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

This study has two goals. One of these goals is to see if a new genetic test can determine if
participants are at risk of developing Mild Cognitive Impairment due to Alzheimer's Disease
(MCI-AD) within the next five years. The other goal is to evaluate the study drug called
pioglitazone. Pioglitazone is being tested to delay the onset of MCI-AD. This study will look
at the effectiveness of pioglitazone in delaying the onset of MCI-AD in cognitively-normal
people who are at high-risk of developing MCI-AD, as idenfitied by the biomarker in the
non-Hispanic/Latino Caucasian participants. In addition, approximately 300 cognitively normal
elderly participants will participate in a volumetric magnetic resonance imaging (vMRI)
substudy at selected sites. In the vMRI substudy, high-risk participants will be randomized
(5:4) to receive either pioglitazone or placebo.

This multi-centre trial will be conducted worldwide. The study will enroll approximately 3500
subjects. Participants will be assigned to high or low risk groups for developing MCI- AD
within the next five years, based on the results of the biomarker risk algorithm.
Participants in the high risk group will be randomly assigned to one of the two treatment
groups—which will remain unknown to the participant and study doctor during the study (unless
there is an urgent medical need):

- Pioglitazone tablet

- Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has
no active ingredient.

Participants in the low risk group will be assigned to placebo. The assignment of each
participant to the high or low risk group, as well as the participant's treatment assignment,
will remain undisclosed to the participants and study doctor during the study (unless there
is an urgent medical need).

All participants will be asked to take one tablet at the same time each day throughout the
study.

The overall time to participate in this study is approximately 5 years. Participants will
make up to 14 visits to the clinic, and will be contacted by telephone 3 months after each
treatment visit for a follow-up assessment, and 2 weeks after the final visit.

Inclusion Criteria:

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

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

3. Is able to physically perform the cognitive tests in the opinion of the investigator
and 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 stanard deviation (SD) of the demographically
corrected normative mean.

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

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

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

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

Exclusion Criteria:

1. Has a current diagnosis or history of any type of cognitive impairment or dementia, or
has a current diagnosis or history of neurological/psychiatric disorder or any other
diagnosis 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) (or
DSM-V when published) (including but not limited to major depressive disorder, anxiety
disorders) and is in an acute phase/episode, or the participant has a current
diagnosis or history of schizophrenia or bipolar disorder.

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

4. Has a clinically significant unstable illness, for example, hepatic impairment or
renal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/p
gastric bypass), endocrine, neurological, rheumatologic, immunologic, infectious, skin
and subcutaneous tissue disorders, or metabolic disturbance. History of HIV infection
is considered exclusionary for this study.

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

6. Is an immediate family member, testing center employee, or is in a dependent
relationship 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 Medications
Section.

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

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

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

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

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

11. Has a condition or takes medication that, in the opinion of the Investigator, could
interfer with the assessments of safety, tolerability, or efficacy, or prevent the
participant from adequately participating in the study or continue for the anticipated
duration of the study.

12. Has received any investigational compound within 30 days prior to screening or 5
half-lives prior to Screening or is currently participating in another study which
entails the administration of an investigational or marketed drug, supplement or
intervention including, but not limited to diet, exercise, lifestyle or invasive
procedure.

13. Has a history of any cancer that has been in remission for less than 2 years from the
Screening Visit. Participants with basal cell or stage I squamous cell carcinoma of
the skin will be eligible. Participants with history of bladder cancer are not
eligible irrespective of the remission status.

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

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

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

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

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