The More Brain Tools, the Better

A Multinutrient Approach to
Alzheimer’s Disease

The aging brain’s changing nutritional needs are best
addressed on different fronts that reinforce each other
By Will Block

ou are what you eat.” We’ve heard that old saw a million times, and there’s truth in it, especially where micronutrients are concerned. Those are the items we consume in very small quantities (vitamins, minerals, herbs, spices, etc.) compared with the Big Three macronutrients: proteins, carbohydrates, and fats. Although virtually everyone in the developed world gets enough of those three, many people do not get enough of the healthiest kinds, particularly where carbs and fats are concerned. That means that they’re consuming too much of the less healthy kinds. (And a majority of people in our society consume too much food, period—but that’s another story.)

Many people, furthermore, do not get enough of the micronutrients they need, especially as they get older, when the importance of those substances looms ever larger for their aging bodies—and for their aging brains. It’s ironic that, with all the thinking we do about the importance of good nutrition, we tend to give short shrift to the source of those thoughts: our brain, which seems to take itself for granted.

As much as any other organ you could name, your brain depends on being given the right balance of nutrients, including micronutrients, for its continued health and vitality as you get older. And with age come ever greater needs for certain nutrients to offset potential deficits caused by factors such as poorer eating habits (often due to declining senses of smell and taste), adverse food-drug interactions, and the body’s declining ability to assimilate and utilize some nutrients efficiently (the bioavailability problem).

Eat—and Supplement—for Your Brain

The health and vitality of your brain also depend strongly on regular physical activity—exercise—which is the single best thing you can do to maintain your cognitive faculties and avoid one of the most insidious and dreadful consequences of aging: dementia.

There are many reasons why exercise is beneficial for your brain (and, of course, the rest of your body). This article, however, is about “The potential role of nutritional components in the management of Alzheimer’s disease.” That’s the title of a manuscript, by two Dutch researchers, which has been accepted for publication by the European Journal of Pharmacology.1 We will give an overview of it for you here, based on an unedited preprint posted on the Internet.*


*The online document states, “Please note that during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.” The authors are affiliated with Numico Research N.V., a multinational baby food and clinical nutrition conglomerate based in the Netherlands (it was formerly the parent company of GNC and Rexall Sundown). The manuscript places much emphasis on research conducted by the eminent MIT neuroscientist Richard J. Wurtman, and the only listed reviewer is Professor Wurtman himself, who, it must also be noted, has strong financial ties with Numico through an exclusive licensing agreement involving his own company, Back Bay Scientific.

This represents major conflicts of interest and does not comport with widely accepted standards of objectivity and integrity in scientific publishing. Nonetheless, we believe the manuscript has sufficient merit to be worth discussing here. We cannot assume that it is scientifically correct in all respects (such an assumption is never possible, even under the best of circumstances), nor can we claim that this article is scientifically correct in all respects, despite our best effort (as always) to make it so. Please see the legal disclaimer.


We begin by quoting the manuscript’s own summary, which makes a strong case for the value of nutritional strategies targeted to the prevention of Alzheimer’s disease:

Epidemiological evidence linking nutrition to the incidence and risk of Alzheimer disease is rapidly increasing. The specific nutritional deficiencies in Alzheimer patients may suggest a relative shortage of specific macro- and micronutrients. These include omega-3 fatty acids, several B-vitamins, and antioxidants such as vitamins E and C. Recent mechanistic studies in cell systems and animal models also support the idea that nutritional components are able to counteract specific aspects of the neurodegenerative and pathological processes in the brain.
In addition, it has been shown that several nutritional components can also effectively stimulate membrane formation and synapse formation as well as improve behavior and cerebrovascular health. The suggested synergy between nutritional components to improve neuronal plasticity and function is supported by epidemiological studies as well as experimental studies in animal models. The ability of nutritional compositions to stimulate synapse formation and effectively reduce Alzheimer disease neuropathology in these preclinical models provides a solid basis to predict potential to modify the disease process, especially during the early phases of Alzheimer disease.

If you’re not familiar with neuronal plasticity, now would be a good time to learn about this vitally important concept by reading the sidebar “Quo Vadis, Brain of Benjamin?”.

Quo Vadis, Brain of Benjamin?

Plasticity is the ability of a substance to be easily deformed, enabling it to take on a more or less permanent new shape. This is a marvelously useful property, as Mr. Robinson clearly understood when he intoned the word “Plastics” to a bemused Benjamin (Dustin Hoffman) in The Graduate. As a fresh college grad, Benjamin was full of newfound knowledge, but even he may not have realized how plastic his own young brain was—plastic in the neurological sense, that is.

