Curcumin: A Powerful Brain Protection Supplement, © 2005-2017 by John M. Smart

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Sections

Curcumin Overview
The Nelson Anti-Curcumin Study: Mildly Valuable But Mostly Incorrect
NovaSOL Micellar Curcumin - Everyone Seeking to Prevent Alzheimer's Should Be Taking This Now!
Curcumin for Neuroprotection: A Literature Review
Longvida Curcumin: An Alternative Supplement Choice

The Apo e4 Gene and Your Alzheimer's Risk: What You Should Know

Retinal Amyloid Imaging for Alzheimers Prevention

Intermittent Fasting for Neuroprotection (and Alzheimer's Prevention)

 

Curcumin Overview

Curcumin is an inexpensive dietary supplement that offers powerful protection for aging brains, via general inflammation reduction, by protecting brain mitochondria, and by binding to and helping the brain clear amyloid plaque accumulation. It has been used as a food additive for thousands of years in the East as the active ingredient in turmeric, or yellow curry spice. One of its most helpful effects is that it reduces the buildup of Alzheimer's-related amyloid in our brains as we age (for details, see this nice 2008 overview by Mishra of USC[1]).

Since 2000, curcumin's many memory and brain benefits are being slowly uncovered by scientists, clinicians and gerontologists (researchers who study the aging process). Curcumin has many, many mild physiologic effects when we eat it as a nutritional supplement. It is anti-inflammatory, anti-cancer, and anti-diabetic in its actions, and has been proven tolerable and safe in daily doses up to 8 g for at least three months.

Many folks take curcumin daily to reduce their inflammation. If you go online at Amazon and look over the reviews on curcumin supplements, you'll find hundreds of folks who have seen big reductions in joint pain, GI pain, and other pain while taking this supplement. You'll also find scores of folks who talk about the reduction of "brain fog", and the return of their memories. This impressive effect, and curcumin's mental benefits have been well documented in animal models, but it will be several more years before the more definitive long-term human studies are completed and its use can and very likely will be recommended to the general public. Fortunately, hundreds of millions of Asian Indians eat it daily, and once you understand its benefits, you can too.

Amyloid buildup is a degenerative process that affects all of us, without exception as we age, steadily gunking up our brains with protein deposits and decreasing our brain's memory and learning abilities. It is one of those things we all die "with," and an unlucky few of us die "of." Fortunately, because we all have "cognitive reserve" (redundant ways to learn everything important that we do), this steady loss of our brain's function isn't necessarily noticable to others around us, but it means our minds have to work harder and harder and harder over time to do things that were previously easy. If we pay attention (many of us don't, perhaps because it is an unpleasant realization), almost all of us will typically begin to notice creeping recall, learning, and awareness ("brain fog") issues beginning in our 30's (or even late 20's for some) and steadily becoming worse with advancing years. Eventually, with enough damage, even your reserve capacity begins to fail and significantly reduced mental ability, forgetfulness, and in your later years, even full-blown Alzhiemer's can emerge.

If you care about protecting your mind and learning capacity throughout your long future life, we hope you will take this article to your physician for further evaluation. As outlined in my companion article, "A Basic Brain Protection Plan," 2006, you may significantly improve your future mental performance by following some version of this very affordable supplementation plan under the advice of your physician.

2017 Update: A curcumin-doubting perspective article by Nelson et al. was published Jan 2017 in J Medicinal Chemistry. For why it is both incorrect and dangerous misinformation for neuroprotectors, see my commentary in this article.

Disclaimer

This article alone is not medical advice. Take this information to your physician. You should always seek expert medical advice before starting any new drug or supplement regimen.

Article

As medical science keeps us alive longer than ever before, age-associated diseases have become a prime health concern for us all. Alzheimer's Disease (AD) is presently the fourth leading cause of death among elderly in the developed nations, after heart disease, cancer, and stroke. Preventing it is the subject of this article.

Just like progressive atherosclerosis (arterial plaques), which everyone begins to collect to varying degrees in their circulatory system even in their teens, we all die with the buildup of varying degrees of amyloid plaque deposits in our brain. New research has shown that it is primarily these amyloid plaques and their associated effects that create Alzheimer's when they have sufficiently advanced in size and scope within the brain.

While most of us won't die from Alzheimer's, all of us will die with insoluble toxic amyloid buildup in our brains, which increasingly impairs our memory and learning capacities as we age. Amyloid accumulates in different brains at different rates, depending on our diet, genetics, and lifetime stress-immune histories. The more we have, the more we will notice mild-to-significant progessive cognitive impairment, particularly after the age of 50. Our 50's and beyond is the time of our lives when we finally have enough experience, connections, capital, and collective wisdom to do some of our most important work. But we need healthy brains to do so. Fortunately, this handout relays important new therapeutic information which, with your doctor's approval, might significantly improve your mental prime in your later years.

Greg Cole, Ph.D[2] is professor of medicine and neurology at the UCLA David Geffen School of Medicine, associate director of the UCLA Alzheimer's Disease Research Center, and associate director of the Geriatric Research, Education, and Clinical Center at the LA Sepulveda VA. For over twenty years Dr. Cole has systematically explored potential Alzheimer's prevention drugs including supplements like DHA, NSAIDs, vitamin E, and many others, as well as the etiology and pathophysiology of neurodegeneration.

After learning of his fascinating work, we invited Dr. Cole to speak at our July 2005 Los Angeles Future Salon. The following is my unauthorized summary of his fascinating presentation, see his PowerPoint [3] below, in my own attempt to publicize the breakthroughs that he and his colleagues have recently made.

In recent years Dr. Cole has been studying curcumin, the active ingredient in Indian yellow curry spice, which is made from turmeric root (left). Indians consume large quantities of yellow curry turmeric in their diet, and it has long been a component of their Ayurvedic medicine. We in the West are only now coming to understand the value of this dietary supplement.

