Lifting the Fog of Memory

Nicotinamide Restores
Cognition in Alzheimer’s Disease

Reduces Alzheimer’s tau lesions and memory loss in mice
By Will Block

Memory is a way of holding onto the things you love,
the things you are, the things you never want to lose.

— The Wonder Years

t is a simple truth that we value something more when it becomes harder to retain. Take the quality of our hair or skin or vision, as examples. Or consider how little we valued our memory over the earlier course of our lives, compared with now, when we have aged. Precious memory! Where would we be without it?

We would be lost without our memories, like a rudderless sailboat adrift in a fog-enshrouded sea . . . not knowing who we are . . . not knowing who we’ve been . . . not knowing those most dear to us. Alzheimer’s disease provides such a fate—the tragedy of lost memory—and although this dilemma is progressively prevalent for those in their 60s, 70s, and 80s, in actuality it starts far earlier for some. One of the things about Alzheimer’s disease that you may not know is that 10% of those affected by it are under the age of 50. In fact, a recent article in the New York Times dealt with a man who had early-onset Alzheimer’s in his 40s.1 He started to develop symptoms in his 30s!

Alzheimer’s disease may affect as many as 5.2 million Americans, causing senility and often leading to death. The Alzheimer’s Association estimates that the disease will strike one out of eight Baby Boomers. Unfortunately, there is no cure for this neurodegenerative disease. Medication, diet, life style, and supplements offer only limited benefits that are moderately effective in slowing its progression. But they will not stop or reverse Alzheimer’s disease.

So if you are predisposed to Alzheimer’s disease—as is the case if you have an Alzheimer’s gene, or if someone in your family has (or has had) it—or if you wish to live a long time, anything that can help to lessen its likelihood must be welcomed.

Startling Results

A recently published study by University of California, Irvine, scientists working with Alzheimer’s-diseased (AD) mice has found substantial benefit in high doses of a common nutrient in the vitamin B family, nicotinamide, a form of vitamin B3.2 So startling were the results—memory loss was restored in the AD mice—that the researchers are now conducting a clinical trial to determine if it can help to keep memory normal in humans (more on that later).

At the end of the trial, the AD mice performed as well in memory testing as healthy mice, a remarkable result strongly suggesting that nicotinamide had protected their brains from memory loss, and restored memory that would have been lost. “Cognitively, they were cured,” first author of the study, Dr. Kim Green said. “They performed as if they’d never developed the disease.”3 “The vitamin completely prevented cognitive decline associated with the disease, bringing them back to the level they’d be at if they didn’t have the pathology,” said Dr. Green. “It actually improved behavior in non-demented animals too.”4 Meaning that healthy mice fed nicotinamide outperformed mice on a normal diet. “This suggests that not only is it good for Alzheimer’s disease, but if normal people take it, some aspects of their memory might improve,” said Dr. Frank LaFerla, the lead author of the study.


“Cognitively, they were cured,” first
author of the study, Dr. Kim Green
said. “They performed as if they’d
never developed the disease.”


Mapping Uncharted Waters

Previous research suggests that vitamins such as Vitamin E, Vitamin C, vitamin B6, Vitamin B12, and folic acid may help people lower their risk of developing Alzheimer’s disease. Also helpful may be omega-3 fatty acids, choline, galantamine, turmeric, green tea, quercetin, and lithium. But nothing, until now, has suggested that any nutrient or combination of nutrients—let alone any drug—can reverse the cognitive decline associated with any of the dementias, including Alzheimer’s. Consequently, nicotinamide may be mapping uncharted waters.

Other trials with nicotinamide have shown that it possesses benefits for some diabetics and those with certain skin conditions because of its anti-inflammatory properties.

Nicotinamide is a water soluble member of the B vitamin group. Also known as niacinamide, nicotinamide is the amide of nicotinic acid (vitamin B3), also known as niacin. In vivo, niacin is converted to nicotinamide and although the two are identical in their vitamin functions, nicotinamide does not have the same pharmacologic effects of niacin, which may affect the liver negatively in some individuals. Unlike niacin, nicotinamide does not reduce cholesterol or cause flushing. In cells, niacin forms the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Although the pathways for nicotinamide and nicotinic acid are very similar. NAD+ and NADP+ are coenzymes in a wide variety of enzymatic oxidation-reduction reactions.

Nicotinamide belongs to a class of compounds called histone deacetylase (HDAC) inhibitors, which have been shown to protect the central nervous system in rodent models of Parkinson’s and Huntington’s diseases and amyotrophic lateral sclerosis. Clinical trials are underway to learn whether HDAC inhibitors help ALS and Huntington’s patients.*


*None other than sirtuin pioneer Dr. David Sinclair has recently cautioned against the widespread belief that nicotinamide is anti-sirtuin. “One must be careful when calling nicotinamide an ‘inhibitor’ in this experiment. While it is true that our lab showed that nicotinamide is a direct inhibitor of SIRT1 enzyme, it is also a precursor of NAD+, and NAD+ is a co-substrate (i.e., activator) of SIRT1.”

