Six-Month Randomized, Placebo-Controlled, Double-Blind, Pilot Clinical Trial of Curcumin in Patients With Alzheimer Disease

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To the Editors:
Curcumin is a polyphenolic molecule that comprises approximately 5% of turmeric, giving the spice its color but not flavor. It is used in processed foods as a yellow coloring. 1 Because of its anti-inflammatory and antioxidant properties, curcumin has been tested in animal models of Alzheimer disease (AD). In the Tg2576 APPSw mouse and amyloid-infused rat models of AD, 6 months of an oral dose equivalent (as a proportion of body weight) to roughly 1.5 g/d in humans significantly reduced levels of brain amyloid, plaques, oxidized proteins, and isoprostanes and prevented cognitive deficits in the rat model. 2,3 Elderly Singaporeans who ate curry with turmeric had higher Mini- Mental State Examination (MMSE) scores than those who did not. 4 Because no study has been published on the effect of curcumin on human AD patients, we performed a 6-month clinical trial of curcumin to examine its safety and effects on biochemical and cognitive measures in AD.
There are no ideal AD biomarkers. Amyloid β (Aβ) levels were higher in blood of AD patients than controls in some studies but not others. 5 Curcumin can disaggregate Aβ, and AD drug treatment may affect Aβ levels. 6-8 Blood isoprostanes were increased in AD versus controls in some studies but not in others, whereas antioxidants were decreased. 9-11 As an antioxidant, 1-3 curcumin might relieve the load on other antioxidants. Thus, we measured serum Aβ and plasma isoprostanes and antioxidants. Because curcumin has low oral bioavailability, 12 we also measured plasma curcumin and its metabolites.
Patients were eligible for this double-blind, placebo-controlled, randomized, 6-month trial if they were 50 years old or older, ethnic Chinese in Hong Kong, had progressive decline in memory and cognitive function for 6 months, had National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association diagnosis of probable or possible AD, 13 and gave written informed consent. For subjects unable to understand the study and their role in it, consent was obtained from the caregivers. Exclusion criteria were anticoagulant or antiplatelet treatment or bleeding risk factors, current smoking, or severe illness making study completion unlikely. The study was approved by the Hong Kong Clinical Research Ethics Committees for New Territories East and Kowloon West and followed the Helsinki Declaration. Thirty-four patients were recruited: 9 from old age homes and 24 from dementia clinics. When the trial period was nearing conclusion, 2 additional patients were recruited but could only be treated and monitored for 1 month. Patients were randomized to 4, 1 (plus 3 g color-matched placebo powder), or 0 g of curcumin (plus 4 g of placebo) once daily, with stratification by their prestudy Cantonese MMSE 14 score range (≤14, 14-17, or ≥17) to improve matching of baseline scores among dose groups. Of 22 patients randomized to 4 or 1 g, 10 patients chose to take curcumin/placebo as 10 capsules to swallow after a meal; and 12 patients, as a packet of powder to mix with food. Patients were permitted to continue (or to change at any time) any treatment deemed appropriate by their physicians and were also given as a standard treatment, which showed moderate benefit in previous studies, 1 capsule/d 120 mg standardized ginkgo leaf extract (Shanghai Charoma, Shanghai, China). 15 Curcumin was given by Kancor Flavours, Kerala, India, for packets, or bought from Arjuna Natural Extracts, Kerala, India, for capsules.
At 0, 1, and 6 months, plasma was taken to measure isoprostanes iPF2α-III and antioxidants, and so was serum to monitor Aβ and liver and kidney function. At 1 month, plasma was taken to assay curcumin and metabolites.

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