Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study

More than five million Americans currently have Alzheimer's disease (AD) [1] and available treatments have only modest symptomatic benefits. We are in desperate need of readily available, safe interventions that modify disease course. Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been used as a food preservative and to treat various ailments in Ayurvedic medicine. In vitro and in vivo animal studies have demonstrated that curcumin has potentially important biological effects including anti-oxidant and anti-inflammatory properties [2]. As oxidative stress [3] and inflammation [4] are potentially involved in propagating AD pathology, the utility of curcumin in treating and preventing AD is being pursued [5].

There is convergent evidence that overproduction, aberrant aggregation, or decreased elimination of different forms of amyloid beta protein (Aβ) are critical events in the pathogenesis of AD and, therefore, treatment development has focused on these processes. Curcumin has a biphenolic structure similar to Congo Red and binds to amyloid plaques in vivo [6]. Curcumin prevents Aβ-induced toxicity in vitro in various preparations [7] and prevented the aggregation of Aβ into fibrils [8]. Transgenic mice harboring the amyloid precursor protein Swedish mutation (APPsw) fed curcumin for six months had decreased levels of Aβ and inflammatory cytokines in the brain [9]. The ability of curcumin to cross the blood-brain barrier, and bind to and induce rapid dissolution of plaques was verified using multi-photon microscopy in vivo in APPsw/PS1dE9 mice [10]. In further studies of curcumin and tetrahydrocurcumin in the Tg2576 APPsw mouse, curcumin was found to reduce central nervous system levels of IL-1β and isoprostanes (an index of oxidative stress) and to reduce amyloid plaque burden [6].

Although there is extensive experience with human consumption of turmeric oleoresin (85% curcumin) such that it is classified as 'Generally Recognized As Safe' (GRAS) by the US Food and Drug Administration, there is still much to be determined about the tolerability and bioavailability of moderate doses of curcumin when used chronically, particularly in elderly individuals. Prior short-term human studies suggest the potential for gastrointestinal side effects including diarrhea [11] and toxicity studies in rats indicate the possibility of hepatoxicity and thyroid follicular cell hyperplasia [12]. We, therefore, performed a 24-week, randomized, double-blind, placebo-controlled study of two doses of Curcumin C3 Complex^® in persons with mild-to-moderate AD with an open-label extension to 48 weeks. The primary goals were to gather data on safety and tolerability and preliminary data on efficacy with regard to cognition. Secondary goals were to obtain preliminary efficacy data on behavior and activities of daily living and on plasma and cerebrospinal fluid (CSF) AD biomarkers.

Eighty-four subjects were screened between August 2004 and January 2007 of whom 38 were randomized (Figure 1). Two subjects never received study medication (one due to inability to swallow the capsules, another due to intercurrent illness between randomization and baseline visits) and their treatment allocations were re-assigned. Thirty-six subjects therefore received at least one dose of study medication (12 per group). Among the 30 subjects who completed 24 weeks, baseline gender (63% female), years of education (15.2 years), use of AchE-Is (93%) and memantine (77%), average age (73.5 years), MMSE (22.5), total NPI (9.7), ADAS-Cog (19.4), and ADCS-ADL (62.8) scores did not differ among treatment groups (Table 1).

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Between baseline and 24 weeks, six subjects withdrew. One subject (8%) withdrew in the placebo group (worsened memory) and 5/24 subjects (21%) in the curcumin group withdrew due to adverse effects (P = 0.33). Among the curcumin-treated subjects, three withdrew in the 2 gm/day curcumin group (two due to gastrointestinal side effects of black stools and diarrhea, one due to subsequent difficulty swallowing the pills), and two subjects withdrew in the 4 gm/day curcumin group (one due to diarrhea and one due to difficulty swallowing the pills). Of the 30 subjects entering the open-label phase, two subjects originally assigned to placebo dropped out before week 48, one due to deterioration of AD symptoms and one due to weight loss and a low hematocrit.

Overall, adverse events occurred in 91.7% of placebo-treated subjects and 100% of curcumin treated subjects (n.s.). Complaints attributable to the endocrine system were less common in the 2 gm/day curcumin group, occurring at 3% of visits, compared to the placebo group (17%) and the 4 gm/day group (19%, P = 0.02). Patients on placebo reported diarrhea on 4% of visits, patients on 2 gm/day of curcumin at 6% of visits and patients on 4 gm/day on 8% of visits (P = 0.63). Joint pain was reported at 15% of visits for persons on placebo, 9% of visits for persons on 2 gm and 5% of persons on 4 gm of curcumin (P = 0.19). When modeling the difference in joint pain occurrence as a linear function of curcumin dose, a 2.5% trend towards decrease in joint pain per gram of curcumin was found (P = 0.07). There were no serious adverse events in the course of this study.

