of AAV2-NGF for Alzheimer’s disease,* published in the September issue of the scientific journal *Alzheimer’s & Dementia.* (full reference at end of post)

Protecting at-risk neurons
What this treatment aims to do is use targeted genetic therapy to protect neurons that normally degenerate and die in Alzheimer’s disease.

Let’s back up a little and explain the idea behind this:
Cholinergic neurons
It’s been known for a long time that among the first neurons to die in Alzheimer’s disease are neurons in a particular part of the brain (the basal forebrain) that produce and use the neurotransmitter acetylcholine (abbreviated ACh). Neurons that make ACh (a.k.a. cholinergic neurons) send it from their cell bodies to the ends of a communicating process called an axon. When a message must be transmitted from one neuron to the next, the communicating axon releases ACh onto the receiving terminals (called dendrites) of the next cell in line. When that next cell is stimulated by ACh, the message has been passed.
Now imagine that you are a neuron, and that a message is passed to you when a friend pokes you in the arm. Would it be a good idea for your friend to continue poking you in the arm repeatedly, over and over again, after you had already received the message? Clearly not. You would want them to pass the message and then stop prodding you.
Similarly, the neuron needs a way to halt the ACh signal once a message has been received. To stop the signal from going on and on, the receiving neuron produces a molecule called acetylcholinesterase (abbreviated AChE). AChE’s job is to destroy ACh, thus stopping the signal.
Anticholinesterases
In Alzheimer’s disease, cholinergic neurons are degenerating and dying. As this happens, the amount of ACh available to pass messages is decreased. And what little ACh there is, is getting chewed up by AChE. I’m sure you realize that it might be a good idea to stop AChE from destroying acetylcholine molecules.
That’s what biomedical researchers thought also, and today most of the drugs used to treat Alzheimer’s Disease are anticholinesterases—molecules that inhibit AChE, blocking it from destroying ACh.
Anticholinesterase drugs help many with Alzheimer’s, but their dosage must be carefully monitored because in excess these chemicals can cause severe negative side effects, and they are far from being a cure. Unable to rescue dying neurons; these drugs merely boost the signal a degenerating neuron can produce. Helpful? Yes. But merely as a way of getting messages through.
Nerve Growth Factor
Nerve Growth Factor (abbreviated NGF) is a protein that is continuously provided to cholinergic neurons in healthy brain. NGF keeps those neurons alive and functioning. It seems obvious that giving NGF to someone with Alzheimer’s might be a way to stop neurons—at least the cholinergic ones—from dying.
Of course, nothing is ever that simple. Factors like NGF are extremely potent—spreading them randomly throughout the body and brain would likely cause more problems than it would solve. And NGF, like all proteins, has a limited lifespan—it gets old, becomes ineffective, and is removed from the cell. So in order to rescue cholinergic neurons in a human brain, you would need a long-term input of NGF, targeted to the precise region where cholinergic cells were dying.

Long-term input of NGF
How to provide long-term input of NGF? Well, in the past you would have needed some kind of refillable pump that could provide fresh NGF to at-risk neurons over a period of years. The thought of any mechanical approach to providing a factor to the brain for years at a time probably makes you shiver—and well it should. Mini-pumps exist, but to put one in the brain would destroy more brain tissue than is acceptable. So perhaps a delivery device—a super-thin tube leading into the brain with the pump tucked away under the skin somewhere. Again, impractical. The risk of problems while maintaining such a set-up over a timeframe measured in years is much too high.
The solution turns out to be elegant and based on genetic engineering. We can take DNA for NGF—the instructions for making NGF protein—and insert these instructions into cells in the neighborhood of at-risk neurons. This should provide a long-term source of NGF following a single minimally-invasive surgical event.
How?
The NGF instructions in the Phase I trial were attached to a viral vector.
All viruses have the ability to insert their own DNA into our cells. This is how viruses infect us. In genetic engineering, the viral ability to insert DNA into cells can be used to deliver non-viral DNA. To do this, the original virus is so altered that virtually nothing except the delivery mechanism remains. So a viral vector is simply a way to deliver specific DNA instructions to a cell—any cell—in the vicinity of the vector.
When humans are involved, however, extra care is taken. So, in the Phase I trial, extensive work and experimentation was carried out ahead of time to insure that the viral vector produced only human NGF, with no viral components. Then all that remained was to place the vectors into the precise brain regions where cholinergic cells were degenerating.

