Turmeric and Alzheimer ’s disease

Jacob Schor, ND

October 2, 2007

We usually think of curcumin in terms of cancer treatment yet it may play an equally valuable role in the prevention and treatment of Alzheimer’s disease.  A fascinating story of theory, research and clinical trials has quietly unfolded over the last ten years.  Turmeric and curcumin are about to hit the public’s awareness in a big way.

Those of us in practice in the early 1990s and who can still remember anything that far back will recall there was a lot of talk about ibuprofen and other NSAIDs protecting against Alzheimer’s disease (AD). There were about 20 studies showing that people who took NSAIDs (non-steroidal anti-inflammatory drugs) long term for whatever their reason lowered their risk of developing AD. Of course, the problem with ibuprofen is that you can’t suggest people to take it long term because of the potential side effects, especially liver and kidney damage.  Looking for a safer and better ‘drug’, Greg Cole and Sally Frautschy at UCLA tried curcumin. The spice turmeric, from which curcumin is derived, is well known for its anti-inflammatory properties and as we know, is safe to take even in huge amounts. Unlike NSAIDs, curcumin also acts as an antioxidant; it stops damage caused by free radicals. Reactive oxygen damage is a main contributor to Alzheimer's disease.

In 2001, writing in the Journal of Neuroscience, these UCLA scientists reported on their 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 drawn to experiment with curcumin thinking it was safer than ibuprofen, Frautschy et al reported in the November 2001 issue of Neurobiology and Aging, that it was also more effective at protecting experimental mice than ibuprofen.

The leading theory these days is 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 as both an anti-inflammatory but also as a very potent antioxidant.  A ‘dual action’ as future advertisements will probably say.

If curcumin is protective against Alzheimer’s disease one would think that in parts of the world where people eat a lot of turmeric there would be a lower incidence of AD. When Cole and Frautschy started their research, no one had published data on AD rates in India. The first data was 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 of people 65 and older in Ballabgarh, India, only 4.7 per 1,000 show signs of Alzheimer’s disease.  They compared this incidence to that of people of the same age living in Monongahela Valley, Pennsylvania. In the Pennsylvania group, 17.5 people per 1,000 showed signs of Alzheimer’s.  That puts the Indian turmeric eaters at about one fourth the risk of the Americans. The Indians in this study had the lowest incidence of Alzheimer’s seen anywhere in the world.

Eating curry also seems to be protective.  In 2003, Tze-Pin Ng of the National University of Singapore tested 1,010 Singaporeans between 60 and 93 years old. He also surveyed these people about their eating habits.  Those who ate curry "occasionally" or "often or very often" scored better on cognitive performance tests than did people who ate curry only rarely. Curry powder is a blend of spices; the curry powder used in Singapore contains a lot of turmeric.

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.   Wait, there is more;

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 scant 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.

 There’s still more to this story.

Curcumin lowers cholesterol.  In 1992, researchers in Amalanagar, India, gave people 500 milligrams of curcumin a day for just one week and measured a 29% increase in HDL cholesterol, and 11% drop in total cholesterol.  A 2007 paper explains that this effect is because curcumin changes the expression of certain genes that make cholesterol.   Certainly this is relevant to cardiovascular disease,  but this cholesterol lowering effect is also important with Alzheimer’s.

Studies during the 1990s linked high cholesterol with increased risk of Alzheimer's disease. Cholesterol accumulates within the brain plaques and may aid amyloid proteins to bind together. This explains the current push by the pharmaceutical companies to convince us that Alzheimer’s is just a symptom of statin deficiency.   The research, though it links cholesterol with Alzheimer’s, has not shown that statins provide protection.

The immune system also plays a role in AD.  Macrophages normally cruise through the brain and swallow up the amyloid plaques as they form. In people who develop Alzheimer's, these macrophages are not doing their jobs properly.  Milan Fiala from the Los Angeles VA hospital took macrophages from Alzheimer's patients and mixed them with amyloid plaques.  Published just this past July in the Proceedings of the National Academy of Sciences, Fiala’s team report that the macrophages were total slackers, exhibiting anthropomorphic leukocytic shrugs of, “whatever.”  They ignored the plaques and showed no tendency to consume them.  Fiala attributes this lack of response as due to decreased expression of the gene MGAT3.

