Curcumin is only a small part of the story …

The wonder nutrient that you rarely hear about 
is the source of the one that you do 

For every complex problem there is an 
answer that is clear, simple, and wrong. 
— H. L. Mencken

The wonder nutrient that you continue to hear about—in the press, in the media, and on the web—for its antitumor, antioxidant, antiarthritic, antiamyloid, anti-ischemic, and anti-inflammatory properties—is curcumin. Yet the truth remains that curcumin is only part of the story, and for certain uses it may not be that valuable. Turmeric (Curcuma longa), the plant native to tropical South Asia from which curcumin is extracted—the powdered rhizome of which gives curry its golden zing—contains many other potent compounds, many of which offer higher and more varied benefits, and some of which may be beneficial for preventing age-related neurodegeneration, including mild cognitive impairment, dementia, and Alzheimer’s disease.

Turmeric contains many 
other potent compounds, some of 
which may be beneficial for 
preventing age-related 
neurodegeneration, including mild 
cognitive impairment, dementia, and 
Alzheimer’s disease.

The Active Compounds of Turmeric

Turmeric is a perennial rhizomatous plant of the ginger family, Zingiberaceae. Its rhizomes are the horizontal stems of the plant that are found underground, sending out roots and shoots from its nodes. Referred to as creeping rootstalks, these parts of the plant are the principal sources of turmeric’s active compounds, which include: four identified curcuminoids [among them curcumin (Cur), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC)], four identified turmerones(among them alpha-turmerone, beta-turmerone, ar-turmerone, and aromatic-turmerone), as well as alpha-santalene, aromatic-curcumene, curlone, and other compounds.

Anti-Cancer Properties

The precise role of turmerones in Alzheimer’s is unclear, though they have established anti-inflammatory and antioxidative activities that have been thought, but not proven, to reduce neurotoxicity. It is intriguing to note that when compared to ascorbic acid, the hydroxyl radical scavenging activities of turmeric were found to be higher.1

The curcuminoids Cur, 
DBMC, and DMC, as well as 
alpha-turmerone, significantly 
inhibited proliferation of cancer cells 
in a dose-dependent manner.

In a recent paper, the curcuminoids Cur, DMC, and BDMC, as well as alpha-turmerone, significantly inhibited proliferation of cancer cells in a dose-dependent manner.2 Alpha-turmerone also induced a breast cell cancer line to undergo apoptosis, while both alpha-turmerone and aromatic-turmerone showed stimulatory effects on peripheral blood mononuclear cell (such as lymphocyte, monocyte, or macrophage) proliferation and cytokine production. In addition, in this study the anti-proliferative effect of alpha-turmerone and immunomodulatory activities of ar-turmerone was shown for the first time. These findings revealed the potential use of turmeric crude extract (containing water-soluble curcuminoids and lipid-soluble turmerones) as a chemopreventive agent.

Alpha-turmerone also induced 
a breast cell cancer line to 
undergo apoptosis.

According to life extension scientists Durk Pearson & Sandy Shaw …

What’s particularly interesting to us is that curcumin (that’s one of the principal antioxidants in turmeric) is protective, but there are other closely related compounds in turmeric that are even more effective. One of these is about twice as effective; one is 3 times, one is about 5 times, and one is about 10 to 15 times as effective. So if people are taking curcumin alone as a preventive for Alzheimer’s, they’ll probably be helping themselves (if they get the dose right), but taking the entire turmeric package will work better, because there are even more powerful antioxidants in there, and they have evolved together to work … together as an integrated system. 

Optimizing Turmeric for Brain Aging

While previous studies have shown anti-amyloid effects for curcumin, few studies have examined “optimized” turmeric extracts enriched in the curcuminoids. In the first such study published two years ago, three standardized turmeric extracts—HSS-838, HSS-848, and HSS-888—were compared for their ability to inhibit amyloid-β (Aβ) accumulation and Aβ fibril (fAβ) formation from Aβ, attractive therapeutic targets for the treatment of Alzheimer’s disease.3

In addition, the four curcuminoids were also examined. The researchers measured the effects of the extracts and curcuminoids on the aggregation (accumulation) of Aβ. All three extracts and the curcuminoids showed dose-dependent inhibition of fAβ aggregation from Aβ in the cell-free assay. However, only HSS-888, Cur, and DMC significantly decreased Aβ secretion (by approximately 20%) in human amyloid precursor protein (APP). Then, interaction matrices were used to examine possible synergistic interactions between HS-888 and the other extracts, and between the individual curcuminoids, on Aβ aggregation. For the curcuminoids, no synergies were found. Instead, simple additive effects were observed for Aβ aggregation inhibition, supporting the notion that the known curcuminoids are not strong inhibitors of this activity.

