Dapagliflozin In Alzheimer's Disease

This is a double-blind, randomized, placebo-controlled, parallel group, 12-week study
performed at a single site (University of Kansas Alzheimer's Disease Center) to investigate
the effect of dapagliflozin in participants with probable AD (MMSE 15-26 inclusive). A total
of 48 participants will be enrolled with 2:1 randomization to 10mg dapagliflozin once daily
(n=32) for 12 weeks vs matching placebo (n=16).

The primary objective of the study is to assess the effect of 12 weeks of 10mg dapagliflozin
once daily on cerebral NAA (a proxy measure of mitochondrial mass) in participants with AD.

Procedures will include phlebotomy, urine collection, MRI/MRS, FDG-PET, cognitive testing,
DEXA scanning, and indirect calorimetry at baseline and 12 weeks to assess these outcomes:

- N Acetyl-Aspartate (NAA): Cerebral NAA (as measured by MRS) and Systemic NAA levels (in
blood and urine)

- Cerebral metabolism (by FDG PET)

- Systemic metabolic effects: Lipids (total cholesterol, LDL, HDL), Plasma
beta-hydroxybutyrate, Insulin resistance (Hemoglobin A1c, glucose and insulin during
tolerance testing), Catabolic/Anabolic state [activated AKT and MTOR], Mitochondrial
function measures [platelet cytochrome oxidase and citrate synthase], Inflammatory
mechanisms [MCP-1, eotaxin, TNF alpha, CRP], Body composition (DEXA scanning for fat and
lean mass), Resting metabolic rate (indirect calorimetry),

- Cognitive effects will be assessed at baseline and week 12 using the Alzheimer's Disease
Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14) and individual tests of Logical
Memory I and II, Trailmaking A and B, and Stroop Word Color Test.

- 12 participants will be enrolled in an optional MRI/MRS sub-study with repeat MRI/MRS
prior to randomization to assess scan-rescan reliability of the NAA measure.

Safety and tolerability of dapagliflozin (10mg daily) will be monitored throughout the study
and formally at every study visit to assess the incidence and severity of AEs and the rate of
discontinuations due to AEs. Safety assessments will include measuring vital signs and body
weight, safety labs (including a comprehensive metabolic panel [CMP] and complete blood count
[CBC] with differential) and physical and neurological examinations at screening and at end
of treatment (EOT).

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.

2. Have a diagnosis of probable AD per McKhann et al. criteria

3. Have a body mass index (BMI) ≥23

4. Age 50-85

5. Have a Mini Mental Status Exam (MMSE) score of 15-26 (inclusive) at screening visit

6. Have a reliable and competent study partner who is willing to accompany the
participant to all study visits, monitor compliance of study medication
administration, and observe/report any changes in the participant's health throughout
the study duration

7. Are on stable doses of concurrent medications for at least 4 weeks prior to the
screening visit

8. Speaks English as his/her primary language.

9. Females of child-bearing potential (i.e., pre-menopausal) must have a negative urine
pregnancy test at the screening visit and must agree to use of contraception
throughout the trial and for 30 days after the last dose of study medication. The
approved methods of contraception are abstinence, the consistent use of an approved
oral contraceptive (birth control pill or "the pill"), an intrauterine device (IUD),
hormonal implants, contraceptive injection, double barrier method (diaphragm with
spermicidal gel or condom with contraceptive foam).

Exclusion Criteria:

1. Received an investigational product in another clinical study during the last 4 weeks
prior to screening

2. Diagnosis of Type 1 diabetes

3. Diagnosis of Type 2 diabetes treated with insulin, sulfonylureas, glucagon like
peptide1 receptor agonists (GLP-1), thiazolidinedione (TZD) or SGLT2 inhibitors
(metformin monotherapy is allowed).

4. Estimated Glomerular Filtration Rate (eGFR; MDRD) <60 mL/min at screening or unstable
renal disease.

5. Any condition when MRI is contraindicated such as, but not limited to, having a
pacemaker or claustrophobia.

6. Severe hepatic injury and/or significant abnormal liver function defined as aspartate
aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase
(ALT) >3x ULN16. Total bilirubin >2.0 mg/dL (34.2 μmol/L)

7. Intolerance or allergy to dapaglifozin or any other SGLT2 inhibitor or any other
substance in the tablets.

8. Dementia due to causes other than AD

9. History of recurrent urinary tract infection

10. Active mycotic genital infection

11. History of bladder cancer

12. History of diabetic ketoacidosis

13. Potentially confounding, serious, or unstable medical conditions such as:

1. cancer within the past 3 years (except basal cell, squamous cell, or localized
prostate cancer)

2. a recent cardiac event (i.e. heart attack, angioplasty, etc. within the 3 months
prior to screening visit)

3. other conditions that pose a potential safety risk or confounding factor in the
investigator's opinion

14. Any abnormal physical examination assessment or vital sign assessment at the screening
visit that is deemed to be clinically significant by the principal investigator.

15. Any abnormal clinical laboratory test result at the screening visit that is deemed to
be clinically significant by the principal investigator.