It has been long known in epidemiology that Asian Indians have age-adjusted Alzheimer's and other senile dementia rates that are lower than the developed world. See this 2001 study [4] for one example. On learning this fact, Dr. Cole and colleagues postulated that curcumin may be a natural neuroprotectant against Alzheimer's Disease, an decided to study it in greater depth. [2017 Note: Since this 2006 study, we now know that some of this lower rate is due to a lower incidence of Apo e4 in India, particularly in Northern India. But later studies on India's Alzheimers incidence vs the West still allow that diet may have a substantial protective effect.]

As medical researcher and gerontologist Steve Harris, M.D. noted in 2005, "India, where turmeric is consumed daily, has a vastly lower age-specific dementia rate [than the developed world], despite heart disease rates which vary widely across the country and in some cases surpass the West. All this suggests a specific brain-sparing minor component of the Indian diet. We can guess what this may be."

Curcumin is a lipophilic (fat-soluble) yellow-orange pigment that has long been known as a powerful antioxidant and anti-inflammatory agent. It was first significantly studied by U.S. researchers in the 1980's and 1990's for its mild anticancer effects. They discovered curcumin wasn' t particularly effective against cancer, but in the process documented that it has great safety profile. One would expect it to, because hundreds of millions have eaten it for generations in India, with no associated medical problems.

As noted in this Chemical and Engineering News article [5], Dr. Cole first suspected curcumin might be a beta-amyloid plaque binder in the brain when he noticed that the curcumin molecule was structurally very similar to two dyes, Congo Red and RS-0406, dyes commonly used by medical researchers to stain amyloid plaques in brains. This insight, combined with the epidemiological data, motivated his group to a study curcumin in greater detail.

In 2001 he and his colleagues showed that curcumin crosses the blood-brain barrier from the diet into the mouse brain, due to its low molecular weight, central lipophilicity, and polar groups at the ends. Around the same time they also fed curcumin to an Alzheimer's-prone transgenic mouse, a mouse engineered to create rapid amyloid buildup and mental problems. They discovered it had a powerful protective effect against the emergence of mental problems. Then they proved that curcumin also slows brain aging in ordinary Sprague-Dawley rats, by testing age-related decline in their ability to run water mazes [6]. Then in 2005 they uncovered some of the molecular ways in which curcumin binds to amyloid plaques and allows the immune system to break them down in living mouse brains [7].

The slide to the right indicates a number of beneficial inhibitory pathways (-), due to curcumin's ability to protect against oxidative damage and inflammation in the brain, and its apparent inhibition of cholesterol buildup as well (it is already well known that people who take statins to lower their cholesterol have half of the normal Alzheimer's risk). The slide also indictes a beneficial catalytic pathway (+), due to amyloid breakdown and clearance from the brain by the neuroimmune system, once curcumin binds to existing plaques.

Like any natural biomolecule, curcumin is a "dirty" drug with a number of different effects (antioxidant, antiinflammatory, amyloid binder, etc.), but fortunately in this case all of its effects seem to push in the same direction: neuroprotection. Such natural drugs are often much better than synthetic molecules designed by pharmaceutical companies, because the latter are usually designed for one specific biochemical purpose, but as a result often have other unanticipated side effects when used long term. Unanticipated side effects, like unanticipated mutations, are usually negative. There are no perfect drugs, only better and worse ones, and curcumin appears to be as good as they come.

Another interesting fact about curcumin is that it is also the only known therapy other than caloric restriction that reliably will reliably extend lifespan (about 10-12%) in laboratory mice. It seems most reasonable to suspect that curcumin's life extension effect is due to improved total body immunity (mediated, as with most things, through the brain) in old age. There's no reason at present to suspect that benefit wouldn't also operate in humans.

Cole's group also found curcumin is an even better inhibitor of amyloid buildup in the Alzheimer's mouse brain than nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen. Such drugs have have long been known to have significant risk reduction effect in Alzheimer's by slowing inflammation-mediated amyloid buildup in the brain, but they are hard on the gastrointestinal tract (some people can't take them orally without getting upset stomachs and nausea), and they have recently come under suspicion of causing cardiovascular problems [8].

Dr. Cole and colleagues are now testing curcumin on human Alzheimer's patients in clinical trials, but it will take several more years before this data becomes available. Meanwhile, if you are noticing age-related decline in memory or learning ability, I suggest you try curcumin empirically, under the supervision of your physician, to see if you notice any improvement. If you are like me I predict it will have a substantial positive effect.

If you are going to take curcumin in doses beyond the occasional curry dinner, you will want to take supplements. According to Sally Frautschy, Ph.D. a 900mg native curcumin capsule is the rough equivalent of five regular turmeric curry dinners. The only well known problem with curcumin, besides its low absorption into the bloodstream, is that you can't repeatedly take it without food or you will tend to get an upset stomach. Taking it with some fatty food, or ideally with your daily fish oil supplements at the same time, will maximize absorption. As curcumin also has well known in vitro anticancer effects, many of which operate by direct antioxidant effect, and as very little curcumin is absorbed from the gut each time you take it, it is also very likely that you are also significantly preventing colon cancer with a lifetime of curcumin supplementation. As this 2007 study [9] shows, many in vitro studies show curcumin's anticancer effects, and Phase II studies in humans for colorectal cancer prevention are now underway and are very likely to show positive effects in a few years time.

Let me conclude by relaying Dr. Cole's comments on curcumin dosage, safety, and efficacy when I asked him by email in August 2005. Dr. Cole reminded me that he is not a physician, and is not dispensing medical advice, so be sure to take this information to your physician.