No—plasticity, not plastic!
Where the brain is concerned, plasticity refers to the ability of neural circuits to undergo changes in function or organization as a result of previous neural activity or new sensory input. Thus it underlies the processes of learning and memory, the cognitive functions that make us who and what we; they are also the ones that are the most grievously damaged in dementias, such as Alzheimer’s disease. Seen in that light, it behooves us to take the subject of plasticity seriously.

Neural plasticity, aka synaptic plasticity, is defined as the ability of neuronal connections at the synapses, or junctions between neurons, to change strength in response to experience.* What this means is that, within the brain’s physical network of approximately 1 quadrillion (1 million billion) neuronal connections, some neural circuits are biochemically reinforced, leading to memory formation and consolidation, while others are weakened or shut down, leading to memory loss.


*The term neuronal plasticity is sometimes used in the same sense. It can also, however, mean the plasticity of the neuron itself, in the sense of its ability to change in size or shape. Plasticity of this kind is an important feature of all cells, and its gradual loss, owing to degenerative changes in the cell membrane, is a characteristic feature of aging.


This concept is not hypothetical. Using a sophisticated brain-imaging technique developed recently by MIT neuroscientists, it’s possible to observe the molecular changes involved in synaptic plasticity in a single neuron, in real time (i.e., as the changes are occurring), in live mice, as a direct result of their daily experiences.1 Amazing!

Clearly, your brain is a dynamic, adaptive entity that will never again be exactly as it was a moment ago. Which raises the question (while we’re still in movie mode), Quo Vadis?—Whither goest thou? There are two answers, one good and one bad.

The good answer is up, especially for a youngster like Benjamin, who, despite his college degree, was wet behind the ears—his brain was still pretty much a blank slate, ready to be filled with a lifetime of learning, experience, and memories. If Mr. Robinson had been Dr. Robinson the neurologist, he might have clued Benjamin to his bright future with the word “Plasticity,” which Benjamin had in abundance.

Of course, Dr. Robinson would also have known that Benjamin’s neural plasticity, and hence his ability to learn and remember new things, would ultimately go down—but when, and to what degree? If he had been a distinguished neuropharmacologist, like Richard Wurtman, Dr. Robinson would have known that this inevitable aging process can be either accelerated through poor nutrition or decelerated through good nutrition, and he would have had a lot of good advice regarding the latter.

The question is, would Benjamin have taken his advice? How about you?

Reference

  1. Halber D. MIT researchers watch brain in action. Press release, MIT, July 27, 2006.

Will Modern Medicine See the Light?

It’s difficult to argue with the conclusions expressed above, based either on scientific principles or on scientific facts reported in the extensive literature on the subject (some of which has been discussed in previous issues of this magazine). One would think that the great weight of evidence regarding the fundamental role of nutrition in maintaining or improving human health and well-being would make this subject a focal point of medical education. But one would be wrong—more so in the United States than in many other countries, where physicians are better educated in the principles of nutrition.

Like a great ship at sea, though, the American medical profession is slowly turning toward a better understanding and appreciation of what nutritional biochemists have long known: you can do yourself a world of good not only by not eating the wrong things but also by seeking out and eating the right things. The kicker is that what’s right (i.e., optimal) changes somewhat as we age, so we must all learn and adapt as we go along.

Multiple Brain Nutrients—The Key to Better Cognition

In their manuscript, the Dutch researchers pointed to the growing interest in the role of nutrition in diseases of aging, such as dementia, stating that poor nutrition is among the most obvious, yet under-recognized, factors in the impairment of cognitive function. Although epidemiological studies have shown conflicting results in this regard, there is much evidence for specific associations between certain nutrient deficiencies and the risk for Alzheimer’s, particularly in the frail elderly, whose nutrition often leaves much to be desired.

Chief among the nutrients in question are omega-3 fatty acids, choline, B-vitamins, and antioxidants (more on these below), which can directly or indirectly affect brain structure and function, such as membrane building and repair, the formation of synapses, and the production of neurotransmitters. They can also affect the availability of other nutrients to the brain. There is increasing evidence that certain nutrients can not only enhance neural plasticity but also ameliorate age-related degenerative processes, thereby reducing the pathological burden on the brain.