“If people are taking curcumin alone 
as a preventive for Alzheimer’s, 
they’ll probably be helping themselves 
(if they get the dose right), 
but taking the entire turmeric 
package will work better.”

On the other hand, HSS-888, the extract that fared the best, showed strong inhibition of Aβ aggregation and secretion, indicating that there are novel bioactive molecules in this extract that might be important leads for future Alzheimer’s treatment efforts. HSS-888 was enriched in the four curcuminoids—Cur, DMC, BDMC, and THC—in an approximate ratio of 20:4:1:0.01, representing 72% of its composition, along with 28% turmerones.

Simple additive effects were observed 
for Aβ aggregation inhibition, 
supporting the notion that 
the known curcuminoids are not 
strong inhibitors of this activity.

Attention Shifting to Whole Turmeric

Thus, the individual curcuminoids are out of the spotlight, allowing for the on-stage appearance of some combination of whole turmeric’s active ingredients or whole turmeric itself. Indeed, the potential role of whole turmeric as a preventive agent against brain aging and neurodegenerative disorders has been recently reinforced by epidemiological studies showing that in India, where this spice is widely used in the daily diet, there is a lower incidence of Alzheimer’s disease than in the USA.4 But until the “optimized” turmeric study was done two years ago, there has been no concerted effort to sort out the optimal ratios of compounds within turmeric that can reduce the neurodegeneration characteristic of Alzheimer’s disease.

Amyloid-Beta as a Neuropathological Cause of Alzheimer’s

Alzheimer’s disease, the most common cause of dementia among the elderly, is characterized by cognitive deterioration, progressive memory loss, and behavioral problems. Pathologically, Alzheimer’s is characterized post mortem by the presence of senile plaques, neurofibrillary tangles, and neuronal cell loss. The accumulation of Aβ, produced as a cleavage product of APP, both as soluble aggregate oligomers and senile plaques, is a neuropathological hallmark of Alzheimer’s. Furthermore, a fundamental aspect of the current Aβ cascade hypothesis is that Aβ accumulation in the brain initiates a series of pathological reactions that result in Tau aggregation and neuronal dysfunction that are the primary causes of dementia.

Turmeric Extract Decreases Amyloid-Beta and Tau

In the first “optimized” study, it was shown that because the standardized turmeric extract HSS-888 showed strong inhibition of Aβ aggregation and secretion in vitro, this indicated that it might be therapeutically important. Therefore, in a new study not yet in print (Epub only), the same researchers evaluated HSS-888 in vivo using transgenic “Alzheimer” mice that over-expressing Aβ protein.5 Following a six month prevention period where mice received the HSS-888 extract (5mg/mouse/day),* THC, or a control substance, HSS-888 was found to significantly reduce brain levels of soluble (~40%) and insoluble (~20%) Aβ. Recent studies indicate that the soluble form is more damaging to brain function that the insoluble form.

*The human equivalent would be 35 mg/day for a 187 lb. human—not very much indeed. However, this is the amount of the HSS-888 extract that contains 72% curcuminoids, of which 80% is curcumin and the remaining 20% curcuminoids. This means that the 35 mg of HSS-888 contains about 25 mg of curcuminoids, 20 mg of curcumin and 5 mg of the other curcuminoids. Since the amount of curcuminoids in turmeric ranges from 2–6%, with about 50–75% of that (from 1–3% to 1.5–4.5%) curcumin, to get the same amount of curcumin (25 mg), one would have to ingest between 556–1667 or 833–2500 mg mg of turmeric.

As well, HSS-888 reduced phosphorylated Tau protein (~80%). Tau proteins stabilize microtubules, which operate as conveyer belts inside cells, especially in the central nervous system. However, when Tau proteins are made defective through phosphorylation, they no longer stabilize microtubules properly, and this can contribute to dementias such as Alzheimer’s disease.