Exposing the macrophages to curcumin returned MGAT3 to its normal state and restored the macrophage’s interest in destroying plaque, at least in about 50% of the cells.   

Turmeric’s ability to fight cancer has overshadowed its use in treating Alzheimer’s disease.  As of October 1 2007, PubMed lists 765 papers related to turmeric, of which 218 are to do with cancer but only 24 to do with Alzheimer’s disease.

All of these studies added up to enough evidence in support of using curcumin, that in April 2005, John Ringman with Cole, Frautschy and few other associates at UCLA announced the start of  a clinical trial using curcumin in Alzheimer’s patients.   Ringman is comparing two doses, 2000 and 4000 mg per day in a double blinded placebo controlled trial with 33 patients.  His data should tell us if curcumin does for people what it does for rodents.  Their results are expected early next year.

 

J Neurosci. 2001 Nov 1;21(21):8370-7.Click here to read

The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse.

Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM.

Departments of Medicine and Neurology, University of California, Los Angeles, Los Angeles, California 90095, USA.

Inflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1beta, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble beta-amyloid (Abeta), soluble Abeta, and plaque burden were significantly decreased by 43-50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease.

PMID: 11606625 [PubMed - indexed for MEDLINE]

Neurobiol Aging. 2001 Nov-Dec;22(6):993-1005.

Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology.

Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM.

VAGLAHS-Sepulveda GRECC, Departments of Medicine and Neurology, UCLA, 16111 Plummer Street, North Hills, CA, USA. frautsch@ucla.edu

Both oxidative damage and inflammation have been implicated in age-related neurodegenerative diseases including Alzheimer's Disease (AD). The yellow curry spice, curcumin, has both antioxidant and anti-inflammatory activities which confer significant protection against neurotoxic and genotoxic agents. We used 22 month Sprague-Dawley (SD) rats to compare the effects of the conventional NSAID, ibuprofen, and curcumin for their ability to protect against amyloid beta-protein (Abeta)-induced damage. Lipoprotein carrier-mediated, intracerebroventricular infusion of Abeta peptides induced oxidative damage, synaptophysin loss, a microglial response and widespread Abeta deposits. Dietary curcumin (2000 ppm), but not ibuprofen, suppressed oxidative damage (isoprostane levels) and synaptophysin loss. Both ibuprofen and curcumin reduced microgliosis in cortical layers, but curcumin increased microglial labeling within and adjacent to Abeta-ir deposits. In a second group of middle-aged female SD rats, 500 ppm dietary curcumin prevented Abeta-infusion induced spatial memory deficits in the Morris Water Maze and post-synaptic density (PSD)-95 loss and reduced Abeta deposits. Because of its low side-effect profile and long history of safe use, curcumin may find clinical application for AD prevention.

Neurology. 2001 Sep 25;57(6):985-9.

Incidence of Alzheimer's disease in a rural community in India: the Indo-US study.

Chandra V, Pandav R, Dodge HH, Johnston JM, Belle SH, DeKosky ST, Ganguli M.

Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, PA, USA.

OBJECTIVE: To determine overall and age-specific incidence rates of AD in a rural, population-based cohort in Ballabgarh, India, and to compare them with those of a reference US population in the Monongahela Valley of Pennsylvania. METHODS: A 2-year, prospective, epidemiologic study of subjects aged > or =55 years utilizing repeated cognitive and functional ability screening, followed by standardized clinical evaluation using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for the diagnosis, and the Clinical Dementia Rating scale for the staging, of dementia and AD. RESULTS: Incidence rates per 1000 person-years for AD with CDR > or =0.5 were 3.24 (95% CI: 1.48-6.14) for those aged > or =65 years and 1.74 (95% CI: 0.84-3.20) for those aged > or =55 years. Standardized against the age distribution of the 1990 US Census, the overall incidence rate in those aged > or =65 years was 4.7 per 1000 person-years, substantially lower than the corresponding rate of 17.5 per 1000 person-years in the Monongahela Valley. CONCLUSION: These are the first AD incidence rates to be reported from the Indian subcontinent, and they appear to be among the lowest ever reported. However, the relatively short duration of follow-up, cultural factors, and other potential confounders suggest caution in interpreting this finding.

PMID: 11571321 [PubMed - indexed for MEDLINE]

Am J Epidemiol. 2006 Nov 1;164(9):898-906. 26.

Curry consumption and cognitive function in the elderly.