Targeted delivery of NGF
To be effective, NGF must be provided to the specific brain regions where cholinergic neurons are at-risk. This is done by a process called stereotaxic injection. Sophisticated imaging techniques are used to locate the precise regions of the brain normally inhabited by at-risk cholinergic cells. Small holes are drilled through the skull and precise injections of viral vector carrying NGF DNA are made. This technique is only minimally invasive, and requires very little recovery time.

Results of the trial
In the Phase I trial, injections were made using three different concentrations of vector. There were no ill-effects of the injections.
Two years later, the cells that had received the NGF DNA were still producing NGF protein. By the end of the six year study, five of the ten participants had died of causes unrelated to the experimental treatment. (You must remember, they were old when the study began.) These participants had agreed to donate their brains to science, and examination of those brains showed that the experimental treatment had not caused any unexpected damage to the brains. (There were, of course, the “normal” lesions found in Alzheimer’s disease brains.)

Did the treatment help?
We will have to wait for results from the Phase II trial to know that.
Tests designed to measure function were given to the Phase I trial participants, but it is impossible to say anything about improvement or a lack of improvement based upon the small number of persons receiving each dosage of DNA. While the number of participants was enough to establish a lack of severe negative side effects, subtle changes in brain function will require data from many more volunteers. Still, it is exciting and hopeful that this treatment option has been shown to be safe.

Reference:

Raffia MS, Baumann TL, Bakay RAE, Ostrove JM, Siffert J, Fleisher AS, Herzog CD, Barba D, Pay M, Salmon DP, Chu Y, Kordower JH, Bishop K, Keator D, Potkin S, Bartus RT. A phase 1 study of stereotaxic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement 2014;10:571-581.

As usual, in this informal report, I have not referenced information that is common knowledge among those who study Alzheimer’s disease. However, the report itself has an extensive reference list for those who wish to track down further detail.

Alzheimer’s Disease: risk factors and nutrition

It’s time to look at the risk factors for Alzheimer’s disease. As most people know, there is no specific, single cause for Alzheimer’s. Rather, the disorder seems to be what scientist call multifactorial, which just means there are many things that may contribute to it’s development.

Over the years, many possible causes have been researched.

Gene mutations

For example, there are some specific gene mutations that are known to increase the likelihood of a person getting Alzheimer’s. Those gene mutations are most often found in well-studied groups of related people and result in familial Alzheimer’s disease, also called early onset Alzheimer’s disease. They account for roughly 10% of Alzheimer’s cases. Only one of these mutations, the one producing the epsilon 4 variety of a cholesterol-transport protein called Apoliporotein E, is likely to be found in the general population, where it could increase the likelihood of you or I having Alzheimer’s. Even then, it is only a risk factor, not an absolute cause, and is most dangerous only if you have inherited the epsilon 4 allele from both of your parents. (In other words, if instead of having one epsilon 4 allele, you have two, the likelihood of developing Alzheimer’s increases dramatically, but is still not guaranteed.) The frequency of the epsilon 4 allele in the general population runs from 12 to 14 percent in the sources I reviewed.

Other Risk Factors

Genes aside, what other risk factors can increase your chances of getting Alzheimer’s?

  1. Getting older.  Though Alzheimer’s is NOT part of normal aging, it is more prevalent in older groups.
  2. Having a close blood relative (sibling or parent) with Alzheimer’s.

That’s the whole list for well-documented risk factors. Other factors which MAY (or may not) put you at higher risk for developing Alzheimer’s include

  1. Head trauma, especially multiple instances including loss of consciousness.
  2. A long history of high blood pressure.
  3. Being female (though this may simply be a reflection of the fact that women as a group live longer lives than men).