"We have a small pilot clinical trial at UCLA which is testing two fairly high doses of 2,000 and 4,000 mgs of curcumin manufactured as an extract by Sabinsa. Long term trials have not shown side effects at ~1200 mg for three years while short term (3 mos) trials in cancer patients report no problems up to 8 grams a day, but other studies suggest some patients get diarrhea at 3 or 4 grams [3,000 - 4,000 mg/day]. As I said in my talk, one reason the doses are so high is poor absorption. Curcumin is poorly soluble and poorly absorbed because of glucuronidation and high first pass metabolism[, a problem that] that the addition of piperine [in the Life Extension Foundation and Sabinsa formulations] is supposed to limit a bit. For now, curcumin should be taken with a fatty meal—milk products, plant or animal fat sources are all handled the same way. I would suggest people who want to try it start on around 500-1,000 mg a day, which seems to have useful effects in small trials in people and if they have no tolerance problems and have say mild Alzheimer's Disease or are on the cusp of getting it maybe go up to 2,000 mg, but not higher. I have never heard of a problem with people taking less than 2,000 mg/day, but it could happen because large scale human trials with high doses still have not been done. Small trials for cancer claim no adverse effects up to 8 grams/day, but I definitely wouldn't go there.

We believe that curcumin synergizes with omega-3 fatty acids in [preventing] Alzheimer's Disease and probably other neurodegenerative conditions and would suggest taking it with fish oil or algal DHA, based on our animal data. The American Heart Association recommends 2 or 3 fish oil capsules (1 gram each) a day and they have clinical trial and safety data backing this up. DHA will soon go into large multicenter trials. Unfortunately, all of my current thoughts about dose and efficacy are just guesstimates since we have no trial data on curcumin or omega-3 fatty acids. We are currently seeking grant support to address the issue of curcumin bioavailability which is a problem that we think we can solve. At least we have some reasonable things to test. All we have now are anecdotal reports suggesting some efficacy and of course our animal model data. Without trial data we cannot formally recommend anything, so Caveat Emptor!"

In summary, curcumin appears to be a powerful natural neuroprotectant, at least as good for your brain as DHA/fish oils, and perhaps much better. It is a substance that people may only learn slowly about for the time being because, as Dr. Cole points out, drug companies cannot patent it, so it falls in the realm of nutritional supplements. Supplements are a crowded field full of lots of hype and misinformation, and an area where multimillion dollar studies proving efficacy are slow to fund and emerge. Fortunately, armed with the information you can find here and on the web, you may not have to wait.

Let me close with my personal story: As outlined in "A Basic Brain Protection Plan," 2006, I take two 900 mg capsules of Super Curcumin with Bioperine, from LEF.org.

(2017 Note: The best curcumin now available is NovaSOL micellar curcumin, a formulation roughly 180X more bioavailable and effective than standard curcumin. It is available from the following suppliers in the US:

Quantum Serum Curcumin + CoQ10
RevGenetics MetaCurcumin 200
Solgar Full Spectrum Curcumin
Bio-Sorb 185x Curcumin
Puritan’s Pride Fast Absorb Curcumin
Natural Stacks Curcumin
Arrow Essentials Turmeric Curcumin

Folks who are e4 heterozygotes, and anyone particularly concerned about subjective memory decline, should probably take Solgar Full Spectrum (NovaSOL micellar) Curcumin, at a dosage of 6 capsules a day (2 in the morning and 4 with your evening meal if you are fasting, or two with each meal on the days you eat three meals). Start with 1/3 of this dose the first week, to avoid any GI problems, and scale up each week by thirds. At this dosage, the 90 capsule version at Amazon or Walmart will cost you between $2.50 and $3/day. Folks who are apo e4/e4 homozygotes should consider taking as much as 9-12 capsules per day. You should also be taking roughly 3,000 mg/day of Omega-3 fish oil or algal DHA (ten regular strength capsules/day), in the same ratio with your curcumin. Please take this information to your physician, and see section below for research details.

If you care about brain health, please start taking micellar curcumin now!

As of this writing (2005) I've been on a curcumin and fish oils regimen for six months, long enough for any placebo effect to have worn off, and journaling my impressions. Here's what I self-observed: After noticing increasing difficulty over the last several years recalling things both recently and distantly learned, and having to speak sentences that aren't what I want to say because I have a word on the tip of my tongue but can't immediately remember the name for it, I have seen a clear improvement in my working, verbal, and long term memory and learning ability. I've also noticed I can do more activities than I did before on the computer and in other complex mental tasks.

Before you begin these supplements you should think about taking a formal before test and after test of your memory (make sure it is six months after starting curcumin, so there is no longer any placebo effect), to better validate your own subjective impressions of their benefit. A quick $20 online memory assessment designed for individuals betweeen 45 and 86 years of age can be found at Cognicheck.com. Free online tests may also available, but I haven't found any good ones yet. I was too busy at the time of starting curcumin to search out and take a formal test, but you don't have to make the same mistake.

Best of luck and thank you for passing on this information to those who may benefit from it. I wish you and yours many future years of healthy mind!

References

[1] Mishra S, Palanivelu K. The effect of curcumin (turmeric) on Alzheimer's disease: An overview. Ann Indian Acad Neurol [serial online] 2008 [cited 2008 Jul 30];11:13-9. Available from: http://www.annalsofian.org/text.asp?2008/11/1/13/40220
[2] Dr. Cole's home page: http://www.neurology.ucla.edu/faculty/ColeG.htm
[3] Dr. Cole's PowerPoint slides from his LA Future Salon talk: http://accelerating.org/ftp/Alzheimers(GregCole05).ppt
[4] Vas CJ et. al. Prevalence of dementia in an urban Indian population. Int Psychogeriatr, 2001 Dec;13(4):439-50. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=12003250
[5] Rovner, S.L. (2005). "Untangling Alzheimer's," Chemical and Engineering News, 83(8), 38-45.
[6] Frautschy SA, Cole GM, etc (2001).,"Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology," , Neurobiol Aging, 22(6):993-1005 (http://nootropics.com/curcumin/)
[7] Yang F, Cole GM, etc (2005)., "Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo.," J Biol Chem, 280(7):5892-5901
[8] Marx, V (2005). "Doubts escalate over painkillers," Chemical and Engineering News, 82(31), 7.
[9] Johnson, JJ, Mukhtar H. Curcumin for chemoprevention of colon cancer. Cancer Letters, 2007 Oct 8;255(2):170-81. Epub 2007 Apr 19.

