18-Month Study of Memory Effects of Curcumin

Several lines of evidence suggest that the neuropathological and clinical decline leading to
Alzheimer disease (AD) begins years before patients develop the full AD clinical syndrome
(NINCDS-ADRDA diagnostic criteria; McKhann et al, 1984). Mild memory complaints build
gradually years before patients develop dementia. The neuropathological hallmarks of AD,
"preclinical" neuritic plaques (Braak & Braak, 1991) and neurofibrillary tangles (Price &
Morris, 1999), are also present years prior to clinical diagnosis. These abnormal protein
deposits correlate strongly with cognitive decline.

Preclinical amyloid deposits may begin decades prior to dementia onset. In fact, diffuse
plaques in non-demented elderly persons are associated with an accelerated age-related
cortical cholinergic deficit, consistent with preclinical AD (Beach et al, 1997; Arai et al,
1999). Also consistent with a prolonged preclinical disease stage is our own work showing
that position emission tomography (PET) measures of cerebral glucose metabolism vary
according to AD genetic risk (apolipoprotein E-4 [APOE-4]) and predict cerebral metabolic and
cognitive decline in people with mild cognitive complaints (age-associated memory impairment
[AAMI]; Small et al, 2000). Such observations have stimulated interest in preclinical AD
markers or biomarkers of brain aging that may assist in tracking treatments of AAMI and
related conditions. New PET imaging methods now make it possible to provide in vivo measures
of cerebral amyloid neuritic plaques (e.g., florbetapir-PET; Clarke et al, 2011) and tau
neurofibrillary tangles (e.g. FDDNP-PET; Small et al, 2006, 2009).

Despite these previous research findings, clinical trials (including those using biomarkers
as response measures) and subsequent treatment recommendations have been limited to patients
with the full clinical dementia syndrome or mild cognitive impairment (MCI), a condition that
increases the risk for developing dementia (Petersen et al, 2001). Cholinesterase inhibitors
are currently the only drugs that have FDA clearance for treatment of AD, but previous
studies (e.g., Ringman et al, 2005) suggest that other interventions, such as dietary or
herbal supplements, may benefit cognition, and possibly interrupt the accumulation of
abnormal amyloid protein deposits in the brain. For example, curcumin (diferulomethane), a
low molecular weight molecule with antioxidant and anti-inflammatory activities that is
derived from dietary spice, may have both cognitive-enhancing and anti-amyloid properties
(Ringman et al, 2005; Yang et al, 2005).

To address such issues, the investigators propose to build upon our group's previous
longitudinal brain imaging and genetic risk studies in people with age-related memory
decline. Because previous studies suggest that curcumin may improve cognitive ability and
prevent the build-up of age-associated plaques and tangles in the brain, the investigators
will perform a double-blind, placebo-controlled trial of curcumin to test the following
hypotheses:

1. People with age-related cognitive decline (i.e., MCI, AAMI or normal aging),, who
receive curcumin 90 mg twice each day will show less evidence of cognitive decline (as
measured with neuropsychological assessments) than those receiving placebo after 18
months.

2. People with age-related cognitive decline who receive an oral dose of curcumin 90 mg
twice each day will show less build-up of plaques and tangles (as measured with
FDDNP-PET imaging) than those receiving placebo after 18 months.

3. People with age-related cognitive decline, who receive curcumin 90 mg twice each day,
will show decreased measures of inflammation in the blood compared with those receiving
placebo after 18 months.

4. Cognitive change, FDDNP-PET measures, and treatment response will vary according to
genotypes found to influence age at dementia onset (e.g., apolipoprotein E [APOE]
TOMM40).

Because curcumin may alter inflammatory markers in the blood, the investigators will draw
blood samples at baseline and at 18 months and freeze them for later analyses.

To test theses hypotheses, subjects with age-related cognitive decline will be enrolled
(Crook et al, 1986; Petersen et al, 2001). Subjects will be randomized, using a double-blind
design, to one of two treatment groups: curcumin (three 30 mg capsules twice each day) or
placebo, and followed for 18 months. FDDNP-PET scanning will be performed at baseline and at
18 months. Magnetic resonance imaging (MRI) scans also will be performed for co-registration
of PET and assistance in identifying regions of interest. Neuropsychological assessments will
be performed at baseline, 6 months, 12 months and at the conclusion of the clinical trial (18
months). Blood will be drawn at baseline to perform genotyping.

Inclusion Criteria

1. Agreement to participate in the 18-month double-blind, placebo-controlled clinical
trial of curcumin.

2. Diagnostic criteria for mild cognitive impairment (MCI) or any age related memory
decline according to standard criteria (Petersen et al, 2001; Crook et al, 1986).

3. Age 50 to 90 years.

4. No significant cerebrovascular disease: modified Ischemic Score of < 4 (Rosen et al,
1980).

5. Adequate visual and auditory acuity to allow neuropsychological testing.

6. Screening laboratory tests and EKG without significant abnormalities that might
interfere with the study.

Exclusion Criteria

1. Diagnosis of probable Alzheimer's disease (AD) or any other dementia (e.g., vascular,
Lewy body, frontotemporal) (McKhann et al, 1984).

2. Evidence of other neurological or physical illness that can produce cognitive
deterioration. Volunteers with a history of stroke, TIA, carotid bruits, or lacunes on
MRI scans will be excluded.

3. Inability to undergo MRI.

4. Evidence of Parkinson's disease as determined by the motor examination (items 18-31)
of the Unified Parkinson's Disease Rating Scale (Fahn et al, 1987).

5. History of myocardial infarction within the previous year, or unstable cardiac
disease.

6. Uncontrolled hypertension (systolic BP > 170 or diastolic BP > 100).

7. History of significant liver disease, clinically-significant pulmonary disease,
diabetes, or cancer.

8. Current diagnosis of any major psychiatric disorder according to the DSM-IV TR
criteria (APA, 2000).

9. Current diagnosis or history of alcoholism or substance addiction.

10. Regular use of any medication that may affect cognitive functioning including:
centrally active beta-blockers, narcotics, Clonidine, anti-Parkinsonian medications,
antipsychotics, benzodiazepines, systemic corticosteroids, medications with
significant cholinergic or anticholinergic effects, anti-convulsants, or Warfarin.
Occasional chloral hydrate use will be allowed, but discouraged, for insomnia.

11. Use of more than one multivitamin per day. Vitamins other than the standard
multivitamin supplement will not be allowed.

12. Use of medications known to affect FDDNP-PET binding (e.g., ibuprofen, naproxen).

13. Use of more than one daily baby aspirin (81mg) and/or use of any medication containing
curcumin.

14. Use of cognitive enhancing supplements (e.g. Ginkgo biloba).

15. Use of any investigational drugs within the previous month or longer, depending on
drug half-life.

16. Pregnancy.

17. HIV infection.

18. Evidence of vasogenic edema; specifically, evidence of more than 4 cerebral
microhemorrhages (regardless of their anatomical location or diagnostic
characterization as "possible" or "definite") or a single area of superficial
siderosis), or evidence of a prior macrohemorrhage at screening or baseline.