NOT Risk Factors

Some factors once considered possible causes of Alzheimer’s have been thoroughly studied and shown to NOT cause the disorder. These include

  1. Aluminum
  2. Lead
  3. Mercury

While the last two in particular are not good for brain cells, the damage they cause is not related to Alzheimer’s disease.

Nutritional deficiencies

Nutritional deficiencies are not uncommon in persons with Alzheimer’s, but have never been shown to produce the disorder. In addition, supplements have never been shown to reliably improve the function of Alzheimer’s patients and cannot be shown to prevent the development of the disease.

Great care should be taken with supplements and herbal remedies. More is not necessarily better and it is possible to produce toxic effects if you take too much of almost any vitamin. (With the possible exception of vitamin C, since excess C is flushed from the body when we urinate.)

One herb in particular should be mentioned: Ginkgo biloba. Well-designed studies have shown that it does NOT lower your chance of developing dementia. And ginkgo can be dangerous if taken with blood thinners like Coumadin (warfarin) or with MAOIs (monoamine oxidase inhibitors—a group of antidepressants).

I would like to recommend two very good sources of information, written in understandable language. The first is a newsletter from Boston University. If you follow the link, it will take you to the newsletter. There is an excellent article called, “Reflecting on PAIRS,” that may be encouraging to those of you who are caregivers. The second is from Methodist hospital in Houston. I hope you find these helpful.

Apologies for running late this week. My husband came home yesterday after major surgery, and it’s been a less smooth transition than I’d hoped. But he is doing well now. Until next time…

–Susan.

 

Fructose and Alzheimer’s disease?

We are critically examining the claims of the article, Astaxanthin: A Rising Star in Alzheimer’s Prevention. The last few articles in this series dealt with astaxanthin itself, but today we have reached the point where the Astaxanthin article begins to talk about risk factors for Alzheimer’s disease.

The first thing mentioned is fructose.

Now, as a scientist, I take immediate offense at the impassioned diatribe against this simple sugar found naturally in fruits. HOWEVER, we are dealing once again with oversimplification leading to imprecision.

It is entirely possible that you will already know what I am about to say. (I hope that is the case.) But the fructose controversy is alive and well in all types of media, so it is worth trying to shed a little light on what is really not so complex an issue.

1. What is fructose?

Fructose is a simple sugar found in fruits, berries, and some vegetables. It has the same chemical formula as glucose, the simple sugar preferred by brain neurons. That is, a molecule of either sugar contains six carbon atoms, six oxygen atoms and twelve hydrogen atoms.glucose-fructose

 

The difference between fructose and glucose lies in the arrangement of the atoms.

2. Does the difference in shape matter?

Well, yes, actually it does. If you read my earlier series of articles on drug discovery in Alzheimer’s, you may recall that 3-D shape is critical to protein function. Since it is the job of some proteins to make the energy from foods we eat available to our cells, it follows that the 3-D shape of the molecules in our food might also be important.

In the case of fructose and glucose, the difference in shape causes them to follow two different metabolic pathways. Glucose is dismantled very effectively by the metabolic machinery of cells and produces abundant energy in a form cells can easily use. Fructose is also metabolized, but it follows a different pathway than glucose does (because of its different shape) and becomes a free fatty acid instead of being converted easily to energy for the cell.

Your body can, and does, deal effectively with the fatty acids formed from fructose… up to a point. That point seems to be the amount of fatty acid formed from 25g of fructose per day. And therein lies the problem.

3. So what is the problem?

The problem is that many of us consume much more than 25g per day of fructose. And don’t blame the apple you ate at lunch. It is virtually impossible to exceed 25g per day of fructose if fresh fruits and vegetables are your only source. The culprit is the processed food we eat.