The Nelson Anti-Curcumin Study 2017: Mildly Valuable But Mostly Incorrect

In 2017, Nelson et al. published a mildly valuable but also quite flawed new review on curcumin as a drug, claiming it has "likely false activity" in vitro and in vivo, and that it is a "highly improbable lead" in the search for better medical therapeutics. See these links for the details:

The Nelson Anti-Curcumin Study:
The Essential Medicinal Chemistry of Curcumin, Journal of Medicinal Chemistry, Nelson et al., 2017
Relevant Nature commentary:
http://www.nature.com/news/deceptive-curcumin-offers-cautionary-tale-for-chemists-1.21269
Science Translational Medicine commentary:
http://blogs.sciencemag.org/pipeline/archives/2017/01/12/curcumin-will-waste-your-time

I'm told a rebuttal to a number of its in vivo claims, authored or contributed to by at least a dozen curcumin researchers, has been submitted to a major journal and is now pending approval for publication, so stay tuned for more.

In my lay opinion, this Nelson review (perspective, opinion piece) offers a useful corrective on the overclaiming that has been done regarding curcumin as a multi-disease therapeutic in the literature. But it is also a classic example of Big Pharma bias. The authors are using their field, drug discovery, and its still-evolving screening tools, which apparently weren't even applied rigorously in this case (see Peter Kenny's comment in the STM commentary for details) to attempt to discredit a natural substance with a ton of conflicting chemical actions, including the modulation of chemical kinetics of scores of enzymes in a variety of subtle ways.

Biochemically, curcumin is one of the dirtiest substances around. It bolloxes up all kinds of assays, thus they see it as a poor "drug." But the whole single-action, high potency drug model is just the current dogma of pharma. It's where they need to start, in an incredibly complex space. So good for them in developing better first-gen activity measurement tools. But much of biology, and many natural substances, work very weakly, over long times, by mild synergistic effects.There's also a school of naturopath physicians who think weak, multi-action substances, given over long times, is a better way to go than high-potency single action drugs, both for disease prevention (for example curcumin for colon cancer) and for managing some chronic and degenerative diseases, like Alzheimers. Naturopathic medical schools are nearly extinct in the US vs allopathic medical schools, but they aren't dead yet, and their way of looking at disease and medicine is a valuable counterbalance to the philosophy of modern Big Pharma.

Big Pharma and the drug discovery field that it funds seems currently biased toward using an evolving a set of tools, like PAINS assays, to identify more high-potency, single action candidates, but both their tools and assumptions are presently inadequate for dealing with the subtle cellular and molecular biological effects of many dirty natural substances, which we're just now trying to get a handle on.

I do like the way the Nelson paper argues that much of the literature on curcumin is very poor and is overclaiming. Many Indian researchers, raised in the tradition of Ayrvedic approches to healing, and many in the natural supplements and alternative medicine industry, are emotionally and/or financially attached to the success of curcumin. Some of their research is likely to be even more biased toward curcumin's efficacy than this new study is biased against it. For a good example, one Indian curcumin researcher, Bharat Aggarwal, has been accused of systematic fraud and has had 18 of his publications retracted so far (see Retraction Watch). Unfortunately, several of Aggarwal's studies continue to be dubiously cited by folks who are unaware of his history. But that doesn't mean all the ongoing curcumin studies are biased and flawed. Far from it.

We've known for over a decade that mice get curcumin into their brains via an oral route, where it is long-term stable in fatty neural membranes, binds to amyloid plaque, and reduces plaque burden. We also know it reverses cognitive deficits in a variety of AD mice models. I cited some of that research in my original 2005 Curcumin Overview above.

The form of curcumin you take is hugely important to its bioavailability. Oral curcumin is very poor at getting through the GI wall into the blood. Once in the blood, the liver also tags blood curcumin with glucuronidation to greatly increase its clearance. So manufacturers have come up with various methods to increase bioavailablity. There are relatively mild methods to increase bioavailability, like adding pepper (piperidine) to reduce glucuronidation, but there is also a much more powerful method: surrounding the curcumin with lipids.

There are three ways to do that. You can add oil to your curcumin, increasing its solubility in your GI tract, you can surround it with solid lipids in a nanoparticle (SLNP curcumin), or you can surround it with a phospholipid "micelle", a polar fatty membrane just like your cell membrane. It turns out that the last two processes, both SNLP curcumin and especially micellar curcumin, are the only two that are significantly bioavailable in your bloodstream. Read on for the details.

NovaSOL Micellar Curcumin - Everyone Seeking to Prevent Alzheimer's Should Be Taking This Now!

Alzheimers is a risk for everyone in later life. But there is a markedly elevated risk for early onset Alzheimers for the between 10 and 40% of the global population (your frequency depends on your heritage). These are folks with at least one copy of the Apo e4 gene. The Apo e4 gene is called the "ancestral allele", as it was much more prevalent in early humans, and has steadily been disappearing since food became plentiful for us. I explain how it works in the section on Apo e4 and Alzheimers below.

You should get tested for this gene, and if you have it, you owe it to yourself and your family to start on micellar curcumin as soon as you reach adulthood. As detailed below, the best form of micellar curcumin presently available is called NovaSOL curcumin, and it is made by a company in Germany called AQUANOVA. They supply this curcumin to supplement retailers around the world.

In the US, Solgar is the oldest and most respected supplement company seeling NovaSOL curcumin at present. Solgar full spectrum (NovaSOL) curcumin is therefore the supplement I would presently recommend taking for neuroprotection. In my opinion, micellar curcumin is the best neural antinflammatory and amyliod plaque prevention compound available in the world today.

Disclaimer: I am not a physican, so please take this information to your physician.

In my current read of the literature cited below, I would recommend that Apo e4 heterozygotes, and anyone subjectively concerned about memory decline, should take a dosage of 6 capsules of Solgar's full spectrum curcumin per day. At that dose, you'll be getting 288 mg of total micellar curcuminoids per day (see label right). Start with 1/3 of this dose the first week, to avoid any GI problems, and scale up each week by thirds.

