June 15, 2010
Jacob Schor, ND, FABNO
Denver Naturopathic Clinic
A new paper by Sally Frautschy and Greg Cole on Alzheimer’s disease was published early this June. We’ve been following the work of these two doctors for almost a decade. Together, since 1991, they have co-authored 47 papers on this disease.
In a 2001 paper, they were the first to put forth the idea that curcumin might be useful in preventing or treating Alzheimer’s disease (AD). During the 1990s about 20 studies had been published saying that people who took non steroidal anti-inflammatory drugs (NSAIDs) long term for any reason lowered their risk of developing AD. Of course, the problem with these medications is that you can’t tell people to take them long term because of the potential side effects. Looking for a safer ‘drug’, Cole and Frautschy experimented with curcumin. Curcumin is derived from the spice turmeric and is well known for its anti-inflammatory properties and is safe to take even in large amounts. Unlike NSAIDs, curcumin also acts as an antioxidant; it stops damage caused by free radicals. Reactive oxygen damage is considered a main contributor to Alzheimer's disease.
In their 2001 paper, published in the Journal of Neuroscience, Cole and Frautschy reported on several early experiments. They tested curcumin on mice forced to develop amyloid plaques in their brains like those seen in Alzheimer's disease. The mice eating food spiced with turmeric developed about half the amount of brain plaque as mice not eating turmeric. 
Though they initially tested curcumin hoping to find a safe alternative to ibuprofen, Frautschy reported in the November 2001 issue of Neurobiology and Aging, that curcumin was actually more effective at protecting experimental mice than ibuprofen. 
The leading theory in those days was that AD is caused by small bits of protein called amyloid that clump together in the brain into toxic lumps called plaques. These plaques kill brain cells because they trigger inflammation that damages the cells. The plaques also produce free radicals that cause oxidative damage to nerve cells. Ibuprofen apparently slows this process by slowing the inflammatory reactions. Curcumin acts both to decrease inflammation but also as an antioxidant.
If curcumin protects against Alzheimer’s disease one would wonder if in parts of the world where people eat a lot of turmeric if there would be a lower incidence of AD. Data that answered this question were published in 2001; people in India have the lowest incidence of AD in the world.
Chandra et al reported in a 2001 issue of Neurology that only 0.47% of older people in Ballabgarh, India, showed signs of Alzheimer’s disease compared to farmers living in Pennsylvania where 1.75% showed signs of Alzheimer’s. Thus the turmeric eaters had about one fourth the risk of the Americans and the lowest incidence of Alzheimer’s seen anywhere in the world. 
A 2006 study on people in China revealed that the more curry people ate, the lower their risk for AD. The study was conducted in Singapore, a place that customarily uses lots of turmeric in their curry. 
A February 2005 paper by Yang et al, says that curcumin does more than act as an anti-inflammatory and antioxidant in the brain. It doesn’t just prevent the amyloid clumps from causing damage, it actually prevents them from forming into plaques in the first place. 
In 2004, Ono et al reported that curcumin triggers amyloid plaques to break apart.  Structurally, curcumin resembles the chemicals used as contrast material in CT brain scans to make plaques more visible. Because of this similarity, curcumin apparently binds to amyloid. This binding ability may explain why curcumin interferes with plaque formation and degrades existing plaques.
In April 2005, John Ringman along with Cole, Frautschy and few other colleagues from UCLA began a clinical trial using curcumin in Alzheimer’s patients. Ringman’s study compared two doses of curcumin, either 2,000 or 4,000 mg per day in a double-blinded placebo controlled trial with 33 patients. 
That was five years ago.
Seeing this new paper by Cole and Frautschy made me think that at long last the results had been published. I am mistaken; this new paper is a review of current knowledge of the mechanisms that underlie Alzheimer’s disease and a suggestion for a new protocol. There is no mention of the Ringman study except for an oblique phrase, “Monotherapy targeting early single steps in this complicated cascade may explain disappointments …”
When contacted, Dr. Ringman readily admits that, “Our initial study did not reveal any evidence of benefit in AD, possibly because inadequate amounts of curcumin were absorbed into the bloodstream.” 