4. Have you heard of High Fructose Corn Syrup?

Of course you have! This highly concentrated natural sweetener is found in all kinds of processed food–not just cakes, pies and bread, but pizza dough, ketchup, mustard, soup, and more. It is almost impossible to find a food that hasn’t been sweetened by some company or other, these days. We have a natural, instinctive liking for sweet foods–and the food industry takes advantage of that by adding sweeteners to all sorts of things. Read the labels! Even things that should be healthy for you–dried fruit… simple, right?–may have been treated. I just read this on a container of trail mix: “dried sweetened cranberries.”

If you only ate 25g per day of fructose, but it came from high fructose corn syrup, would that be a problem? Probably not, though I know some would argue with me on that.

5. So foods sweetened with sugar are better for me, right?

I cannot bring myself to say that they are. Here’s the deal:

Table sugar, cane sugar, pure cane sugar… the chemical name for all of these is sucrose. sucroseSucrose is a disaccharide. That is, it is made of two simple sugar molecules hooked together. (di- means two, -saccharide means sugar) Each molecule of sucrose is made from one molecule of glucose hooked to one molecule of fructose.  If you look at the diagram at right and compare it to the one above, you will see this. So what we call sugar is half glucose and half fructose, and most of us eat much more than we should of that combination. The sweetener in my trail mix was sugar. So how much sugar did it take to sweeten those dried cranberries?  Well, the total sugars in 1/4 cup of trail mix was 7g. So if I eat a handful of trail mix four times in a day, and have NO OTHER SOURCE OF SUGAR IN MY DIET, I’m good.  But what about the bread I made my lunch sandwich with? What about the cereal I ate for breakfast? What about the dressing on my dinner salad?  You get the point.

Sugars are everywhere, they can contribute to obesity and to type 2 diabetes, and, in excess, will harm your body and your brain.

6. Isn’t fructose natural?

Of course it is. So is sugar. So is vitamin D. So is alcohol. Being natural does not mean something is good for you. There are no rules about what may be labeled natural. Natural is just a word the food industry uses to make you feel good about the processed foods you eat.

Why we love the word natural is beyond me. Spider venom is natural. Hurricanes and tsunamis and tornadoes are natural. All the poisonous plants in the world are natural. So when something is labeled “All Natural,” look a little closer at the label. Sometimes the product will actually be a healthy choice, other times not. You have to read the fine print.

7. Is there anything good to eat?

Yes. The best advice if you really want to eat healthy is to eat real food–fruits and vegetables you buy fresh (and organic, if you can afford it) and meats that are hormone free.  The most succinct advice I’ve seen on the subject was in a little book I browsed in my chiropractor’s waiting room. It said simply, “If your grandmother [or great-grandmother] wouldn’t recognize it as food, don’t eat it.” I have not forgotten the advice, though I don’t know who to thank for it. (If you know who the author was, please let me know so I can give proper credit!)

8. What about supplements?

I am not against them, with these caveats:

Remember that more is NOT always better (Too much of a good thing can be toxic.) Be sure to buy from a reputable vendor. Look carefully at the sources from which supplements are derived. Read the fine print.

I recommend reading this good, simple article on fructose and Alzheimer’s. It’s short and (dare I say it?) sweet. Enjoy.

Next time more on the presumed sources of Alzheimer’s disease.

See you then. –Susan

More on Astaxanthin…

We’re talking about astaxanthin, the antioxidant touted in the online article, Astaxanthin: A Rising Star in Alzheimer’s Prevention. Among antioxidants, astaxanthin does appear to have some unique characteristics.

Tiny photosynthetic organisms found in marine environments—microalgae and phytoplankton, synthesize astaxanthin. The richest natural source is the microalgae Haematococcus pluvialis. In addition, Roche pharmaceutical company began large-scale production of synthetic astaxanthin in 1990 (Ref. 3).

It appears that astaxanthin from H. pluvialis has high bioavailability, meaning it is well absorbed by the body. There is evidence (in rats) that it can protect living cells from damage by free radicals (Ref. 3). In vitro (in a test tube… literally in glass), astaxanthin has ten times higher antioxidant activity than other carotenoids, and 100 times higher antioxidant activity than vitamin E (Ref. 3).

