My last post on niacinamide and Alzheimer’s (it’s supposed to reverse Alzheimer’s de-mentiaThe Coenzyme nicotinamide adenine dinucleotide (NADH) has been used as medication in 17 patients suffering from de-mentia of the Alzheimer type in an open label trial. In all patients evaluated so far, an improvement in their cognitive dysfunction was observed. Based on the minimental state examination, the minimum improvement was 6 points and the maximum improvement 14 points with a mean value of 8.35 points. The improvement on the basis of the global deterioration scale (GDS) was a minimum of 1 point and a maximum of 2 points with a mean value of 1.82. The duration of therapy was between 8 and 12 weeks. No side effects or adverse effects have been reported from the patients or their caregivers during the observation period which is, in some patients, more than a year. This open label trial represents a pilot study from which no definitive conclusion can be drawn. A double-blind placebo controlled study is necessary to demonstrate the clinical efficacy of NADH. The planning and the fulfillment of all requirements for such a study are in progress.) ended with a contradiction: niacinamide has been found to help neurodegenerative diseases like Alzheimer’s by inhibiting SIRT1, yet SIRT1 expression is associated with increased longevity and cognitive health.
[Note on this post: some links expand with further information when you mouse over them]
I can’t stand contradictions, so I’ve been digging through scientific abstracts trying to find how both of these facts can be true, and I also embarked on an experiement with niacinamide to see if any interesting information would pop up to help clear up the above contradiction.
Upon learning that niacinamide (aka nicotinamide, aka NAD–which switches to and from NADH in the body) is a crucial co-enzyme in glucose metabolism, and knowing that one of the markers of Alzheimer’s Disease is lowered glucose metabolism in the brain, I set up an experiment using four family members to see if oral niacinamide would alter the glucose metabolism in any of the subjects, and if so, what the implications were for the SIRT1 expression/inhibition contradiction. Since SIRT1 is important in keeping a steady supply of glucoseHomeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1—which modulates ageing in several species1, 2, 3 —controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1 at specific lysine residues in an NAD+-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1, but does not regulate the effects of PGC-1 on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan. in the body (by producing it in the liver during fasting hours), if niacinamide works to tone down glucose spikes and even out the curve, it may be the reason SIRT1 is inhibited with use of niacinamide.
Below are the graphs representing four family members’ glucose levels after a high-glycemic breakfast. Each graph shows at least three days without niacinamide and three days with 500mg niacinamide taken just before a high-glycemic breakfast (to force a spike). A normal curve after a high-sugar/carb breakfast would be a spike within 45 minutes with a gradual decline to normal glucose after two hours.
Below the graphs is a multiple choice question: which one of these four graphs represents an 81-year-old woman with advanced Alzheimer’s weighing 90 lbs with no history of diabetes in the family? (The other three are her children). If you suspect you know the answer, please vote and add your comments at the end of the post. (Note: handheld finger prick glucometers are not as accurate as laboratory tests on whole blood samples, so the above results should be taken with a grain of skepticism). Mouse over the thumbnails for a larger picture.
Glucose, Niacinamide, and Alzheimer’s
The answer to the above is *.family member 3
Hopefully readers will catch that this is a trick poll. In asking it, it is assumed that glucose readings from finger pricks can reveal Alzheimer’s. As far as I know, it can’t. Consequently, from these glucose tests I can gather nothing about whether or how niacinamide affects cognition in Alzheimer’s. Yes, Mom’s metabolism is a little quirky . Should this be worrysome to her kids, given that Alzheimer’s is linked to the mother’s phenotypeBrain imaging studies using 2-[ (18) F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG PET) have shown that NL individuals with a maternal history of LOAD, but not with a paternal family history, express a phenotype characterised by a pattern of progressive reductions of brain glucose metabolism, similar to that in AD patients. As maternally inherited AD may be associated with as many as 20 per cent of the total LOAD population, understanding the causes and mechanisms of expression of this form of AD is of great relevance.? The niacinamide seems to tone down the spikes and drops, but there is no clear correlation between peripheral metabolism and cognition. Besides, all three offspring have different body metabolisms as shown in the graphs above, yet we’re all going somewhat batty at about the same rate (our minds are not nearly as sharp as they used to be). If Mom’s Alzheimer’s is due to her quirky peripheral metabolism, what accounts for her children’s faltering cognition? And if cognitive failure occurs with all kinds of body metabolisms, then niacinamide’s role in cognition via its effect on metabolism would be difficult to establish (you’d need a lab that could do the above test with brain metabolism, not body metabolism).
