ADNI Objectives, Study Design, Sample Size, Key Eligibility Criteria, Procedures,  Outcome Measures, Safety Parameters and Statistical Considerations.

Primary Objectives
The major goals of the ADNI are to:
1. Develop improved methods which will lead to uniform standards for acquiring longitudinal, multi-site MRI and PET data on patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and elderly controls.
2. Acquire a generally accessible data repository which describes
longitudinal changes in brain structure and metabolism. In parallel,
acquire clinical cognitive and biomarker data for validation of imaging surrogates.
3. Develop methods which will provide maximum power to determine treatment effects in trials involving these patients.
4. Test a series of hypotheses based on the clinical and biomarker
data as outlined in the statistical analysis section.

Study Design
This is a non-randomized natural history non-treatment study in which a total of 800 subjects including 200 normal controls, 400 individuals with MCI, and 200 subjects with mild AD will be recruited at approximately 50 sites in the United States and Canada for longitudinal follow up.

Sample Size
Eight hundred subjects from 50 sites from the United States and Canada.

Key Eligibility Criteria
Enrolled subjects will be between 55-90 (inclusive) years of age, have a study partner able to provide an independent evaluation of functioning, and will speak either English or Spanish. All subjects must be willing and able to undergo all test procedures including neuroimaging and agree to longitudinal follow up. Between twenty and fifty percent must be willing to undergo two lumbar punctures, spaced one year apart. Specific psychoactive medications will be excluded. General inclusion/exclusion criteria are as follows:

1. Normal subjects: MMSE scores between 24-30 (inclusive), a CDR of 0, non-depressed, non MCI, and nondemented. The age range of normal subjects will be roughly matched to that of MCI and AD subjects. Therefore, there should be minimal enrollment of normals under the age of 70.

2. MCI subjects: MMSE scores between 24-30 (inclusive), a memory complaint, have objective memory loss measured by education adjusted scores on Wechsler Memory Scale Logical Memory II, a CDR of 0.5, absence of significant levels of impairment in other cognitive domains, essentially preserved activities of daily living, and an absence of dementia.

3. Mild AD: MMSE scores between 20-26 (inclusive), CDR of 0.5 or 1.0, and meets NINCDS/ADRDA criteria for probable AD.

Procedures
All subjects will have clinical/cognitive assessments and 1.5 T structural MRI at specified intervals (6 or 12 month) for 2-3 years. Approximately 50% of subjects will also have FDG PET scans at the same time intervals and 25% of subjects (who have not been scanned using PET) will have MRI at 3 Tesla.

AD subjects (n=200) will be studied at 0, 6, 12, and 24 months. MCI subjects at high risk for conversion to AD (n= 400) will be studied at 0, 6, 12, 18, 24 and 36 months. Age matched controls (n=200) will be studied at 0, 6, 12, 24 and 36 months. All MRI and PET scans will be rapidly assessed for quality so that subjects may be rescanned if necessary. All clinical data will be collected, monitored, and stored by the Coordinating Center at the ADCS. U Penn will collect biomarker samples. All raw and processed image data will be archived at LONI.

Outcome Measures
1. Rate of conversion from MCI to AD.
2. Rate of volume change of whole brain, hippocampus, and entorhinal cortex.
3. Rates of change for each specified biomarker.
4. Rates of change of glucose metabolism for specified regions of interest on PET scanning.
5. Group differences for each imaging and biomarker measurement.
6. Tensor based and voxel based morphometric maps.

Safety Parameters
Adverse events, symptom checklist, vital signs, physical, neurological examination and laboratory tests.

Statistical
As specified in the protocol. Additionally, many other statistical considerations analyses not specified in the protocol will be carried out on this data set.