Astaxanthin from H. pluvialis seems to be safe. A 2008 clinical study using astaxanthin to treat indigestion showed that 40 mg per day of H. pluvialis astaxanthin did not show any harmful effects during a 4-wk treatment period (Ref. 4).  The original article cites a 2011 study that used 6 or 12 mg of astaxanthin for 12 weeks. I did not find any studies looking at longer than a 12-week period.

In the 12-week study, the researchers concluded that “concentrations of erythrocyte and plasma astaxanthin were not different between the 6 and 12 mg astaxanthin groups, suggesting that 6 mg astaxanthin is effective enough to show antioxidative benefit in vivo.” Those researchers were looking at decreases in markers for oxidative damage (the PLOOH mentioned in the original article) found in red blood cells and blood plasma (Ref. 7).

The same researchers have undertaken a new study testing daily doses from 3 to 6 mg of astaxanthin. Their concern is to find the lowest effective dosage. Finding the lowest effective dose is important, because when dealing with bioactive molecules, more is NOT necessarily better.

Numerous studies have shown that astaxanthin protects neuronal cells in rats and mice from oxidative damage. When researchers took neuron-like cells from a human cell line (human cells, often derived originally from cancers or tumors, that have been raised artificially for many years and many generations in laboratories) and exposed them to oxidative damage that would normally cause cell death, astaxanthin treatment was able to reduce the number of cells that died. (Refs. 5 and 6) The cells in this study were dopaminergic, which means that they use the neurotransmitter dopamine, similar to the cells that die in Parkinson’s disease.

Does that mean astaxanthin could help stop cell death in Parkinson’s? Maybe, but only if those cells are dying for the same reason as the cells in the study. You see, all we can ever do, prior to clinical testing results, is make an educated guess about what a supplement will or won’t do in humans.

And so far, clinical antioxidant studies looking for memory effects have not been too promising. They have found that vitamin E does not significantly slow down memory decline for Alzheimer’s patients or early Parkinson’s patients. Furthermore, a combination of vitamins E and C did not significantly improve college students’ performance on specific cognitive tasks. I was unable to access the “small clinical trial” that found astaxanthin “improved cognition.” I hope to remedy that problem before my next post.

Astaxanthin appears to be a good antioxidant. It has extremely high antioxidant activity. It looks like it is probably safe. And it appears that the best source is H. pluvialis. 

Would I spend a lot of money on one specific antioxidant supplement? No, not a lot of money. But if it was reasonably priced I might add one to my diet. Still, I always prefer real food to pills! And with real food, I know my body has been designed to do a good job of absorbing the nutrients (and antioxidants) I ingest.

The next section of the article goes into other avenues, some of which have been clearly shown to enhance brain health. More on that next time.

References

1) Eric A. Johnson and Gil-Hwan An, Astaxanthin from Microbial Sources, Critical Reviews in Biotechnology, 1991, Vol. 11, No. 4, pages 297-326.

2) Paola Palozza and Norman I. Krinsky, Astaxanthin and canthaxanthin are potent antioxidants in a membrane model, Archives of Biochemistry and Biophysics, 1992, Vol. 297, Issue 2, pages 291-295.

3) Jian-Ping Yuan, Juan Peng, Kai Yin and Jiang-Hai Wang, Potential health-promoting effects of astaxanthin: A high-value carotenoid mostly from microalgae, Mol. Nutr. Food Res., 2011, Vol. 55, pages150–165.

4) Kupcinskas, L., Lafolie, P., Lignell, A, Kiudelis, G. et al., Efficacy of the natural antioxidant astaxanthin in the treatment of functional dyspepsia in patients with or without Helicobacter pylori infection: a prospective, randomized, double blind, and placebo-controlled study, Phytomedicine, 2008, Vol. 15, pages 391–399.

5) Ikeda, Y., Tsuji, S., Satoh, A., Ishikura, M. et al., Protective effects of astaxanthin on 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells, J. Neurochem., 2008, Vol. 107, pages 1730–1740.