Ng TP, Chiam PC, Lee T, Chua HC, Lim L, Kua EH.

Department of Psychological Medicine, National University of Singapore, Republic of Singapore. pcmngtp@nus.edu.sg

Curcumin, from the curry spice turmeric, has been shown to possess potent antioxidant and antiinflammatory properties and to reduce beta-amyloid and plaque burden in experimental studies, but epidemiologic evidence is lacking. The authors investigated the association between usual curry consumption level and cognitive function in elderly Asians. In a population-based cohort (n = 1,010) of nondemented elderly Asian subjects aged 60-93 years in 2003, the authors compared Mini-Mental State Examination (MMSE) scores for three categories of regular curry consumption, taking into account known sociodemographic, health, and behavioral correlates of MMSE performance. Those who consumed curry "occasionally" and "often or very often" had significantly better MMSE scores than did subjects who "never or rarely" consumed curry. The authors reported tentative evidence of better cognitive performance from curry consumption in nondemented elderly Asians, which should be confirmed in future studies.

PMID: 16870699 [PubMed - indexed for MEDLINE]

J Biol Chem. 2005 Feb 18;280(7):5892-901. Epub 2004 Dec 7.

Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo.

Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM.

Department of Medicine, UCLA, Los Angeles, CA 90095, USA.

Alzheimer's disease (AD) involves amyloid beta (Abeta) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and anti-inflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential Abeta binding, we investigated whether its efficacy in AD models could be explained by effects on Abeta aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC(50) = 0.8 microM) as well as disaggregated fibrillar Abeta40 (IC(50) = 1 microM), indicating favorable stoichiometry for inhibition. Curcumin was a better Abeta40 aggregation inhibitor than ibuprofen and naproxen, and prevented Abeta42 oligomer formation and toxicity between 0.1 and 1.0 microM. Under EM, curcumin decreased dose dependently Abeta fibril formation beginning with 0.125 microM. The effects of curcumin did not depend on Abeta sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.

PMID: 15590663 [PubMed - indexed for MEDLINE]

J Neurosci Res. 2004 Mar 15;75(6):742-50.

Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro.

Ono K, Hasegawa K, Naiki H, Yamada M.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the destabilization of preformed fAbeta in the central nervous system, would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). We reported previously that nordihydroguaiaretic acid (NDGA) and wine-related polyphenols inhibit fAbeta formation from Abeta(1-40) and Abeta(1-42) and destabilize preformed fAbeta(1-40) and fAbeta(1-42) dose-dependently in vitro. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of curcumin (Cur) and rosmarinic acid (RA) on the formation, extension, and destabilization of fAbeta(1-40) and fAbeta(1-42) at pH 7.5 at 37 degrees C in vitro. We next compared the anti-amyloidogenic activities of Cur and RA with NDGA. Cur and RA dose-dependently inhibited fAbeta formation from Abeta(1-40) and Abeta(1-42), as well as their extension. In addition, they dose-dependently destabilized preformed fAbetas. The overall activities of Cur, RA, and NDGA were similar. The effective concentrations (EC(50)) of Cur, RA, and NDGA for the formation, extension, and destabilization of fAbetas were in the order of 0.1-1 microM. Although the mechanism by which Cur and RA inhibit fAbeta formation from Abeta and destabilize preformed fAbeta in vitro remains unclear, they could be a key molecule for the development of therapeutics for AD. Copyright 2004 Wiley-Liss, Inc.

PMID: 14994335 [PubMed - indexed for MEDLINE]

Indian J Physiol Pharmacol. 1992 Oct;36(4):273-5.

Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers.

Soni KB, Kuttan R.

Amala Cancer Research Centre, Amala Nagar, Trichur.

The effect of curcumin administration in reducing the serum levels of cholesterol and lipid peroxides was studied in ten healthy human volunteers, receiving 500 mg of curcumin per day for 7 days. A significant decrease in the level of serum lipid peroxides (33%), increase in HDL Cholesterol (29%), and a decrease in total serum cholesterol (11.63%) were noted. As curcumin reduced serum lipid peroxides and serum cholesterol, the study of curcumin as a chemopreventive substance against arterial diseases is suggested.

PMID: 1291482 [PubMed - indexed for MEDLINE]

J Nutr Biochem. 2007 Feb;18(2):113-9. Epub 2006 May 18.