You can take two capsules with each meal if you eat three times a day, or two in the morning and four in the evening on the days you do intermittent fasting (see my section on Intermittent Fasting below). If you buy the 90 capsule version of Solgar curcumin at Amazon, or through occasional discounts at online stores like Walmart, this supplement will cost you between $2.50 and $3/day. This is a lot of money for most folks, and I am now looking into ways to find it in bulk. Apo e4/e4 homozygotes may need to take as much as nine to twelve capsules a day. The literature is unclear on this point at present.

Apo e4/e4 hetero and homozygotes should also strongly consider engaging in at least 30 to 60 minutes of sweating (cardiovascular) exercise every day. A Schuit 2001 study of 75 year old e4 homozygotes found those doing 60 minutes or more of exercise a day sharply reduced their risk of cognitive decline over three years. A Head et al. 2012 study of 45-88 year old females found a significant reduction in brain amyloid deposits for e4 carriers, as assessed via PIB imaging, at a (self-reported) exercise level of 30 minutes a day. They specifically propose that daily cardiovascular exercise may allow e4 carriers to maintain brain amyloid levels equivalent to e4 negative individuals. Animal studies have shown that cardiovascular exercise is particularly protective against amyloid deposition. These data are still scanty, but they make a good initial case for regular daily cardiovascular exercise being uniquely important for e4 carriers.

See also this excellent review and opinion, Exercise, APOE genotype, and the evolution of the human lifespan, by Raichlen and Alexander, Trends in Neurosciences, 37(5) 2014, for more on Apo e4, the ancestor allele. If they exercise daily, fast frequently, and avoid bad diets, Apo e4 carriers can greatly protect themselves from cognitive decline.

If you are like the folks in this 2016 Mol Nutr. Food Res study (on 294 mg micellar curcuminoids per day), after about three weeks on this regimen, your fasting curcuminoid plasma concentration should reach an average of 49 nmol/L. This study showed good early evidence of safety and tolerability at this dose. Neither blood lipids, inflammation markers, glucose, iron levels, or liver enzymes varied at this dose versus placebo. So as far as we know today, this dosage will generate no negative effects. Of course, if you get any feeling of nausea or an upset stomach, which are the most common side effects reported, or notice anything else negative over time, you should scale back your dose and observe the results. You may need to ease into this dose over time, ramping back as necessary until your body accomodates.

Also keep in mind that we know there is wide variation in individuals and by sex in the dosage necessary to reach an effective plasma concentation, and there is still real uncertainty as to what is an efffective average plasma concentration for neuroprotective effects. This dosage is just my best current guess as to an effective dosage, based on my survey of the literature cited on this page. Your physician may have a different opinion, so ask her.

If you want to be sure you're hitting this concentration for yourself, you could ask your physician to test your fasting blood levels after three weeks, to see if you are around 50 nmol/L. I am presently looking for a private lab where you could get your blood tested, if your physician is not able to do so, or it isn't covered by insurance.

Here's the exciting part: If you complain about memory issues, occasional or persistent mental fog, inflammation-related aches and pains, rheumatoid arthritis, or inflammatory bowel issues, I predict you'll find these symptoms disappear, or are greatly reduced, after three weeks on the above dose. These results are commonly reported by users of native (standard) curcumin supplements in online reviews, but I bet you will experience more dramatic and consistent examples of these effects with micellar curcumin, at the dosage I've recommended above. But don't take my word for it. Try it for yourself and see.

Curcumin for Neuroprotection: A Brief Literature Review

For those who want the details, below are some highlights from the literature on both standard and micellar curcumin's neuroprotective benefits.

Since 2001, curcumin studies in both mice and humans have shown neuroprotection via a range of mechanisms. Most important may be the way curcumin quenches general brain inflammation, but curcumin also has been shown to bind to and reduce amyloid plaque accumulation, to have general antioxidant effects, and to protect brain mitochondria (energy suppliers) from aging and dying.

Here are a few of the many studies in this regard:
https://www.ncbi.nlm.nih.gov/pubmed/11755008 (curcumin reverses cognitive deficits and neuropathology in a rat model, 2001)
https://www.ncbi.nlm.nih.gov/pubmed/15590663 (curcumin reduces amyloid accumulation in vivo, 2005)
https://www.ncbi.nlm.nih.gov/pubmed/20413894 (curcumin is a PPAR gamma agonist and inhibits inflammation in Abeta treated astrocytes in a mouse model, 2010)
https://www.ncbi.nlm.nih.gov/pubmed/28004737 (curcumin has a molecular interaction with amyloid in manufactured lipid bilayer, 2016)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990744 (curcumin attenuates beta amyloid induced neuroinflammation via activation of PPAR gamma function in rat model, 2016)

We now know that even ordinary curcumin can get across the blood brain barrier (tightly connected epithelial cells and astrocytes surrounding the arteries and veins that go through brains, which works to keep out toxins) into the brain. We also know that surrounding curcumin with lipid micelles greatly increases curcumin levels in the brain.

For details, see this 2013 paper by Jan Frank's group at the University of Hohenheim in Germany, which demonstrates that even ordinary curcumin gets past the blood brain barrier into mice brains, where it prevents mitochondrial dysfunction in a senescence-accelerated mouse model. In 2015 Neurochem Int. study, Frank's group showed that both orally delivered ordinary and micellar curcumin offered some protection for mice brain mitochondia from oxidative stress and swelling, but micellar curcumin was much more effective.

In an impressive 2014 study (full text here, graphic below), Franks group showed the oral bioavailability of curcumin in humans is significantly increased when you either micronize it (make it into smaller particles ) or put it into micelles (small lipid spheres that are fully water soluble). Micronizing made circumin 14X more bioavailable in women, but only 5X more in men. But micellizing curcumin made it 277X more bioavailable in women and 114X more in men. No one knows yet why the sex differences in bioavailablity are so big. The average increase in total area under the curve (AUC) bioavailability for humans was an 185-fold increase.

