I have recently increased my curcumin with piperine to 3,000mg per day.
That sounds a lot, but the following report says,

"
Curcumin extremely safe and well tolerated
At least three different Phase I clinical trials have indicated that curcumin is extremely safe and well tolerated when taken in doses as high as 12 g/day
(12,000mg)

The number of useful functions with few side effects is impressive, but do take it with piperine, (bioperine), or it is not well absorbed
Ron


http://www.lmreview.com/articles/alz...ic.html#Aref70
Current Research on Promising Nutraceuticals

1. Curcumin

Curcumin is the most active of the three curcuminoids found in the yellow-orange Indian curry spice, turmeric (Curcuma longa); the other two are demethoxycurcumin and bis-demethoxycurcumin.

In vitro research has shown curcumin to be a pleiotropic anti-amyloid, antioxidant, anti-inflammatory and immune-modulating treatment for AD.26

Anti-amyloid: By directly binding small Abeta species, curcumin blocks Abeta
aggregation and fibril formation in vitro and in vivo. Adding curcumin to pre-aggregated oligomers results in the appearance of intense monomeric bands, indicating de-aggregation.27

Anti-oxidant: A number of in vitro studies, including research presented at the American Physiological Society's 2004 annual conference in Washington, D.C., have confirmed that curcumin strongly induces expression of the gene hemeoxygenase-1 (HO-1) in astrocytes from the hippocampal region of the brain. HO induction, by generating the vasoactive molecule carbon monoxide and the powerful antioxidant bilirubin, is a protective system against brain oxidative injury. Curcumin also exerts potent antioxidant activity against NO-related radical generation.27,28

Anti-inflammatory: Most inflammatory stimuli activate 1 of 3 independent MAPK pathways, which lead to activation of the p44/42 MAPK (also called ERK1/ERK2), JNK, or the p38 MAPK pathway, respectively. Curcumin inhibits all three pathways directly or indirectly.29,27

Metal chelation: A consistent observation in AD is a dysregulation of metal ions [(Fe(2+), Cu(2+) and Zn(2+)] homeostasis and consequential induction of oxidative stress, associated with Abeta aggregation and amyloid plaque formation. In addition, Abeta has been shown to spontaneously self-aggregate in the presence of divalent metals (Fe2+, Cu2+, Zn2+) into neurotoxic amyloid fibrils in the neocortex. Metal chelation is known to reduce both oxidative stress and amyloid plaque formation. Curcumin has well characterized chelating actions and readily binds both Cu2+ and Fe2+.30,27

Immune modulation: Over the last two decades, curcumin has been shown to be a potent immunomodulatory agent that can regulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various pro-inflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB. Interestingly, however, at low doses, curcumin also enhances antibody responses.31,32

Curcumin in Animal Models of AD
In numerous animal models of AD, curcumin has been shown to cross the blood-brain barrier and reduce senile plaques and cerebrovascular amyloid angiopathy.33
Systemic treatment of mice with curcumin for 7 days clears existing plaques, indicating a potent disaggregation effect. Curcumin also causes significant reversal of structural changes in dystrophic dendrites, including abnormal curvature and dystrophy size. Together, these data suggest that curcumin reverses existing Abeta pathology and associated neurotoxicity in a mouse model of AD.34

Animal studies have demonstrated that curcumin not only clears Abeta from the brain, but reduces AD-related inflammation in brain tissue. Curcumin's brain antioxidant effects have been well-documented in animal models of cerebral ischemia and brain trauma. Not only has plaque buildup been reduced in curcumin-fed rats, but they also outperformed rats on control diets when carrying out maze-based memory tests.27

In AD, several mediators in the inflammation cascade contribute both to neurodegeneration and the production and accumulation of Abeta peptide. Animal studies have shown that curcumin antagonizes many steps in the inflammatory cascade, including AP-1 transcription, activation of NF-kappaB, iNOS and JNK.27

IL-1, an index of neuroinflammation, is also thought to contribute to AD pathogenesis and is elevated in animal models of AD. IL-1 is effectively reduced in curcumin-fed mice compared to controls. The stress-activated (phosphorylated) c-Jun N-terminal kinase (pJNK), also elevated in animal models of AD, is significantly reduced by curcumin as well, and the degree of soluble Abeta reduction is proportional to that of pJNK reduction.27 (JNK is a tau kinase hypothesized to mediate end stage neurodegeneration in AD models.)