Cole and Frautschy, without acknowledging any failure in their initial study, do explain why there was ‘no evidence of benefit.’ The first reason is that AD has a long prodromal period in which damage builds up before any changes in mental symptoms are apparent; “…much of the pathology occurs preceding rather than in parallel with cognitive decline.” Thus even if curcumin were to reverse amyloid deposition, the disease progression may be too far advanced to slow down. Clearly this disease is far more complicated than we once thought.
The second reason curcumin has not been a miracle cure is that it is poorly absorbed in humans. In a clinical trial in which patients received either 2 or 4 gram per day doses, no curcumin was detected in their blood plasma. 
If the curcumin doesn’t get into the blood, it certainly doesn’t get into the brain and so it is no surprise that it was worthless in Ringman’s study
It is no coincidence that Cole and Frautschy, the UCLA Alzheimer’s researchers, in the last few years have developed and patented a highly absorbable chemical form of curcumin. 
Although this patented UCLA curcumin is not yet commercially available, other products claiming enhanced absorption have made it to the shelves and are now sold as ‘liposomal’ curcumin. These products do appear far better absorbed than earlier products and far superior at reducing physical symptoms such as pain and inflammation than earlier products. Whether they work as well as what we refer to as the, UCLA Curcumin’ is not clear.
Their new approach to treating Alzheimer’s is also to use more than one supplement. In their current review, Cole and Frautschy focus on a combination of curcumin and the fish oil derivative docosahexanoic acid (DHA), hoping that the two together might have the desired effects against Alzheimer’s disease.
Using DHA is not a new idea. Cole and Frautschy have written ten papers on DHA and Alzheimer’s since their first one in 2004.  Their most recent paper was published in April 2010.  Thus their suggestion to use both fish oil and curcumin extracts together to treat Alzheimer’s should not come as a surprise. There is an additional supplement that Cole and Frautschy mention only briefly but that is still worth considering.
It is alpha-lipoic acid. Lynn Shinto, a naturopathic physician conducting research at Oregon Health Sciences University has a 2008 abstract in Neurology suggesting that alpha lipoic acid taken in conjunction with fish oil might be, “…effective in preventing cognitive decline.” Dr. Shinto is about to begin a clinical trial of fish oil and alpha-lipoic acid with Alzheimer’s disease patients that will be funded by the National Institutes of Health.
The practice of naturopathic medicine is certainly not static. Our protocols change with the advancement of science. As a result of these studies we have expanded our suggested protocol for patients who are either at high risk for Alzheimer’s disease or who already have signs of cognitive decline. In addition to other supplements and dietary changes, as a result of following this research, we now suggest a combination of liposomal curcumin, fish oil and alpha-lipoic acid as daily supplements for these people.
An online version of this article is posted at: http://denvernaturopathic.com/Alzheimers2010update.htm
1. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci. 2001 Nov 1;21(21):8370-7.
2. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging. 2001 Nov-Dec;22(6):993-1005.
3. Chandra V, Pandav R, Dodge HH, Johnston JM, Belle SH, DeKosky ST, Ganguli M. Incidence of Alzheimer's disease in a rural community in India: the Indo-US study.Neurology. 2001 Sep 25;57(6):985-9.
4. Ng TP, Chiam PC, Lee T, Chua HC, Lim L, Kua EH. Am J Epidemiol. 2006 Nov 1;164(9):898-906. 26. Curry consumption and cognitive function in the elderly.
5. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005 Feb 18;280(7):5892-901.
6. Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. J Neurosci Res. 2004 Mar 15;75(6):742-50.
7. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL. A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res. 2005Apr;2(2):131-6.
8. Private communication: John Ringman, June 17, 2010
9. Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008 Feb;28(1):110-3.
10. 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 disease. J Pharmacol Exp Ther. 2008 Jul;326(1):196-208. Epub 2008 Apr 16.
11. Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N Jr, Ashe KH, Frautschy SA, Cole GM. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004 Sep 2;43(5):633-45.
12. Cole GM, Frautschy SA. DHA may prevent age-related dementia. J Nutr. 2010 Apr;140(4):869-74. Epub 2010 Feb 24.