Moreover, “We should entertain the possibility that nicotinamide is activating SIRT1 in vivo, not inhibiting it. This would fit with other papers showing that SIRT1 is neuroprotective.”

— Sinclair D. Alzheimer’s Research Forum. Nov. 11, 2008.


Figuring Out the Water Maze and Avoiding Shock

In their study, Green and colleagues used mice genetically engineered to develop the equivalent of Alzheimer’s disease. They added the vitamin to drinking water (200 mg/kg/day) fed to the mice (4-months of age at study onset) and then tested the rodents’ short-term and long-term memory over time (4 months). Cognition was tested to examine hippocampal-, amygdala-, and cortical-dependent learning, which comprise the major brain areas affected by AD pathology in this mouse model.

Three different tests were used: a spatial memory version of the Morris water maze (hippocampal-dependent learning), a contextual fear-conditioning test designed to measure passive inhibitory avoidance (hippocampal- and amygdala-dependent learning), and a novel object recognition test designed to measure preference of novel objects over familiar ones (cortex-dependant learning).

In the Morris test mice are trained to find a submerged platform in a tank of water. Around the sides of the tank are symbols, and the goal entails (pun intended) that the mice remember the location of the platform, to save themselves from exerting energy to stay afloat by refinding the platform and emerging from the water. What the researchers found is that AD mice given nicotinamide performed at the same level as normal mice, while untreated AD mice experienced memory loss. Moreover, normal mice actually improved; their memories got better. The mice received the equivalence of about 2 g of nicotinamide for humans.

In the contextual fear-conditioning test, AD mice given nicotinamide avoided the dark, shock-associated compartment over the short and long term, while AD mice not so treated, entered it rapidly.

Finally, in the novel object recognition test, no difference could be discerned between nicotinamide-treated AD mice and those to whom it was not given.

According to the researchers, “These results show that oral nicotinamide treatment prevents the cognitive deficits that manifest in the [AD mice], while improving short-term spatial memory in non-demented control animals.”

Memory is an Essential Cognitive Process

We start off in this world by first using our senses. These are the primary channels by which we are made aware of the world. Seeing, touching, tasting, smelling, hearing: these provide us with the core of evidence that is the base of our knowledge. John Locke, the 17th Century British philosopher—who was well-read by America’s founders and generally regarded to be one of the most influential Enlightenment thinkers—believed that we come into this world without any knowledge and with a mind that is a blank slate (tabula rasa).

John Locke
1632–1704
In the beginning of life, it is the sensations of our experience that fill the slate of our empty minds and provide us with the beginnings of knowledge. Locke goes on to distinguish what he calls simple ideas and complex ideas. Simple ideas are acquired passively and arise directly from sensations. Seeing a lemon gives rise to the simple idea of “yellow”. This idea cannot be reduced to simpler ideas. On the other hand, complex ideas involve an active use of one’s mind in which one uses simple ideas to form mental combinations. These ideas are created through the volitional use of one’s mental faculties and can be reduced to the simple ideas that comprise them. For example, the complex idea of lemon can be broken down to the simple ideas of yellow, firm, sour, and so forth.

Cognitive theories are debated endlessly, and what appears above and below in this sidebar are controversial to many in the field. However, if you’d like to know more, I recommend Cognitive Science, An Introduction to the Study of Mind by Jay Friedenberg and Gordon Silverman (Sage Publications, Inc. Thousand Oaks, CA, 2006). Actually a textbook, Cognitive Science offers a well-developed summary of the major disciplines of the subject and up-to-date discussions on its history, its evolution, and current state. Costly, but worth the price. Lively and brilliant, Cognitive Science is not pitched at a level so high as to be incomprehensible to an intelligent lay audience. It’s very readable.

The principle keys to understanding how we learn—and how we get to become who we are—are the essential cognitive processes: memory, imagery, and problem solving. In the widest sense, memory is the means by which we retain information over time and serve that information to our active minds for processing. Memory allows us to learn from our mistakes, and to store our experiences and to access them in new circumstances, so as to better adapt and to thrive. It is important to know that there are three essential types of memory: sensory memory, working memory (aka, short-term memory), and long-term memory. Each of these plays a special part of cognitive processes.

Sensory memory is very brief (lasting no longer than 30 seconds and usually far less), but necessary for recognition, and while you may only apprehend something for a fraction of a second, it is enough for your selection and pattern recognition systems to identify what it is. A different sensory memory exists for each of your five senses, and some are longer than others. For example, echoic memory for hearing last several seconds, while iconic memory for seeing lasts far less than a second.

Working memory holds less information than sensory mechanism, but it holds that information for a longer period, usually in the range of several minutes. It is useful to think of working memory as a kind of memory workshop, where materials and tools are gathered for a brief while to create an outcome. It is in the memory workshop that cognitive tools are called upon and where thinking takes place. The outcome of the processing might be navigating oneself around a city, remembering a telephone number, or solving an arithmetic problem. Or something more complex.