6) Liu, X. B., Shibata, T., Hisaka, S., Osawa, T., Astaxanthin inhibits reactive oxygen species-mediated cellular toxicity in dopaminergic SH-SY5Y cells via mitochondria-targeted protective mechanism, Brain Research, 2009, Vol. 1254, pages 18–27.

7) Kiyotaka Nakagawa, Takehiro Kiko, Taiki Miyazawa, Gregor Carpentero Burdeos, Fumiko Kimura, Akira Satoh and Teruo Miyazawa, Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes, British Journal of Nutrition, 2011, Vol. 105, pages 1563–1571.

Astaxanthin–a word I now know how to spell!

We are discussing—some would say dissecting—the article, Astaxanthin: A Rising Star in Alzheimer’s Prevention. In my opinion, the first six paragraphs of this article were reasonably accurate, but did make some misleading implications.

The most inaccurate implication made was the notion that there is some regimen that is known to protect one against Alzheimer’s disease. There is not. Although we are aware of some factors that increase the probability of getting the disorder, avoiding those things does not guarantee protection. And although we are also aware of some behaviors that enhance brain health, practicing those behaviors does not necessarily protect against neurodegeneration.

from Tattooed JJ’s Photostream

But let’s move on. The article talks about astaxanthin, a potent natural antioxidant. Research on astaxanthin is not new—the reference cited in the article is from 2009, but there has been a large commercial market for astaxanthin for over thirty years (Ref. 1).

Astaxanthin is a carotenoid, a natural pigment in the same family as the pigments that give color to carrots and pumpkin. Carotenoids are interesting because in addition to providing attractive color to many foods, they often play essential roles in cell health. Animals cannot make carotenoids. They get these pigments from their diet.

As mentioned in the original article, astaxanthin in their diet changes flamingo feathers from grayish to pink.  This is not an exciting or mysterious process. Astaxanthin is a pigment that builds up in the feathers, so it simply dyes them pink.

The rich pink color of salmon meat also comes from astaxanthin, which the fish ingest in the wild as part of their natural diet. When salmon are farmed, astaxanthin is added to their food to give the meat the color consumers expect it to have. So the commercial market for astaxanthin developed in the early 1980s, as salmon farming became more common. By 1990, Roche pharmaceutical company began large-scale production of synthetic astaxanthin (Ref. 3).

As early as 1992, astaxanthin had been recognized as a molecule capable of strongly opposing oxidation (a potent antioxidant—Ref. 2). When most people think of oxidation, they think of rust. But in a biological system, oxidation amounts to the stealing of electrons from one molecule by another molecule containing an electron-hungry atom. Oxygen is notoriously electron-hungry and is very common in biological systems, which is probably why the process got named oxidation. But there is more to the story.

You have probably heard of free radicals, and know that they are dangerous to cells. Well, a free radical is nothing more than a molecule that is a super-strong oxidizing agent. That is, it can rip electrons from other molecules with great ease. This is not a good thing.

Why not? Because having a full compliment of electrons (a full outer shell, if you remember some chemistry) stabilizes molecular structure. Just like a well-placed hit with a wrecking ball can bring a whole building down, so an interaction with a free radical can destroy a molecule.

Anti-oxidants (like astaxanthin) go one-on-one with free radicals and neutralize them. That is how they protect cells from damage.

Do cells need this protection?

Sometimes.

Cells normally manufacture antioxidant molecules themselves. Plant cells manufacture carotenoids like astaxanthin. Animal cells make their own antioxidants, too. In a perfect world, between the antioxidants our cells produce and the antioxidants in a healthy diet, we’d have plenty of defense against free radicals. But the world isn’t perfect. There are many environmental stresses that increase the number of free radicals our bodies must contend with. The highly processed foods we eat don’t help matters any. It is not a bad idea to increase our intake of antioxidants. You probably could name a handful of foods high in antioxidants without even thinking too hard:  blueberries, dark chocolate, many vegetables, green tea, and more.