The researchers stated,1

With the limited therapeutic utility of current pharmacological treatments for Alzheimer disease, the question arises what nutrition may contribute to our toolbox to address the specific needs of the Alzheimer patient. We advocate that a multinutrient composition specifically targeting membrane formation has the capacity to modulate all of these processes and may provide a useful way, in conjunction with the pharmaceutical route, to treat the Alzheimer patient effectively.

(For a prior discussion of the “toolbox” concept of supplemental nutrition for the brain, see “Molecular Tools for Maintaining the Brain” in the June 2005 issue of Life Enhancement.)

The Central Importance of the Cell Membrane

The term membrane—meaning cell membrane—has been invoked several times so far in this article. That reflects the Dutch researchers’ focus on the central importance of this remarkable entity in maintaining the integrity of the brain’s structure and function. The cell membrane, aka plasma membrane, is a lipid bilayer, so called because it consists of a gossamer film of lipidic (fatty) substance that’s only two molecules thick. Despite its delicacy, the cell membrane is remarkably resilient. Its properties are as much fluid as they are solid—and fluidity is, in fact, one of the membrane’s key attributes.

The cell membrane is to the cell as your skin is to your body: it holds things together and prevents them from leaking out. That’s a useful and necessary function, of course, but it’s just a scratch on the surface, so to speak. Far from being mere “sacks” to contain fluids, your skin and your cell membranes are complex, dynamic entities that serve a variety of life-and-death functions—literally—by regulating the inflow and outflow of various substances so as to maintain the health and vitality of what’s inside them. In both cases, the transport of molecules can occur either by diffusion through the wall itself (skin or cell membrane) or via channels in the walls that open and close at appropriate times.


Schematic of a typical cell membrane (lipid bilayer)

The channels in cell membranes consist of many different kinds of protein complexes that are embedded in the wall (the lipid bilayer). Ordinarily closed (like your mouth or anus, e.g.), these proteins respond to specific chemical stimuli from within or from without, causing their molecular structure to alter temporarily in such a way as to open a channel right through them. Various substances, such as water, ions, nutrients, and metabolic waste products, can then pass through them (in single file, one molecule or ion after another).

Brain Activity Depends on What You Eat

Thus cell membranes, especially those of brain cells (neurons), are hotbeds of chemical and physical activity, involving not just their transport functions but also the rebuilding of existing membranes to repair any damage or to accommodate changing functional needs, as well as the formation of new membranes when old cells die off and are replaced by new ones. In many neurons—especially in the hippocampus and neocortex, where most learning and memory take place—there is constant structural and functional change going on as some neural circuits are strengthened and old ones are weakened. And that, as you know from having read the sidebar (you did, didn’t you?), is what defines synaptic plasticity.

The efficiency with which these myriad activities are carried out depends strongly on the chemical composition of the membranes (and their proteins and other attached molecules). And the chemical composition of the membranes depends strongly on the availability of precursor molecules, the building blocks from which the final components are made. And the availability of the precursor molecules depends, in large part, on what we eat, and how much of it we eat, and how much of that is absorbed by the body and transported to the brain, where it’s needed. In other words, it all depends, in large part, on our nutrition.

In the Brain, Bad Things Lead to Alzheimer’s

And that is the problem. As we age, the structure and function of our cell membranes are degraded by changes in chemical composition, notably a decline in the proportion of polyunsaturated fatty acids (PUFAs), which are components of the phospholipids that make up the bulk of the lipid bilayer, as well as by increases in the proportions of saturated fatty acids and cholesterol.* Membrane fluidity suffers, and with it the neurons’ ability to adapt quickly and easily to changing needs; synaptic plasticity suffers, and with it our capacity for learning and memory. These are properties that normally facilitate the efficient neurotransmission of signals between adjacent neurons. Neurotransmission, of course, underlies all cognitive processes.


*The brain, by the way, contains almost 25% of all the body’s cholesterol, which is involved in the formation and maintenance of synaptic connections. It’s just as important to have enough cholesterol in the brain as it is not to have too much, because cholesterol depletion activates production of amyloid-beta, the protein from which the destructive plaques in Alzheimer’s disease are largely made.


There is a growing belief, supported by a great deal of epidemiological and experimental evidence, that the problems outlined above are due in part to changing, age-related nutritional needs that are not being met—but that could be met, easily, through judicious choices in foods and supplements.