Long-term memory holds the most information and it lasts for a lifetime. It is also divided into various types including procedural (skill-set knowledge for various activities such as riding a bike), declarative (memory that can be verbalized), episodic (the memory of events in your life) and semantic memory (memory of the knowledge of meanings, understandings and factual knowledge).

Over all, we possess the abilities to see both into the future and into the past, thanks to our memories. Anything that helps us to excel at this process is something worth pursuing.

Good Scaffolding and More Stable Cellular Highways

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by several hallmarks, including the formation of two different types of lesions: one that involves neurofibrillary tangles and the other amyloid plaque. It is not clearly understood. In the Green et al. study, nicotinamide was found to lower levels of a protein called phosphorylated tau that leads to the development of tangles (see Fig. 1). Of further consequence, the vitamin also strengthened the “scaffolding” along which information travels in brain cells. Good scaffolding helps preserve neurons, thereby further preventing symptoms in mice genetically wired to develop Alzheimer’s.

LEM0901tangles546.jpg
(Click image for full sized image)

Figure 1. Tau, which usually has a certain number of phosphate molecules attached to it, binds to microtubules and appears to stabilize them. In AD, an abnormally large number of additional phosphate molecules attach to tau. As a result of this “hyperphosphorylation,” tau disengages from the microtubules and begins to come together with other tau threads. These tau threads form structures called paired helical filaments, which can become enmeshed with one another, forming tangles within the cell. The microtubules can disintegrate in the process, collapsing the neuron’s internal transport network. This collapse damages the ability of neurons to communicate with each other.

In their search for just what was going on, nicotinamide did not affect levels of the protein beta amyloid, which clumps in the brain to form plaques, the second type of Alzheimer’s lesion. Given this lack of effect on beta amyloid levels, the researchers figured the compound must be improving cognition through some other mechanism. Upon analyzing protein extracts from whole brain samples of treated and control AD mice, they found a 20 percent reduction in levels of tau in the nicotinamide-treated animals. They saw no differences at several tau sites typically phosphorylated in AD mice at the end of eight months, but a whopping 60 percent reduction in Thr231-phospho-tau—a particular species of tau that has been reported to interfere with microtubule polymerization and is a commonly used biomarker for AD—in the nicotinamide group compared with vehicle. “It’s incredibly dramatic,” Green told the Alzheimer’s Research Forum. “This thing [a biomarker for AD] is just wiped from the brain very specifically.”5


According to the researchers, “These
results show that oral nicotinamide
treatment prevents the cognitive
deficits that manifest in the [AD
mice], while improving short-term
spatial memory in non-demented
control animals.”


Nicotinamide, they found, led to an increase in proteins that strengthen microtubules, the scaffolding within brain cells along which information travels. When this scaffolding breaks down, the brain cells can die. Neuronal death leads to dementia experienced by Alzheimer’s patients. “Microtubules are like highways inside cells. What we’re doing with nicotinamide is making a wider, more stable highway,” Green said. “In Alzheimer’s disease, this highway breaks down. We are preventing that from happening.”

“At the moment we’re talking about a disease for which there is no sort of treatment and this is likely to be far safer than any of the upcoming drugs. Nicotinamide is just vitamin B3, it’s really cheap, it’s safe and easy to get hold of,” said Green.

New Clinical Study in Humans

According to Dr. Green, “Nicotinamide has a very robust effect on neurons.” And because the results of his study were so impressive, he and his group are already moving forward with a six-month clinical trial.

Of 50 mild to moderate AD patients, half will receive placebo and the second half, 1500 mg, twice daily. That seems to be a safe level given that previous studies have only seen serious side effects in doses of 10 g or more. Most over-the-counter vitamin supplements, contain too little nicotinamide to have an effect.

The vitamin is believed to prevent the build-up of “tau” proteins along tracks inside neurons. In the early stages of the disease these protein clumps are thought to make nerve cells work less efficiently, but ultimately they can stop the nerves working completely and kill them off.


“It’s incredibly dramatic,” Green told
the Alzheimer’s Research Forum. “This
[biomarker for AD] is just wiped from
the brain very specifically.”


If these results are confirmed, the newly charted waters of preserving and restoring memory will be celebrated, and indeed we shall end up with a sturdier ship, far less affected by the fog of memory loss and aging.

References

  1. Wang SS. When Alzheimer’s hits at 40. New York Times, Nov. 14, 2008.
  2. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM,LaFerla FM. Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci 2008 Nov 5;28(45):11500-10.
  3. Dotinga R. Vitamin holds promise for Alzheimer’s disease. Healthday Nov. 5, 2008.
  4. Sample I. Vitamin pill that may slow Alzheimer’s goes on trial. The Guardian, Nov. 05 2008.
  5. Anon. Alzheimer’s Research Forum. Nov. 8, 2008.


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

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