At the cellular level, metabolism is dependent on NAD and other enzymes. A breakdown of metabolism at this level could be due to a deficiency in niacinamide, but also to other causes, e.g., an abnormal zinc/copper ratio.Cellular Level Hypoglycemia: This is energy starvation at the level of brain cells. The person may have a normal GTT but presents the same hypoglycemic reactions. This may be caused by a dysfunction in enzymes involved with glucose metabolism, usually as a result of an abnormal zinc/copper ratio. Zinc is a coenzyme in the break down of glucose to simpler biochemical substances, before being used as energy inside brain cells. High copper levels depress zinc levels and vice versa. Other coenzymes and vitamins are also involved in glucose metabolism inside the mitochondria. Perhaps a combination of niacinamide and PBT2the effectiveness of PBT2 lies in a unique combination of complementary activities. PBT2 acts to detoxify A-beta by disarming it of copper and zinc and returns these crucial metals to neurons. Dr. Cherny showed that by returning these metals to neurons, important cell signaling pathways are activated that prevent neuronal death and promote neuronal function. In addition, data was also presented linking the neuroprotective qualities of PBT2 with beneficial effects evident in an animal model of Huntington’s Disease could be used in Alzheimer’s therapy (cover as many bases of the Krebs Cycle as possible)?
It is possible that the niacinamide in our experiment accounts for Mom’s more subdued behavior as a result of toning down the spikes and crashes in glucose levels. Mood disorders and mental illnesses have been associated with wild glucose swings, and the effect this vitamin had on Mom’s demeanor seems to fit this hypothesis.
Besides testing the effect of niacinamide on glucose metabolism over a few days, the experiment with niacinamide extended over a three month period. Out of this period there are other tentative conclusions drawn. Stay tuned for a future post titled Does Alzheimer’s Take Guts? The Niacinamide Experiment Part 2.
It will be especially interesting to see the results of a clinical trial of niacinamide on Alzheimer’s subjects in progress at U.C. Irvine.
Points to ponder
It is true that AD attacks the brain’s default networkYet another line of inquiry involves the brain’s default network: a system of cells that is always turned on at some level. It includes the hippocampus, the brain’s memory center, but also other areas, and is the brain’s mind-wandering mode — the part that is active when, for instance, you’re driving in your car and you start thinking about what you will make for dinner. That brain system, scientists find, is exactly the network that is attacked by Alzheimer’s, and protecting it in some way might help keep the brain healthier longer. […] The default network is costly for the brain to run, using huge amounts of glucose, Dr. Raichle said. And one indication that a person is getting Alzheimer’s is that in scans, the brain’s glucose use is markedly lower. The observation that Alzheimer’s attacks the default network, then, explains the observation that a low use of glucose by the brain is associated with Alzheimer’s disease. (see also: Alzheimer’s and the Brain’s Default Network) which needs enormous amounts of glucose to function. But I don’t know if brain glucose levels are the same as body glucose levels in Alzheimer’s, so I can’t draw conclusions from the effect of niacinamide on peripheral glucose levels for how niacinamide affects that aspect of Alzheimer’s.
Studies show connections between hyperinsulinemia, Diabetes and Alzheimer’s Disease:
Insulin can cross the blood brain barrier from the periphery to the central nervous system and compete with Aβ for insulin degrading enzyme (IDE) in the brain, including the hippocampus (Farris et al., 2003). Insulin is also produced in the brain, and may have alternatively have a beneficial effect in amyloid clearance (Reger et al., 2006). Peripheral hyperinsulinemia may inhibit brain insulin production which, in turn results in impaired amyloid clearance and a higher risk of Alzheimer’s disease (Reger et al., 2006).
In the current issue of Neurology®, Mosconi et al. 1 use FDG PET to demonstrate a critical link between a maternal family history of Alzheimer disease (AD) and a pattern of regional metabolic abnormalities similar to that identified in patients with clinically diagnosed AD. By contrast, significant metabolic abnormalities (at baseline or follow-up) were not evident in subjects with a paternal history of AD nor in those without a family history of disease. Given that mitochondrial DNA is inherited maternally in humans, the authors speculate that their data are compatible with mitochondrial dysfunction as the root cause of AD. This mechanism has likewise been hypothesized for other common neurodegenerative conditions.
“Zinc Neurotoxicity is Dependent on Intracellular NAD Levels and the Sirtuin Path”NAD(+) was recently demonstrated to permeate neurons and glia, and we have now shown that exogenous NAD(+) can reduce Zn(2+) neurotoxicity, and 3-acetylpyridine, which generates inactive NAD(+), potentiated Zn(2+) neurotoxicity. Sirtinol and 2-hydroxynaphthaldehyde, inhibitors of the sirtuin pathway (SIRT proteins are NAD(+)-catabolic protein deacetylases), attenuated both acute and chronic Zn(2+) neurotoxicity.
A bunch of articles that correlate a mother’s AD to child’s decreased brain metabolism.
“Relationship Between Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase Subunit p22phox Gene Polymorphism and Obstructive Sleep Apnea-Hypopnea Syndrome in the Chinese Han Population”
“PET Scan Glucose Use Correlation With Beta Amyloid Deposition Over Time in Alzheimer’s Disease”
“Nicotinamide and Insulin Secretion in Normal Subjects.”Nicotinamide does not affect insulin secretion and glucose kinetics in normal subjects, confirming its suitability for trials designed to delay or prevent the onset of Type 1 diabetes.