This is a major therapeutic advance. Everyone who cares about a healthy aging brain should know about this, and be taking a more bioavailable curcumin now, as long as you don't have any exotic medical conditions. See your doctor first if you do, and let her know you're taking this supplement as well.

Here's a key slide from Frank's deck, showing mean plasma curcumin following a single dose of 500 mg curcuminoids. Even a quick glance makes clear that Micronized (squares) are more than 10X more available in the blood than standard (native) curcumin. Micellized (triangles) are more than 10X higher plasma concentrations than micronized. Notice the low bioavailability of standard curcumin below (dotted curves).

To me, this graphic demonstrates that almost all the standard (non-micellar) curcumin supplements being sold today, and all the ongoing human clinical studies with such curcumin, are almost worthless by comparison.

 

In Germany, has been making micellar curcumin since at least 2014, under the brand name NovaSol Curcumin. Jan Frank's group used AQUANOVA curcumin in the curcumin studies cited above, and they are involved in a large number of ongoing research projects evaluating micellized curcumin for oncology, rheumatoid arthritis, Alzheimers, bowel disease, and other inflammation-mediated diseases. Here are some of the highlights from those additional studies:

In a 2016 Plant Foods Hum Nutr study, Frank's group showed that the enhanced bioavailability of micellar curcumin is likely due to increased asbsorption into and transport through small intestinal epithelial cells. This study was done at a dose of 98 mg total curcuminoids, in micellar form.

In a 2016 Nutrition and Cancer study, they showed that a daily dose of 210 mg total curcuminoids (micellar form) in humans was able to enter glioblastoma cells, which acheived a mean intertumoral concentration of 56 pg/mg (range 9-151) of cancer tissue. They speculate that this concentration is significant enough to have cellular effects, including altering tumor energy metabolism.

In a 2016 Mol Nutr. Food Res study, Frank's group showed that at a dose of 294 mg micellar curcuminoids per day, for as little as three weeks, resulted in fasting curcuminoid plasma concentrations of 49 nmol/ in 42 (double-blind, crossover) subjects. Apparently it took three weeks to reach this biologically significant concentration. They also showed that blood lipids, inflammation markers, glucose, iron, and liver enzymes did not vary versus placebo in these subjects.

In a 2015 Oncotarget study using mice with cancer xenografts, at a concentration of 60 mg/KG of body weight (4800 mg/day for a 180 lb human, though such conversions are always suspect) they showed blood concentrations of 2,000 - 9,000 nmol/L in the first hour after administration, and a range of clinically significant antitumor effects.

Here's an excellent 25 min YouTube interview with Dr. Frank about micellized curcumin. It also addresses the safety questions one would have when bioavailability increases as dramatically as it does with this form of curcumin.

Longvida Curcumin: An Alternative Supplement Choice

There is another form of curcumin sold in the US, Longvida curcumin that is significantly better than native curcumin, but apparently one that is also a lot less bioavailable than micellar curcumin. You should know about the difference.

This form is called solid lipid nanoparticle (SLNP) circumin. It was developed circa 2006 by Drs. Sally Frautschy and Greg Cole at UCLA. These excellent researchers are described in my 2005 article on curcumin, above.

A US patent for SNLP curcumin was filed by them in 2007 and granted in Nov 2015. This was then apparently licensed to Verdure Sciences, a US company that marketing this curcumin under the Longvida curcumin brand name. Circa 2014, Verdure Sciences put up their Longvida website, touting its benefits to researchers and consumers. Longvida SNLP curcumin is available at Amazon from companies like ProHealth, Nutrivene, Myodyne, and Now Foods.

In 2010, a group of US academics published a paper, Acute human bioavailability of a solid lipid curcumin particle forumulation [Longvida], by Gota et al., J. Ag Food Chem 2010 58(4): 2095-2099, which showed far superior bioavailability for Longvida's SLNP curcumin over standard curcumin, and its tolerability at high plasma levels, in late-stage osteosarcoma patients. On their Longvida website, quoting this 2010 study, Verdure claims their formulation is "at least 67-285 Times More Bioavailable than Standard 95% Curcumin Depending upon Cmax, AUC, and AUC Normalized Calculations." Verdure also posted a good 5 min Vimeo video on Longvida curcumin in 2015.

This is an important advance, but it is apparently also a lot less bioavailable than NovaSOL curcumin. According to Dr. Frank's interpretation of their results, relayed to me by email, "patients ingesting 2 g Longvida had Cmax of 88 nmol/L and for 650 mg Longvida they report Cmax of 60 nmol/L. But my group found Cmax of 3,228 nmol/L with 410 mg [of NovaSOL] micellar curcumin in healthy subjects."

Clearly the NovaSOL curcumin has a much higher Cmax, and is much more bioavailable per milligram than SNLP curcumin.

My read of the Alzheimers mice and rat literature (and keep in mind that I am not an expert) indicates that a blood Cmax of between 300 and 1,000 nmol/L is sufficient to start reducing brain amyloid plaques.

As Longvida's Cmax appears to nonlinearly saturate with dose (see bold statement above), it is not clear to me that a Cmax of 300 nmol/L can be reached even with a high daily dose of, say, 8 g/day. That's the largest dose I know of where at least some studies indicate long term (at least for three months) tolerability and safety.

Both micellar and SNLP curcumin could be used to reach the average fasting curcuminoid plasma concentration of 49 nmol/L that may be an ideal level for general neural antiinflammatory protection. But you'd have to take a lot more Longvida curcumin every day to get to a plaque-arresting or plaque-reducing dose.

I have inquired of Dr. Frautschy and Dr. Cole of the specific Longvida dosage that would be necessary to an average blood concentration of 300 - 1,000 nmol/L, and I will let you know of their response.