Turmeric Extract Also Improves Immune Function

In addition, in primary cultures of microglia from these mice, HSS-888 showed increased expression of the cytokines IL-4, a cytokine that induces differentiation of naive helper T cells. IL-4 is also known to reduce the production of inflammation mediators in microglia. It also inhibits microglial activation and subsequent inflammation induced by Aβ. Additionally, the sustained expression of IL-4 reduces Aβ oligomerization and deposition and improves neurogenesis. Oligomerization makes Aβ plaque more soluble and therefore more damaging to memory function.

†Microglia are a type of glial cell that maintain homeostasis, form myelin, and provide support and protection for the brain’s neurons. Microglia are the resident macrophages of the brain and spinal cord; they are the first and main form of active immune defense in the central nervous system.

These data indicate that HSS-888 is also likely to reduce inflammation and neuronal cell death via IL-4 production. Also, this increase in IL-4 is likely to assist with the clearance of Aβ in vivo, thereby reducing neurotoxicity. HSS-888 effectively altered three primary mechanisms of Alzheimer’s progression: 1) the reduction of plaque burden in the entorhinal cortex and hippocampus; 2) the reduction of Tau phosphorylation; and 3) an increase in IL-4 production.

Along with IL-4, HSS-888 also increased expression of IL-2, a lymphokine that induces the proliferation of responsive T-cells. In different ways, both IL-4 and IL-2 play a central role in the regulation of the immune responses with an increased ratio of Il-4 to IL-2 highly desirable. HSS-888 increased the ratio of IL-4 to IL-2 from 0.73 to 1.11, indicating that HSS-888 may afford microgolia protection via the anti-inflammatory activity of specific cytokines.

Tetrahydrocurcumin Weak By Comparison

In contrast, THC treatment only weakly reduced phosphorylated Tau protein and failed to significantly alter plaque burden and cytokine expression. Altogether, these results reveal that the turmeric extract HSS-888 represents an important step in botanical-based therapies for Alzheimer’s disease by inhibiting plaque burden, Tau phosphorylation, and microglial inflammation leading to neuronal toxicity.

HSS-888 showed strong inhibition of 
Aβ aggregation and secretion, 
indicating that there are novel 
bioactive molecules in this extract 
that might determine the future of 
Alzheimer’s treatments.

These are significant findings, namely that Alzheimer’s mice receiving the turmeric extract HSS-888 daily for six months had significantly lower levels of amyloid plaque and phosphorylated Tau. And also that primary cultures of microglia from these mice exhibited enhanced cellular immunity. The current in vivo results confirm the prior study’s in vitro findings with turmeric extract HSS-888.

Protection from Tau Formation

Previous studies have suggested that soluble hyperphosphorylated isoforms are ultimately the neurotoxic species of Tau. HSS-888 may afford protection from the effects of these toxic Tau isoforms. HSS-888 may also provide site specific inhibition of Tau phosphorylation due to its reduction of phosphorylation. According to the researchers, this is the first demonstration of a turmeric-type extract having in vivo efficacy against Tau hyperphosphorylation.

Administration of THC also decreased Tau hyperphosphorylation in the present study. However, it was less effective than HSS-888 and failed to significantly affect other therapeutic endpoints such as Aβ accumulation, plaque burden, and cytokine expression. These findings are consistent with the researchers previous in vitro study.

Easing Alzheimer’s Effects on Memory

Collectively, these results indicate that the turmeric extract HSS-888 contributes to the easing of Alzheimer’s pathologies in vivo through both direct and indirect effects on Aβ aggregation and deposition and neuronal cell protection through anti-inflammatory routes. The properties of is components may also include:

  • Aβ-binding properties: Some of the compounds in turmeric proffer direct anti-amyloid and anti-Aβ oligomer activity in vitro and in vivo. The binding affinity of curcumin for Aβ aggregates is quite high. In principle, curcumin could also bind other β-pleated sheet structures including prion aggregates as well as synucleinand Tau aggregates.

  • Tau-binding properties: The curcuminoids and related polyphenols have been found to act as Tau aggregation inhibitors.

  • Stimulation of phagocytic Aβ clearance: Much as the amyloid vaccine operates, curcuminoids and perhaps other turmeric compounds appeared to increase the association of phagocytic (cell eating) cells with plaque structures in a rat Alzheimer’s model. These effects may derive from modulation of microglial activation through effects on arachidonic acid metabolites.