Complete safety laboratory data at baseline and 24 weeks were available for 11 completers on placebo, 9 on 2 gm/day and 9 on 4 gm/day of curcumin. Controlling for baseline values, subjects on curcumin had statistically lower hematocrit (placebo = 42.9%, standard error of the mean (SEM) = 0.49, 2 gm = 41.8%, SEM = 0.55, 4 gm = 42.3%, SEM. = 0.54; P = 0.014) and higher glucose levels (placebo = 85.9 mg/dL, SEM = 4.2, 2 gm = 91.6 mg/dL, SEM = 4.5; 4 gm = 90.5 mg/dL, SEM = 4.5, P = 0.043) while being treated.

In this 24-week double-blind placebo-controlled study with a 24-week extension, we examined the tolerability of 2 gm/day and 4 gm/day of Curcumin C3 Complex^® in persons with mild-to-moderate AD. A total of 4/35 (11.4%) subjects dropped out of the study while on curcumin, due to gastrointestinal side effects. Two subjects had black stools consistent with melena but in no subject was there unequivocal evidence of gastrointestinal hemorrhage or hemodynamic compromise. A subset of subjects underwent bleeding time assessments and no significant effect of curcumin was observed. The reason for the observed increased plasma glucose levels in persons treated with curcumin is unclear. These changes in hematocrit and blood glucose were relatively minor and values did not exceed the range of normal.

Following single doses of 2 gram and 4 gram doses of Curcumin C3 Complex^°, we were unable to measure significant plasma levels of native curcumin based on the half maximal inhibitory concentration IC50's identified in Begum et al. [6]. Recent studies of curcumin suggest limited bioavailability [20], likely due to extensive metabolism in the gastrointestinal tract. In animal models, the diketone bridge of native curcumin was required for its plaque-reducing effects, presumably due to its requirement for amyloid-binding [6]. As an equivocal ameliorative peripheral effect on joint inflammation was suggested by our findings, the current results do not exclude a peripheral effect of glucuronidated curcuminoids, which were high, but as has been shown in mice [21], not likely to penetrate the blood brain barrier. However, we did not observe an effect on F₂-IsoP levels that have been previously shown to be influenced by the administration of curcumin in a rat model of Aβ-induced injury [22] and by antioxidants in humans [23]. Alternative formulations of curcumin that are better absorbed are being studied [24] for their potential use in AD.

We were unable to demonstrate clinical or biochemical evidence of efficacy against AD. Considering the small sample size and short duration of this study, significant impact on clinical indices was not expected. Additionally, variability in the baseline disease severity may have masked effects, particularly if the intervention was effective in a subgroup (for example, persons with milder disease). However, there were non-significant trends for both MMSE score and the ADAS-Cog score to worsen slightly in the curcumin-treated groups relative to placebo. Though the small sample size and non-significance precludes definitive conclusions from this observation, it is possible that curcumin might exert a minor encephalopathic effect though the mechanism of this would be unknown.

A prior six-month study of curcumin in 34 persons with AD similarly failed to demonstrate an impact on clinical measures [25]. This study similarly found high levels of glucuronidated curcuminoids in plasma and a trend for increased Aβ40 with a 4 gram dose of curcumin was noted, possibly reflecting mobilization of Aβ40. However, we did not observe such an effect in our study and no effects on CSF AD biomarkers, including Aβ42, were found.

There have been relatively few clinical trials in which comprehensive biomarker data have been collected at six-month intervals. The data collected here show the baseline and 24-week variation in plasma Aβ, CSF Aβ₄₂, CSF t-tau and p-tau₁₈₁ and CSF isoprostanes (Table 2). Although the numbers are small these values may be of comparative interest for other trials.

Curcumin has anti-oxidant, anti-inflammatory and anti-amyloid effects in vitro and prior studies in animal AD models make it a promising avenue to pursue in human AD. There are many possible explanations for the results of our study including differences in the biology of rodent models of amyloidosis and human AD [26] and differences in the metabolism of curcumin between humans and rodents. It is unclear whether lack of a demonstrable benefit is due to problems with bioavailability of this specific formulation of curcumin or to inefficacy of curcumin as an intervention for AD. Further studies of other preparations of curcumin for AD are ongoing.

Most importantly, we would like to thank the participants of this study for their involvement. This study was supported by the John Douglas French Foundation and the Institute for the Study of Aging. The investigational product was provided by Sabinsa Corporation, Piscataway, NJ. Further support for this study came from the Sidell Kagan Foundation, the Shirley and Jack Goldberg Trust, Alzheimer's Disease Research Center Grant P50 AG-16570 and U01AG28583 (SAF) from the National Institute on Aging, General Clinical Research Centers Program M01-RR00865, a California Alzheimer's Disease Center grant, and the Easton Consortium for Alzheimer's Disease Drug Discovery and Biomarkers.