The Apo e4 Gene and Your Alzheimer's Risk: What You Should Know

According to this study, the frequency of Alzheimers Disease (AD) acquisition, and mean age at clinical onset, are 91% and 68 years of age in e4 homozygotes, 47% and 76 years of age in e4 heterozygotes, and 20% and 84 years in e4 noncarriers. Clearly, both e4 heterozygotes and homozygotes should be greatly motivated to reduce their AD risk by any means easily available.

Apo e4/e4 homozygotes are about 1.5% of the global population, but up to 16% of regional or tribal populations.

Apo e4 heterogyzotes are 13.7% of the global population, and 7-40% of various regional or tribal populations.

Though it will likely take years before this is fully proven to the global medical community, the literature shows curcumin clearly has a very significant general neuroprotective effect, primarily via neural and general inflammation reduction. Curcumin is also a vastly more tolerable and safe daily medicine than, for example, ibuprofen, which itself has long been shown to reduce Alzheimer's risk and age of onset, in folks who take it long-term for joint inflammation or other issues.

Thus, in my view, there are roughly about a billion people today (13.7% x 7.4 Billion, or 1.036 Billion people) who could benefit from both e4 genetic testing and better treatment information.

I recommend getting tested for apoE4. Knowledge is power! If you have at least one copy of this gene, I also recommend browsing the discussion forums at apoE4.info regularly, where you'll find a lot of good lifestyle advice.

Apo e4 is often called the "ancestral allele", as the global frequency of the e4 allele, versus the evolutionarily newer e2 and e3 alleles, is the highest in populations like Pygmies (0.407), Khoi-San (0.370), New Guineans (0.368), Lapps (0.310), Bantus (0.29), Karelians (0.27), aborigines (Orang asli) of Malaysia (0.240) and Australia (0.260), and some native Americans (0.280). Homozygosity thus ranges greatly among regions. China is 5% e4/e4 for example, giving a total of 68 million homozygotes in that country alone.

In all of these populations, an economy of energetic foraging still exists or still existed until recently, as their food supply is or recently was scarce and sporadically available. Apparently, both CAD and AD are much less prevalent, and in some cases even absent, in some of these ancestral populations, though the data I've seen so far on this claim are old, and I would like to see current replication of it.

What is it about e4 carriers that makes us so vulnerable to AD? According to Dr. Gregory Cole's group at UCLA, the e4 allele seems to accelerate the frequency and age of onset of AD by increasing inflammatory responses to, and impeding recovery from, general inflammatory stimuli, like lipopolysaccharide from bacterial and viral infections, and from the inflammation stimulated by the accumulation of beta amyloid (misfolded proteins) that accumulate in all aging brains. The Cole lab's 2016 Neuroreport paper argues this process is mediated by hyperstimulation of TLR-4 (toll-like receptor) signaling, which activates NFkB, a transcription factor that regulates our innate and adaptive immune system response to damage and stress. They finger a particular microRNA, miRNA-146a, that normally acts to shut down inflammatory response. This miRNA appears to be inhibited in e4 carriers, resulting in chronic inflammation in older e4 brains.

So besides taking the inflammation quencher micellar curcumin at the dose recommended above, what else can e4 carriers do to greatly reduce their Alzheimer's risk?

I think the most important to improving your general health is to cycle every day between good stress (eustress) and good recoveries from that stress, and in the process to avoid any stress that is either too strong, or unremitting (chronic). Understanding the difference between good stress and bad stress is an evolving science today.

For details, see Health- Five Cyclic Habits for Vitality and Longevity, an excerpt from my book, The Foresight Guide, 2016.

In brief, here's a recap of those habits (the last is split into 5A and 5B, but it's really just one cycle). All of these will reduce general brain and body inflammation:

1. Get good sleep every day. Sleep prevents unnecesary brain stress and inflammation.

2. Exercise your brain. Be sure to read, learn, and study something challenging every day. Try to get a headache (good stress) from learning. Also take time every day to relax, rest, and recover from learning as well.

3. Get regular social time. Lots of studies show how beneficial that is to your brain and longevity. Contrast that with regular solitary time, which helps you focus.

4. Exercise your body. There is mounting evidence that extended sweating (cardiovascular) exercise nearly every day, ideally for 40-60 total minutes a day (either in one session/day or in two or three shorter sessions of at least 20 mins each), is especially brain protective for e4 hetero and homozygotes. Get a good daily recovery from your exercise, and consider taking one or two days off each week for a deeper recovery.

5. Eat a good, non-inflammation causing diet.

Besides taking micellar curcumin daily, if we care about brain health, the best current evidence argues we want a high good-fat, moderate protein, low carbohydrate, mostly plant-based diet, as that is how we can best minimize brain and body inflammation and bad stress. Dr. Michael Greger's How Not to Die, 2015. is a great first source for what to eat.

Regarding good fats, we know that PUFAs, polyunsaturated fatty acids, and to a lesser extent MUFAs, monounsaturated fatty acids, are the most beneficial for reducing inflammation, which is especially important for folks with the Apo e4 allele. Stay away from both inflammation-causing saturated fats and trans fats, which are made by too much processing of food.

So look at the labels on what you eat, and try not to eat foods where the Polyunsaturated Fat + Monounsatured Fat over Saturated Fat ratio, gram for gram, is less than 3:1. Stay away from foods with trans fats entirely. Almonds are particularly great (9:1), so are Walnuts (9:1), Peanuts (6:1), and most other nuts. Olive oil (6:1) and most other plant oils are great. Dump crappy hydrogenated oils like Palm, Soy, and Coconut Oil/Butter (1:12, terrible!). Butter is not so good at 2:1, and it typically contains trans fats as well, so try to avoid it. A high PUFA+MUFA margarine like Earth Balance (3.6:1) is better, even though it is more processed. Good-fat veggies like Avocados (5.4:1) are great, and so on.

The Paleolithic diet is a good step away from the traditional American diet, as it dumps high carbs and seeks to recreate ancestral food supply conditions. But the problem with Paleo is that most practitioners typically recommend eating a lot more meat each week than humans would have had access to for most of the last two million years. You don't need to eat meat more than once or twice a week, in small portions, to get all its good vitamins and nutrients.

