This is an additional study to the primary Mild Cognitive Impairment (MCI) study (LSU#H04-049; NCT00243451)that is underway of PET detection of Mild Cognitive Impairment. This study has preliminary data that indicates objective analysis of PET brain image metabolic data is a sensitive marker for AD. The goal of this proposal is to determine the efficacy of curcumin in the treatment of MCI or mild Alzheimer's Disease (AD).

The specific aims of this study include:

• Determine if curcumin has an effect on neuropsychological scores in patients with MCI. Working Hypothesis: Patients with MCI that have evidence of objective memory impairment will have improvement on neuropsychological test scores.
• Determine if curcumin impacts the metabolic lesions found in patients who have MCI or may develop MCI. Working hypothesis: The metabolic lesions present that are consistent with the development of early AD will improve with curcumin treatment.

Patients diagnosed with MCI, patients who have metabolic lesions consistent with premorbid MCI, or mild AD and are currently enrolled in the primary MCI study (LSU#H04-049; NCT00243451) will be invited to participate in this clinical trial.

These subjects will be treated with 5.4 grams of curcumin per day (900 mg pills, two pills 3X/day with meals) with the inclusion of bioperine additive (formulated with the curcumin capsules) to improve bioavailability of the curcumin. Patients will be treated with curcumin/bioperine for 24 months concordant with the last two years of the three year longitudinal primary MCI study. Clinical endpoints will be change in neuropsychological scores, and size of metabolic lesions on the PET scan. Both of these measures will be recorded as part of the primary MCI study.

• Mild Cognitive Impairment
• Mild Alzheimer's Disease

MCI Inclusion Criteria (patients):

MCI criteria met:

1. Memory complaint, preferably corroborated by an informant.
2. Objective memory impairment (based on cognitive test scores).
3. Normal general cognitive function.
4. Intact ADL.

5. Not demented.

   • At least 10 years of education, or GED, or equivalent.
   • Patients with ApoE4 positive homozygous or heterozygous status and/or first-degree relative with probable AD are preferred, but patients who meet all other criteria including well-defined MCI criteria will be accepted.
   • Age: 55-85
   • Have normal or clinically unimportant physical exam, beyond those consistent with a diagnosis of MCI.
   • Able to give informed consent, or assent and informed consent from a legal representative.
   • Centrally acting medications will be closely tracked, patients on any such medications will be PET-scanned only after a 24-hour washout, with meds restarted immediately after the scan.
   • Because depression and depressive pseudodementia are often prodromal to cognitive decline, these diagnoses will not be exclusive.
   • MRI findings must be normal or unremarkable for the age of the patient. Examples of abnormal (exclusory) findings are occult lacunar infarct, arteriovenous malformation) Examples of non-exclusory findings include mild atrophy, mild to moderate periventricular white matter changes. Other MRI findings will be evaluated in consultation with coinvestigator neuroradiologists and clinical judgment will be used to determine if the subject can continue in the study.

MCI Exclusion Criteria (patients):

• Other neuropsychiatric diagnoses (e.g., stroke, head trauma, any psychotic disorder, Parkinson's) other than MCI.
• Major medical illness (e.g., diabetes, severe or uncontrolled hypertension), especially potential secondary causes of cognitive decline (e.g., hypothyroidism).
• Disease, combination of disease, or presentation that, in the clinician's judgment, could introduce intolerable variance into the PET brain scan image (example: coronary artery disease, hypercholesterolemia, on 5 medications, HTN 2 yrs controlled with meds, random glucose of 125, but no Dx of DM, Hx of ?TIA).
• Current substance or alcohol dependence or history of same, and no alcohol or substance abuse within the last eight weeks.

Mild Alzheimer's Disease (AD) Inclusion criteria (patients):

1. You must have a Mini Mental State Examination score of greater than 20.
2. You must have one or more of these signs and symptoms of mild AD:

Cognitive impairment manifested as memory problems, problems with language, difficulty carrying out motor activities, difficulty naming things, and/or problems planning or organizing, all of which impair function and are worsening over time.