Curcumin induces changes in expression of genes involved in cholesterol homeostasis.

Peschel D, Koerting R, Nass N.

BMBF Group Molecular Nutrition Halle, Institute of Nutritional Sciences, Martin-Luther University Halle-Wittenberg, D-06108 Halle, Germany.

Curcuminoids, the yellow pigments of curcuma, exhibit anticarcinogenic, antioxidative and hypocholesterolemic activities. To understand the molecular basis for the hypocholesterolemic effects, we examined the effects of curcumin on hepatic gene expression, using the human hepatoma cell line HepG2 as a model system. Curcumin treatment caused an up to sevenfold, concentration-dependent increase in LDL-receptor mRNA, whereas mRNAs of the genes encoding the sterol biosynthetic enzymes HMG CoA reductase and farnesyl diphosphate synthase were only slightly increased at high curcumin concentrations where cell viability was reduced. Expression of the regulatory SREBP genes was moderately increased, whereas mRNAs of the PPARalpha target genes CD36/fatty acid translocase and fatty acid binding protein 1 were down-regulated. LXRalpha expression and accumulation of mRNA of the LXRalpha target gene ABCg1 were increased at low curcumin concentrations. Although curcumin strongly inhibited alkaline phosphatase activity, an activation of a retinoic acid response element reporter employing secreted alkaline phosphatase was observed. These changes in gene expression are consistent with the proposed hypocholesterolemic effect of curcumin.

PMID: 16713233 [PubMed - indexed for MEDLINE

Curr Atheroscler Rep. 2007 Aug;9(2):154-61.

Statins and dementia.

Kuller LH.

University of Pittsburgh, GSPH, 130 North Bellefield Avenue, Room 550, Pittsburgh, PA 15213, USA. kullerl@edc.pitt.edu

The incidence and prevalence of dementia are increasing. Dementia is a major cause of disability. Alzheimer's disease (AD) is the most common type of dementia. There are no good prevention or treatment options. Experimental animal and laboratory studies have suggested that cholesterol metabolism in the brain is important in the causal pathway for dementia, possibly by modifying amyloid metabolism. A few studies have showed a possible relationship between mid-life blood cholesterol levels and risk of dementia, including AD. Case-control studies report that patients with AD were less likely to use lipid-lowering drugs, especially statins. Longitudinal epidemiology studies have not demonstrated a decreased risk of AD among statin users versus nonusers. Two clinical trials of statin therapy to reduce cardiovascular disease have not shown any reduction in risk of cognitive decline or dementia. The results of two secondary prevention trials will be reported shortly. In spite of negative studies, the possibility remains that statin therapy may reduce risk of dementia and AD. Primary prevention trials are difficult and expensive and will likely not be done in the United States.

PMID: 17877925 [PubMed - in process]

Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12849-54. Epub 2007 Jul 24.

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin.

Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, Sayre J, Zhang L, Zaghi J, Dejbakhsh S, Chiang B, Hui J, Mahanian M, Baghaee A, Hong P, Cashman J.

Department of Medicine, Greater Los Angeles Veterans Affairs Medical Center, and School of Medicine, University of California-Los Angeles, CA 90095, USA. fiala@mednet.ucla.edu

We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-beta (Abeta) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Abeta into endosomes and lysosomes, and AD monocytes do not efficiently clear Abeta from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Abeta to endosomes and lysosomes, and monocytes of these subjects clear Abeta in AD brain sections. Upon Abeta stimulation, mononuclear cells of normal subjects up-regulate the transcription of beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of Abeta may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon Abeta stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of Abeta, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.

PMID: 17652175 [PubMed - indexed for MEDLINE]

Curr Alzheimer Res. 2005 Apr;2(2):131-6.  

A potential role of the curry spice curcumin in Alzheimer's disease.

Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL.

University of California, Los Angeles, Department of Neurology, Alzheimer's Disease Research Center, Los Angeles, CA 90095, USA. jringman@mednet.ucla.edu

There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of Alzheimer's disease (AD) indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD. Nonetheless, important information regarding curcumin bioavailability, safety and tolerability, particularly in an elderly population is lacking. We are therefore performing a study of curcumin in patients with AD to gather this information in addition to data on the effect of curcumin on biomarkers of AD pathology.

PMID: 15974909 [PubMed - indexed for MEDLINE]