For your meat, I also recommend being mainly Piscetarian, so you can stay with good fatty. high PUFA fish like salmon, tuna, and mackerel. Sure, steak and hamburgers taste great. But there's also good evidence that red meat is bad for you, and you're killing a global-warming-causing, big-brained animal to get that meat, which should also give you some environmental and ethical issues. So switch to fish, which is now available everywher, and eat it in moderation.

6. Fast, which means get a little hungry, every day. Short periods of fasting are a very good body stress, with all kinds of physiological, brain, and gene-repair benefits. See Intermittent Fasting (IF) for Alzheimers Prevention below for my best recommendations on IF.

Fasting has been shown to reduce or stop amyloid accumulation in various studies. I have been doing intermittent fasting for six years now, recreating "ancestral food supply conditions", and can attest that for me it has had a very beneficial effect.

Retinal Amyloid Imaging for Alzheimers Prevention

Excitingly, there has also been a 2014 Cedars-Sinai study where the use of Longvida's SNLP curcumin was shown binding to human retinal amyloid plaques, as detected by laser retinal imaging before and after ingestion. This proves that SNLP curcumin crosses the blood brain barrier in humans. The BBB protects retinal neurons in the same way it protects all our other neurons.

This retinal amyloid imaging system is now being developed by Neurovision Imaging in Sacramento, and will be aimed at early Alzheimer's detection and disease progression. Neurovision started in 2010, and the WSJ reported on them in 2014. In Feb 2016 they expanded a collaboration with Janssen pharmacueticals, a division of Johnson & Johnson, to do the extensive trials they'll need to get this a recommended medical treatment, and in June of 2016 they got $10M in VC funding, so they look like they are on their way.

I expect retinal amyloid imaging will turn out to be a great way for people to find out they have an amyloid problem in early adulthood, to monitor its progression, to monitor the effectiveness of therapeutics like SNLP and micellar curcumin. Let's hope Neurovision keeps working hard and working smart on getting their test to opthalmogists and ideally, also to optometrists around the world.

Having an positive retinal amyloid test result, like having a positive apoE4 test, may also motivate many folks to do even more effective things than curcumin supplementation to prevent further accumulation of plaques in their retina and brain.

What evidence-based therapies are likely to be even more brain-protective than taking micellar or SNLP curcumin, you ask? Read on, friend.

Intermittent Fasting for Neuroprotection (and Alzheimer's Prevention)

For more than a decade now, various animal studies have shown that intermittent fasting slows or stops many molecular mechanisms in brain aging and degeneration, including amyloid plaque and tau tangle accumulation.

Mark Mattson is one of the leading scholars in this area. This 2006 study by Mattson was big news a decade ago, and there have been many more studies since. Here's a 2016 podcast by Mark, and links all his research since, that you may really enjoy.

I've been doing intermittent fasting several times a week since 2010. Like Mattson himself at the time, I initially fasted for an average of 19 hours each day on Mondays to Fridays, restricting my eating to a five hour window (usually 5-10pm) on those five fasting days, and ate throughout the day on weekends. But as intermittent fasting got progressively easier over time, and as I learned to do things like exercise while fasting to keep my brain sharp the entire time, I moved my fasting average up to five to seven days a week, depending in how strong I felt on the weekends. Research shows that the more you do it the better off you are, so it's just a matter of learning how to do it easily and well.

It was a bit tough the first six months, including staying on only coffee, tea, carbonated water with ice, or sugarless gum when others were eating around the table, but it became much easier with time. I also quickly learned that I was often the most attentive person at the table. While others were distracted by eating, the conversation and time with them was my "food". I also knew I'd be eating just a bit later in the day, when it was the best time for me. I learned to be patient, too. Being hungry for two hours, or three, is no big deal. Time moves slower, and the older we get, the more of a blessing that actually is. We become present. A fifteen minute nap in the sun, an aggressive stretch, a brief meditation, or a mile run out the front door of your workplace will get you right back into brain sharpness, believe me.

If you want the full scoop on intermittent fasting, Mike VanDerschelden's The Scientific Approach to Intermittent Fasting, 2016, is the best book available to date, in my view. This book summarizes the great and growing body of evidence for intermittent fasting, and it will motivate you to make the lifestyle change.

There's also an "easy" version of intermittent fasting that I would recommend starting with if you are more than thirty pounds overweight, or if you would like an easy first step into the IF lifestyle. It's called the Mini-Fast Diet (basically, skipping breakfast and taking a walk when you feel hungry), and is well covered in Julian Whitaker's The Mini-Fast Diet, 2013. Whitaker's model will get you down to just 15-25 pounds overweight, but it won't help you shed those last pounds, and you won't get all the major brain and body benefits from fasting until you move up to 14 to 19 hours in your daily fast. That's just how the physiology and genetics work.

I'm not going to detail all the benefits of intermittent fasting here. If you have any desire to either lose weight or improve your health, just listen to the podcast above, or read VanDerschelden's book, then try it for yourself for at least a month. You will be amazed at how much better your brain and body feel. You'll also prevent all kinds of future diseases (cancer, neurodegeneration, heart disease) that you otherwise might have been subject to. So check it out. Seriously.

Even more than a Piscetarian version of Paleolithic diet, which I also recommend, I consider intermittent fasting the single smartest health decision I've made in my life so far. There's a cool new area of Paleolithic diet research, called Autoimune Paleo, that looks promising as well. Using blood tests to gauge the inflammatory response from the various foods we eat, and cutting way back on the worst ones (but still eating them in small doses, to retrain our immune/allergic responses) seems to me to be one of the most important frontiers of better diet. As that research matures, I'll add more about it here.

Thanks for sharing this information with others, and please let me know if I am mistaken in any of these claims, or you have anything you'd like to share with others on this page.

Feedback? Reach me at johnsmart{at}accelerating{dot}org.