• You must have at least 10 years of education, or a GED, or its equivalent.
• We will be drawing blood to determine your ApoE genotype. ApoE4 is a risk factor for Alzheimer's disease. We will share these results with you, if you desire to know the results. ApoE4 is only a risk factor. That means it is possible to get Alzheimer's without being ApoE4 positive, and it is possible to be ApoE4 positive and not get Alzheimer's. If you are positive for the ApoE4 genetic marker, you can be included. If you do NOT have the ApoE4 genetic marker, then you must have all other criteria.
• Age: 55-85.
• Normal or clinically unimportant physical exam, beyond those consistent with a diagnosis of mild AD.
• Able to give informed consent, or assent and informed consent from a legal representative. You will be assessed for capacity and assent/consent obtained as appropriate based on the Consensus Recommendations for Research Consent for Cognitively Impaired Adults (2004, Alzheimer's Disease Association Disorder, 18 (3):171-175).
• If you take medications that have an effect on the brain, they will be closely monitored. You will be PET-scanned only after a 24-hour washout of this medication(s), but this medication(s) will be restarted immediately after the scan.

Mild Alzheimer's Disease (AD) Exclusion Criteria:

• Any problems related to the brain or mental disorders (e.g., stroke, head trauma, any psychotic disorder, Parkinson's) other than mild AD. Some mood disorders will be acceptable because depression is often a precursor to mild AD.
• You will get an MRI of your brain taken on the second visit, and a radiologist will read it. If there are any abnormal findings, you will be told, and these findings will be forwarded to your medical doctor. These findings may or may not result in your exclusion from the study.
• Any major medical illness (e.g., diabetes, severe or uncontrolled hypertension), especially potential secondary causes of cognitive decline (e.g., hypothyroidism).
• Any disease, combination of disease, or presentation that, in the clinician's judgment, could introduce intolerable variance into the PET brain scan image.
• Current diagnosis of substance or alcohol dependence or a history of same, and no alcohol or substance abuse within the last eight weeks.

MCI Inclusion criteria (controls)

• Normal cognitive screening exam.
• Age: 55-85.
• At least 10 years of education or GED, or equivalent.
• Socioeconomic status, age, and sex matched. Able to give informed consent, or assent and informed consent from a legal representative.
• Centrally acting medications will be closely tracked, patients on any such medications will be PET-scanned only after a 24-hour washout, with meds restarted immediately after the scan.

MCI Exclusion criteria (controls)

• First-degree relative with dementia or clinically relevant memory problems.
• Neuropsychiatric diagnoses (e.g., stroke, head trauma, depression, any psychoses).
• Major medical illness (e.g., diabetes, severe /uncontrolled hypertension, hypothyroidism).
• Current substance or alcohol dependence or history of same, and no alcohol or substance abuse within the last eight weeks.

• MRI findings must be normal or unremarkable for the age of the patient. Examples of abnormal (exclusory) findings are occult lacunar infarct, arteriovenous malformation) Examples of non-exclusory findings include mild atrophy, mild to moderate periventricular white matter changes. Other MRI findings will be evaluated in consultation with coinvestigator neuroradiologists and clinical judgment will be used to determine if the subject can continue in the study.

  • Disease, combination of disease, or presentation that, in the clinician's judgment, could introduce intolerable variance into the PET brain scan image (example: coronary artery disease, hypercholesterolemia, on 5 medications, HTN 2 yrs controlled with meds, random glucose of 125, but no Dx of DM, Hx of ?TIA).

Dropout criteria (all):

Subjects that begin the study and are not able to finish the study will be tracked. Ongoing criteria for termination from the study will include:

• Adverse events intolerable to the patient that prevent continued involvement in the study.
• New onset medical disorder of such significance as to prohibit further involvement.
• Initiation or recurrence of alcohol or substance abuse/dependence.
• Subject withdraws consent for any reason.