The purpose of the study is to determine the highest dose of TPI-287 that is safe and tolerable when administered as an intravenous infusion to participants with mild to moderate Alzheimer's disease (AD), to measure pharmacokinetic properties of the drug as well as to gauge preliminary efficacy of TPI-287 on disease progression.

The maximum tolerated dose of TPI-287 will be determined through a planned dose escalation over 3 sequential cohorts, each comprising of 11 participants randomized to either TPI-287 or placebo. TPI-287 or placebo will be administered as an intravenous infusion once every 3 weeks for 9 weeks, for a total of 4 infusions. Participants who successfully complete this phase will have the option of entering into the open label extension phase during which TPI-287 will be administered once every 3 weeks for an additional 6 weeks, for a total of 3 extra infusions.

Pre-medication of diphenhyramine 25 mg (Benadryl) will be given IV within 30 to 60 minutes prior to each study infusion in the study.

Safety and tolerability will be assessed through reporting of adverse events, physical and neurological testing, ECGs, as well as blood and urine analyses. Baseline and end-point measures of cognition and function, MRI brain scans, and cerebrospinal fluid (CSF) biomarker analyses will be used to determine preliminary efficacy of TPI-287 in mild-moderate AD. Pharmacokinetic and pharmacodynamic properties of TPI-287 will be calculated from blood plasma collected after the first infusion, and from CSF collected on the last visit of the placebo-controlled phase.

Inclusion Criteria (all must be met):

1. Between 50 and 82 years of age (inclusive)
2. Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD dementia (McKhann et al. 2011)
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 26 (inclusive)
6. FDA-approved AD medications are allowed as long as the dose is stable for 2 months prior to Screening. Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to Screening
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 2 lumbar punctures
9. Signed and dated written informed consent obtained from the subject and the subject's caregiver in accordance with local IRB regulations
10. 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 (any one of the following will exclude a subject from being enrolled into the study):

1. Any medical condition other than AD that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia)
2. History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof)
3. History of significant peripheral neuropathy
4. History of major psychiatric illness or untreated depression
5. 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 or baseline evaluations
6. 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
7. Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection
8. Current clinically significant viral infection
9. Major surgery within four weeks prior to Screening
10. Unable to tolerate MRI scan at Screening
11. 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 Screening
12. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule or study evaluations
13. Any previous exposure to microtubule inhibitors (including TPI 287) within 5 years of Screening. Treatment with microtubule inhibitors other than TPI287 while on study will not be allowed
14. Participation in another AD clinical trial within 3 months of Screening
15. Treatment with another investigational drug within 30 days of Screening. Treatment with investigational drugs other than TPI 287 while on study will not be allowed
16. Known hypersensitivity to the inactive ingredients in the study drug
17. Pregnant or lactating
18. Positive pregnancy test at Screening or Baseline (Day 1)
19. Cancer within 5 years of Screening, except for non-metastatic skin cancer.