Biomarker Qualification for Risk of Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease (AD) and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset

Inclusion Criteria:

1. In the opinion of the investigator, participant is capable of understanding andcomplying with protocol requirements.

2. Signs and dates a written, informed consent form and any required privacyauthorization prior to the initiation of any study procedures.

3. Is able to physically perform the cognitive tests in the opinion of the investigatorand is fluent in the language that tests will be administered.

4. Is cognitively normal at baseline, scoring as indicated for the following tests:

• Clinical Dementia Rating (CDR)=0.

• At least one memory test above -1.5 standard deviation (SD) of thedemographically corrected normative mean.

5. Must score ≥25 on the Mini-Mental State Examination (MMSE) at the screening visitafter the education and age adjustment.

6. Is male or postmenopausal female between the ages of 65 and 83 years, inclusive, attime of the Screening visit.

7. Has the ability and intention to participate in regular study visits, in the opinionof the Investigator.

8. Has a project partner who can separately complete an Acknowledgement Form on his/herown behalf and take part in the study (with the intent to do so as long as theparticipant is enrolled) to provide information on the cognitive, functional, andbehavioral status of the participant and to assist with monitoring of studymedication, if needed.

Exclusion Criteria:

1. Has a current diagnosis or history of any type of cognitive impairment or dementia orhas a current diagnosis or history of neurological/psychiatric disorder or any otherdiagnosis that significantly affects cognitive performance (eg, mental retardation,organic mental disorder).

2. Has a current diagnosis of significant psychiatric illness, per Diagnostic &Statistical Manual of Mental Disorders, 4th Edition - Text Revision (DSM-IV-TR) (orDSM-V when published) (including but not limited to major depressive disorder, anxietydisorders) and is in an acute phase/episode, or the participant has a currentdiagnosis or history of schizophrenia or bipolar disorder.

3. Has a glycosylated hemoglobin (HbA1c) >8.0% at the time of baseline or requirestreatment with insulin, triple oral antidiabetic therapy or a peroxisomeproliferator-activated receptor-gamma (PPAR-γ) agonist. The participant should be on astable antidiabetic regimen for at least 3 months prior to enrollment.

4. Has a clinically significant unstable illness, for example, hepatic impairment orrenal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/pgastric bypass), endocrine, neurological, rheumatologic, immunologic, infectious, skinand subcutaneous tissue disorders, or metabolic disturbance. History of HIV infectionis considered exclusionary for this study.

5. Has a history of drug abuse (defined as any illicit drug use) or a history of alcoholabuse/dependence within 2 years prior to the Screening Visit.

6. Is an immediate family member, testing center employee, or is in a dependentrelationship with a testing center employee who is involved in conduct of this study (eg, spouse, parent, child, and sibling) or may consent under duress.

7. Has a history of hypersensitivity or allergies to pioglitazone or related compounds.

8. Is required to take excluded medications as specified in the Excluded MedicationsSection.

9. Had any of the following values at the Baseline Visit (Visit 2):

10. A serum total bilirubin value >1.5× upper limit of normal (ULN).

11. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2xULN.

12. Unexplained microscopic/macroscopic hematuria on one repeat examinations within 2weeks of the initial assessment.

13. Is positive for either Hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) antibodies at the Baseline Visit (Visit 2).

14. Has a condition or takes medication that, in the opinion of the Investigator, couldinterfere with the assessments of safety, tolerability, or efficacy, or prevent theparticipant from adequately participating in the study or continue for the anticipatedduration of the study.

15. Has received any investigational compound within 30 days prior to screening or 5half-lives prior to Screening or is currently participating in another study whichentails the administration of an investigational or marketed drug, supplement orintervention including, but not limited to diet, exercise, lifestyle or invasiveprocedure.

16. Has a history of any cancer that has been in remission for less than 2 years from theScreening Visit. Participants with basal cell or stage I squamous cell carcinoma ofthe skin will be eligible. Participants with history of bladder cancer are noteligible irrespective of the remission status.

17. Has a history or current diagnosis of macular edema or macular degeneration.

18. If female, has a history of postmenopausal fractures with no or minimal trauma (eg,wrist, hip, lumbar or thoracic vertebral fracture).

19. Has a history or current diagnosis of congestive heart failure (CHF), New York HeartAssociation Class III-IV.

20. Has been exposed to the cognitive tests performed in this study within 6 months priorto the Screening Visit, with the exception of the MMSE.

21. Participant's Translocase of the Outer Mitochondrial Membrane 40 homolog (TOMM40)rs10524523 or apolipoprotein E (APOE) genotypes or APOE phenotype are known by theparticipant or the study staff participating in this study.