Adding fuel to the fire are neurodegenerative processes attributable to poor circulation and endothelial dysfunction in cerebral blood vessels, brought about by obesity, hypertension, atherosclerosis, and insulin resistance or diabetes. (Remember that the Great Preventer of cardiovascular and cerebrovascular disorders is physical exercise, which is a brain tonic in countless ways.) And for reasons that are still not well understood, inadequate nutrition (in terms of certain key nutrients) and lack of exercise increase the risk for real trouble: neuritic plaques and neurofibrillary tangles, which foul the brain and kill neurons by the millions—Alzheimer’s disease.


†It must be noted that the risk for Alzheimer’s disease is increased not only by nutritional deficiencies but also by nutritional excesses, such as overconsumption of saturated fatty acids and of high-calorie foods in general.


Here’s What to Take (for Starters) . . .

The Dutch researchers cited many studies of various kinds pointing to what they believe is an inescapable conclusion: that multinutrient interventions aimed at improving the biochemical environment of the brain so as to maintain the integrity of its components—the cell membranes in particular—can help prevent or alleviate age-related neurodegeneration and Alzheimer’s disease. The specific nutrients they believe are most important in this regard are:

  • Omega-3 fatty acids – These are a special category of PUFAs found mainly in fish oil from coldwater fish. Their value in preventing cardiovascular disease is well established (and formally acknowledged by the FDA), and this benefit also applies to cerebrovascular disease, which is known to be a major risk factor for dementia, including Alzheimer’s disease. More to the point, however, is that the omega-3 fatty acids DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) are major fatty acid constituents of the lipid bilayer’s phospholipids. If other fatty acids replace them because of a nutritional deficiency of the omega-3s, the cell membranes suffer, and synaptic plasticity is impaired. Significantly, the levels of omega-3s in the brains of Alzheimer’s patients are typically lower than those in age-matched, cognitively normal individuals.

  • Choline – This compound is a precursor of phosphatidylcholine, the dominant phospholipid in cell membranes, and of acetylcholine, the dominant neurotransmitter involved in cognitive functions, such as learning and memory. A hallmark of Alzheimer’s disease is a sharp decline in acetylcholine levels. If the levels become too low, the brain begins to cannibalize itself by taking choline from phosphatidylcholine in the cell membranes so as to be able to synthesize more acetylcholine. With the cell membranes thus damaged, a bad situation becomes even worse, accelerating the downward spiral.

  • B-vitamins – Folic acid is the most important of these in the present context, because of its key role in regulating the levels of homocysteine, a highly deleterious amino acid whose biological catalog of horrors includes cerebrovascular damage and an increased risk for Alzheimer’s disease. Folic acid should always be taken together with vitamin B12 and, preferably, vitamin B6, both of which help maintain healthy endothelial function in the cerebral vasculature, thus protecting against neurodegeneration. They also play important roles in cellular energy metabolism.

  • Antioxidants – Vitamins E and C stand out (there are, of course, many others) because of their known activity in preventing lipoprotein oxidation (which leads to atherosclerosis) and protecting endothelial function, particularly when they’re taken together. Healthy endothelial function is critical for vasodilation, which helps regulate blood pressure and maintain good circulation, thereby providing the brain with adequate amounts of the vital nutrients it needs—mainly oxygen and glucose, but also substances such as omega-3 fatty acids and choline.

Fundamental to the researchers’ viewpoint is their hypothesis that a multinutrient, rather than single-nutrient, approach is essential, owing to synergistic interactions by which various nutrients potentiate one another’s activity so as to make the total effect greater than the sum of its parts. There is reason to believe that the celebrated Mediterranean diet—one of the best there is—provides its myriad health benefits not only through the value of its individual components (flavonoid-rich fruits and vegetables, herbs, berries, nuts, fresh fish, olive oil, wine in moderation, and whole-grain bread, cereal, and pasta) but also through synergistic interactions among them.

. . . And Here’s Why

The authors concluded by saying (literature citations omitted),1

. . . the current epidemiological evidence points to a role of nutrition in the prevention of Alzheimer disease. The contribution of both macro- and micronutrients in this respect is supported by epidemiological data that emphasize the relevance of diet context (i.e., a multinutrient approach) rather than single nutrients, . . . In addition, recent mechanistic studies specifically support benefits of selective nutritional components in counteracting some of the neurodegenerative and pathological processes. The potential synergy between nutritional components to stimulate neuronal plasticity and function and reduce neuropathology provides a solid basis to investigate the potential benefits of such nutrient combinations in a clinical setting.