But are these things a defense against Alzheimer’s?

Maybe. In many illnesses, including Alzheimer’s, free radicals tend to be increased. Maybe more of these nasty molecules are being made, or maybe the body’s own defensive antioxidant production is dropping off. Either way, adding more protective antioxidants would seem to be a good idea. But when clinical trials have been run to test this idea, the results have been mixed, largely because in any dietary study there are so many variables that are hard to control.

The idea still has merit. The National Institute on Aging is beginning a new, nationwide clinical trial, not on astaxanthin, but on resveratrol—the antioxidant in red wine and dark chocolate.  Antioxidants are still an area of active research. And among antioxidants, astaxanthin does appear to have some unique characteristics. We’ll get into those next time.

In the meantime, there are many good sources of antioxidants. I include a wide variety of them in my diet because they are delicious and good for me.  In fact, I think I’ll go snack on some blueberries right now!

Until next time,

–Susan.

References:

1) Eric A. Johnson and Gil-Hwan An, Astaxanthin from Microbial Sources, Critical Reviews in Biotechnology, 1991, Vol. 11, No. 4, pages 297-326.

2) Paola Palozza and Norman I. Krinsky, Astaxanthin and canthaxanthin are potent antioxidants in a membrane model, Archives of Biochemistry and Biophysics, 1992, Vol. 297, Issue 2, pages 291-295.

3) Jian-Ping Yuan, Juan Peng, Kai Yin and Jiang-Hai Wang, Potential health-promoting effects of astaxanthin: A high-value carotenoid mostly from microalgae, Mol. Nutr. Food Res.,2011, Vol. 55, pages150–165.

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…

–Susan.

Misfolded Proteins of Alzheimer’s Disease: Tau Protein

Way back in May, I introduced the topic of misfolded proteins in Alzheimer’s disease.

In the post called Developing new drugs for Alzheimer’s disease: Targeting Misfolded ProteinsI explained that the folded shape of a protein is critical to its function, and introduced the two misfolded proteins of Alzheimer’s disease: Beta-amyloid and Tau.

Up until now, I have only discussed Beta amyloid. Now it’s time to move on to the second misfiled protein in Alzheimer’s brain, hyperphosphorylated Tau.

Tau is a structural protein playing an important role in intracellular transport. Similar in function to railroad ties, it stabilizes microtubules in neuronal axons.

Microtubules do not carry a information, but they do transport a whole host of things necessary to the health and well-being of the cell. They move organelles like mitochondria from one place to another. They carry structural components to the locations that need them. They carry proteins needed for cellular metabolism.

In Alzheimer’s disease, the protein Tau, which normally binds to microtubules, gets twisted into short filaments that are unable to stabilize the tracks. When the microtubule network of the cell is destabilized, transport within the cell is disrupted. The twisted Tau filaments aggregate, forming intracellular deposits called neurofibrillary tangles. These can fill the entire cell, leading to the death of the neuron.

There are some drugs that prevent Tau misfolding and aggregation. In animal testing, these reduce tangle formation and  limit neuronal death, but so far none of them have made it past phase three clinical trials. The reason has generally been lack of efficacy–failure to produce cognitive and functional improvement–rather than issues related to toxicity.

As you can see, there are many approaches being taken to develop drugs that will fight Alzheimer’s disease. And each new fact discovered about the causes and progress of the disorder will lead to more avenues through which researchers can attempt to fight the disease.

This post concludes the series on drug development in Alzheimer’s disease. Once again, I will mention that information about specific drugs has come 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). Sources for background information have not been mentioned because the background is common knowledge among those of us who study this disorder. However, if you have specific questions, I will be happy to answer them or direct you to additional resources.

Tomorrow I begin a new job as Dean of Science at a small university here in Austin. I anticipate that the transition will result in a decrease in the number of posts I can produce each week. My plan is to continue this blog on a once a week schedule. My other blog, Transition Time, which has been a daily blog, will also move to once a week. Hope to see you there!

–Susan.