  • Anti-inflammatory: The active compounds of turmeric limit arachidonic acid substrates and aberrant inflammatory cytokine production. Unlike classical nonsteroidal anti-inflammatory drugs (NSAIDs), the curcuminoids do not appear to directly inhibit COX (an enzyme that is responsible for formation of important biological mediators called prostanoids; the inhibition of COX can provide relief from inflammation and pain). But unlike the omega-3 fatty acid docosahexaenoic acid (DHA), it has profound effects on limiting multiple arachidonic acid metabolites.

  • Antioxidant: Unlike ibuprofen (an NSAID), curcuminoids can effectively protect against oxidative damage in Alzheimer’s. Curcumin is typically used as a food preservative for reason of its antioxidant properties. In fact, it can protect polyunsaturated fatty acids from lipid peroxidation, and thus possibly do the same for highly unsaturated omega-3 fatty acids.

  • Metal chelation: Another important mechanism of curcuminoids is metal chelation, which requires a certain type of bond, without which for example, when curcumin is reduced to tetrahydrocurcumin, it loses its impact on reducing plaque, although it retains its ability to reduce Aβ oligomers.

  • Neurogenesis: Curcuminoids may enhance neurogenesis.

‡Synucleins are a family of soluble proteins, expressed primarily in neural tissue but also found in certain tumors.

Dyssynergy Among Curcuminoids

At the Aga Khan University Medical College, Karachi, Pakistan, researchers recently set out to determine if curcuminoids (a mixture of Cur, DMC and BDMC) have the potential to treat Alzheimer’s.6 The goal of this study was to investigate the effects of a curcuminoid mixture and individual constituents on spatial learning and memory in an Aβ peptide-infused rat model of Alzheimer’s. What they found is that the curcuminoid mixture showed a memory-enhancing effect in rats displaying Alzheimer’s-like neuronal loss but only at 30 mg/kg, whereas individual components were effective at 3-30 mg/kg. This would indicate that there was dyssynergy among the curcuminoids.

A shorter duration treatment with the test compounds showed that the curcuminoid mixture and BDMC increased neuronal expression in the hippocampus at 3–30 mg/kg, with maximum effect at a lower dose (3 mg/kg).

HSS-888 was found to significantly 
reduce brain levels of soluble Aβ 
(~40%) and insoluble Aβ (~20%). 
Also, HSS-888 reduced 
phosphorylated Tau protein (~80%).

However, after a longer duration treatment, two other compounds (Cur and DMC) also increased a measure of neuronal activity respectively at 30 mg/kg. When studied for their effect on synaptic vesicle protein in the hippocampus after the longer duration treatment, the curcuminoid mixture and all three individual constituents increased synaptic activity. Of these, DMC was the most effective.

When studied after longer treatment for their effect on the expression of a protein kinase that inhibits cell suicide in the hippocampus, only DMC at 30 mg/kg increased levels. The overall finding was that these compounds target multiple sites in the rat Alzheimer’s model, suggesting their potential in more than additive ways in spatial memory enhancing and disease modifying in Alzheimer’s. Their effects on memory are complex, with further study needed to arrive at meaningful conclusions.

The Lesson to Take Home

What we have learned is that turmeric offers an abundance of active compounds that are likely to work to protect and enhance memory more effectively in some combinations rather than others. Despite references to HSS-888 as an “optimized” turmeric extract, what we can say is that there is a lot to learn and that curcuminoids may only represent some of turmeric’s more active ingredients, which improve in their power when synergistically combined with other compounds from whole turmeric. Returning to what Durk Pearson and Sandy Shaw have to say …

In turmeric, the root is the longest-lasting part of the plant, and it protects itself with a system of antioxidants whose collective action has been optimized by evolution… the root not only has things that are more effective than curcumin, the plant has evolved a complete antioxidant package that works as a system … And this is an antioxidant package that people have been consuming for thousands of years. 

And don’t forget the case for other memory-enhancing nutrients as well, such as galantamine, lithium, quercetin, green tea (EGCG), and a variety of specific vitamins that have been made repeatedly in this publication. Remember that in the end, it’s your mind. What a shame not to serve it the best mind food and brain maintenance supplements that have been shown to be safe and efficacious.


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