Reference

  1. van der Beek EM., Kamphuis PJGH. The potential role of nutritional components in the management of Alzheimer’s disease. Eur J Pharmacol 2008 [online preprint, unedited].

Lithium and Turmeric—Tools for the Brain

Lithium

Some of your brain cells have not yet been born. The process of neurogenesis, the creation of new neurons, mainly in the brain’s hippocampus, continues into old age. It tends to offset the loss of neurons as we grow older, but it cannot keep pace, especially in the face of neurodegenerative diseases, such as Alzheimer’s. It’s worthwhile, nonetheless, to try to stimulate neurogenesis as much as possible, and for that, nothing beats lithium.*


*For more on this subject, see “Can Lithium Benefit Brain Health?” (June 2004) and “Lithium Promotes the Formation of New Brain Cells” (March 2006).


Lithium, the lightest metal, has long been known to ameliorate a variety of brain disorders, especially bipolar disorder (manic-depressive illness), and research in recent years has shown that it combats some of the brain pathologies associated with dementia. One of these entails an aberrant chemical modification of a structural protein in neurons called tau (rhymes with wow).

Any disease that has this feature is called a tauopathy (tau·AW·pathy). The tau molecules become hyperphosphorylated (too many phosphate groups attached), causing them to form pairs of fibrils that get all tangled up with each other—the dreaded neurofibrillary tangles that cause widespread neuronal death in Alzheimer’s disease (and some other dementias as well).

An important promoter of tau hyperphosphorylation is an enzyme called glycogen synthase kinase-3 (GSK-3), which is known to be inhibited by lithium. Scientists in Spain have developed a transgenic (genetically engineered) strain of mice in which GSK-3 is overexpressed in certain regions of the brain, making the mice highly susceptible to tauopathy. Recently the researchers studied the effects of lithium in these mice to see: (1) whether it could prevent the formation of aberrant tau aggregates, such as neurofibrillary tangles, and (2) whether it could cause existing tau aggregates to disaggregate and revert to normal form.1

The answers were: (1) yes, and (2) no. If administered early in the disease progression (simulating the early stages of the human disease), lithium was effective in prevention. If administered late, it was able to reduce the hyperphosphorylation of tau but not reverse the existing aggregation of tau. This partial success represents another notch in lithium’s belt of accomplishments in the fight against neurodegenerative diseases. The authors cautioned, however, that the amount of lithium required was close to its toxic threshold and suggested that other GSK-3 inhibitors might be more appropriate for therapeutic use.

Turmeric

The strong anti-inflammatory and antioxidant properties of turmeric are attributed to a chemical compound called curcumin and a group of related curcuminoids, which have shown remarkable success in reducing neuroinflammation, a process that underlies the development of many neurodegenerative diseases, including Alzheimer’s. An important consequence of reducing neuroinflammation is inhibition of the formation of neuritic plaques, which consist largely of the protein amyloid-beta.

Turmeric curcuminoids are safe even in very large amounts, but even then, their bioavailability is extremely low, owing to extensive metabolism in the intestines and liver. A group of researchers in California and Japan recently studied the bioavailability and efficacy of both curcumin and one of the curcuminoids, tetrahydrocurcumin, in Alzheimer’s-prone mice, to see whether the latter compound might have significant advantages over the former.2

By and large, it did not. Although tetrahydrocurcumin did reduce neuroinflammation and the levels of some deleterious substances, it showed no ability to reduce the formation of amyloid-beta plaques—the ultimate test. Curcumin, however, passed that test, as had been demonstrated in previous studies.*


*For more on the benefits of turmeric, see “Galantamine Works Well in Real Life” (sidebar “Turmeric Fights Dementia,” February 2007) and “Turmeric’s Curcuminoids Help Prevent Brain Plaque” (October 2007). Regarding the bioavailability problem with curcuminoids, see “Solid-Lipid Nanospheres for Delivering Curcuminoids” (February 2008) and “Getting Our Curcuminoids Is Difficult, but Worth It” (March 2008).


References

  1. Engel T, Goñi-Oliver P, Gómez de Barreda E, Lucas JJ, Hernández F, Avila J. Lithium, a potential protective drug in Alzheimer’s disease. Neurodegen Dis 2008;5:247-9.
  2. Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s. J Pharmacol Exp Ther 2008 [online preprint].


Will Block is the publisher and editorial director of Life Enhancement magazine.

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