The consensus of researchers conducting animal studies has been unanimous: curcumin's extremely low incidence of side effects, combined with its ability to reduce Abeta burden, and anti-inflammatory and anti-oxidant actions, indicate significant therapeutic potential in combating AD in humans.35,36,37

"The prospect of finding a safe and effective new approach to both prevention and treatment of Alzheimer's disease is tremendously exciting," noted Gregory Cole, MD, a professor of medicine and neurology at the David Geffen School of Medicine at UCLA, in a news release after UCLA research showed curcumin not only inhibits Abeta aggregation and dissolves amyloid fibrils, but does so more effectively than ibuprofen and naproxen. Previous studies had shown that people taking these NSAIDs have a decreased risk of developing Alzheimer's disease.38,34

Curcumin in Human Research
Epidemiological studies have noted very low levels of AD and other dementias in elderly Indian populations whose typical diet is liberally spiced with turmeric. In fact, studies have found that AD affects just 1% of people over the age of 65 living in some Indian villages.39

Similar findings have been noted in other populations. In a recent population-based study of 1,010 elderly non-demented Asians, those who consumed curry ‘‘occasionally’’ and ‘‘often or very often’’ scored significantly better on the Mini-Mental State Examination (MMSE), an established measure of cognitive function, than did those who ‘‘never or rarely’’ consumed curry.40

Bisdemethoxycurcumin restores innate immunity & Abeta clearance in AD patients
Phagocytosis of Abeta by macrophages is excellent in normal subjects but deficient in most AD patients. Increased proinflammatory cytokine levels and activated microglia and macrophages in AD patients may be compensatory for defective clearance of Abeta. Consequently, therapeutic interventions that increase phagocytosis of Abeta might decrease brain inflammation as well as reduce inflammation-induced neurodegeneration.

A secondary curcuminoid in Curcuma longa, bisdemethoxycurcumin, has been shown to improve innate immune system activity in AD patients, increasing Abeta clearance from the brain. In healthy individuals, Abeta presentation stimulates upregulation of genes that increase transcription of beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) and other genes, including Toll-like receptors. These increase macrophage transport of Abeta into endosomes and lysosomes; in AD patients, however, an increase in Abeta generally down-regulates these genes, resulting in defective phagocytosis. Using blood samples from AD patients, Drs. Milan Fiala and John Cashman have shown that bisdemethoxycurcumin enhances transcription of MGAT3 and Toll-like receptors, restoring macrophage activity to normal levels and enhancing Abeta phagocytosis.41,42

Curcumin extremely safe and well tolerated
At least three different Phase I clinical trials have indicated that curcumin is extremely safe and well tolerated when taken in doses as high as 12 g/day. These results were further confirmed in a dose-escalation trial to determine curcumin’s maximum tolerated dose and safety in which a standardized powder extract of curcumin was administered to 24 healthy volunteers in single doses ranging from 500 to 12,000 mg. Only minimal, non-dose-related toxicity was seen and only in seven subjects (30%).43

Bioavailability enhanced by piperine, the active phytochemical in black pepper
It has been noted that curcumin is extremely rapidly metabolized via glucuronidation in the liver and intestinal wall, which some believe may limit its therapeutic usefulness. Piperine, a known inhibitor of glucuronidation, has been shown to significantly enhance curcumin’s bioavailability in studies involving both rats and healthy human volunteers. In rat studies, administration of curcumin alone at a dose of 2 g/kg, resulted in only moderate serum concentrations over 4 hours. Concomitant administration with piperine (20 mg/kg) increased the serum concentration of curcumin for 1-2 hours post drug, significantly increased the time to maximum concentration, and significantly decreased elimination half-life and clearance, increasing bioavailability by 154%. In humans, administration of curcumin alone produced undetectable or trace amounts in serum; however, concomitant administration with piperine (20 mg/kg) resulted in much higher concentrations and increased bioavailability by a remarkable 2000%.44

Interestingly, black pepper is a common ingredient, along with curcumin, in curry spice blends, which may contribute to the beneficial effects of turmeric consumption seen in epidemiological studies in India and other areas where curries are standard fare.