The purpose of the study is to test the safety and tolerability of twice daily Salsalate in patients with mild to moderate Alzheimer's Disease. Half of the participants will receive Salsalate and half will receive placebo during the 1-year duration of the study.

This is a Phase 1b, 12-month, randomized, double-blind, placebo-controlled study of the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of salsalate in patients with mild to moderate AD. Approximately 40 subjects will be randomized 1:1 to placebo or active. All study drugs will be administered orally bid [two placebo tablets bid or two 750 mg salsalate tablets bid (for a total daily dose of 3,000 mg)] for 12 months.

This study will test the effects of Salsalate on cerebrospinal fluid (CSF) proteins, brain magnetic resonance imaging (MRI), and cognitive (thinking and memory) tests in subjects with mild to moderate AD. This study uses placebo which looks like the experimental drug but does not have any active drug in it.

Inclusion Criteria:

1. Between 50 and 85 years of age (inclusive);
2. Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD dementia (McKhann et al. 2011) (30);
3. MRI at Screening is consistent with AD (≤ 4 microhemorrhages, and no large strokes or severe white matter disease);
4. MHIS at Screening is ≤ 4;
5. MMSE at Screening is between 14 and 30 (inclusive);
6. FDA-approved AD medications are allowed as long as the dose is stable for 2 months prior to initial Screening visit. Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to initial Screening visit;
7. Has a reliable study partner who agrees to accompany the subject to visits, and spends at least 5 hours per week with the subject;
8. Agrees to the lumbar puncture and CSF collection at Screening and after 11.5 months of study drug administration. The lumbar puncture and CSF collection at the end of Month 6 is optional and is not required for eligibility;
9. Positive amyloid PET scan at Screening. Previous amyloid PET scan positivity or previous AD biomarker (Aβ/tau level) positivity may be used instead of performing an amyloid PET scan at Screening at the Investigator's discretion;
10. Signed and dated written informed consent obtained from the subject and the subject's caregiver in accordance with local IRB regulations;
11. Males and all WCBP agree to abstain from sex or use an adequate method of contraception for the duration of the study and for 30 days after the last dose of study drug.

Exclusion Criteria:

1. Any medical condition other than AD that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia);
2. History of negative AD biomarker studies (CSF Aβ/tau levels or amyloid PET), or a negative amyloid PET scan during Screening;
3. History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof);
4. Systolic blood pressure exceeding 180 mmHg or diastolic blood pressure exceeding 100 mmHg at Screening or Baseline;
5. History of peptic ulcer disease or GI bleeding;
6. History of asthma, urticaria, or allergic-type reactions after taking NSAIDs or aspirin;
7. History of aspirin triad (i.e., aspirin allergy, nasal polyps, and asthma);
8. History of autoimmune disorders deemed clinically significant by the Investigator;
9. History of major psychiatric illness or major depression that in the opinion of the Investigator would pose a safety risk or interfere with the appropriate interpretation of study data;
10. Neutrophil count <1,500/mm3, platelets <100,000/mm3, serum creatinine >1.5 x upper limit of normal (ULN), total bilirubin >1.5 x ULN, alanine aminotransferase (ALT) >3 x ULN, aspartate aminotransferase (AST) >3 x ULN, or INR >1.2 at Screening;
11. Evidence of any clinically significant findings on Screening or baseline evaluations which, in the opinion of the Investigator would pose a safety risk or interfere with appropriate interpretation of study data;
12. Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection;
13. Current clinically significant viral infection. Subjects with chicken pox, influenza, or flu symptoms are not eligible;
14. Major surgery within four weeks prior to initial Screening visit;
15. Unable to tolerate MRI scan at Screening;
16. Any contraindication to or unable to tolerate lumbar puncture at Screening, including use of anti-coagulant medications such as warfarin. Daily administration of 81 mg aspirin will be allowed as long as the dose is stable for 30 days prior to initial Screening visit;
17. Chronic use of other NSAIDs or salicylates for any reason, except for daily baby aspirin (81 mg);
18. Chronic use of oral corticosteroids or other immunosuppressants;
19. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule or study evaluations;
20. Participation in another AD clinical trial within 3 months of initial Screening visit or treatment with another investigational drug within 30 days of initial Screening visit;
21. Known hypersensitivity to the inactive ingredients in the study drug (placebo or active);
22. Pregnant or lactating;
23. Positive pregnancy test at Screening or Baseline (Day 1);
24. Cancer within 5 years of initial Screening visit, except for non-metastatic skin cancer or prostate cancer without signs of metastasis

Double-Blind study. Only investigational pharmacist will be unblinded.