A Phase 2a Study to Evaluate the Effect of Rilapladib (SB-659032) in Alzheimer's Disease

Inclusion Criteria: 1. A clinical diagnosis of possible Alzheimer's disease in accordance with the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria, with radiological (Magnetic Resonance Imaging \[MRI\] or Computed Tomography \[CT\]) evidence of significant cerebrovascular disease (CVD), assessed within the last 12 months 2. Male or female between 50 and 80 years of age inclusive, at the time of signing the informed consent. 3. Subject has a documented history of at least 6 months of ongoing Alzheimer's disease therapy (AChEIs and/or memantine) with stable dosing for at least the last 2 months (and with no intent to change for the duration of the study). 4. Mini-Mental Status Examination (MMSE) score between 20 and 26 at Screening. 5. Clinical Dementia Rating Scale (CDR) score of 0.5 or 1.0 at Screening. 6. A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea; or of child-bearing potential and agrees to use acceptable contraception methods 7. Subject has provided full written informed consent prior to the performance of any protocol-specified procedure; or if the subject is unable to provide informed consent due to cognitive status, the subject will provide assent and full written informed consent will be provided by a legally acceptable representative 8. The subject has a dedicated caregiver who is willing to supervise participation in the study 9. In the opinion of the investigator, the subject has the ability to comply with study procedures (cognitive and other testing) and is fluent in the language used for the administration of the cognitive tests. Exclusion Criteria: 1. History and/or evidence of any other CNS disorder that could be interpreted as a cause of dementia: e.g. structural or developmental abnormality, epilepsy, infectious, degenerative or inflammatory/demyelinating CNS conditions such as, Parkinson's disease and frontotemporal dementia 2. History of significant psychiatric illness such as schizophrenia or bipolar affective disorder that in the opinion of the Investigator would interfere with participation in the study; major depressive disorder (according to DSM-IV) in the past year; current active depression requiring initiation of treatment (or is believed to account for substantial degree of cognitive impairment) 3. Evidence of the following disorders: current vitamin B12 deficiency, positive syphilis serology (unless neurosyphilis was ruled out) or active thyroid dysfunction (particularly suggestive of hypothyroidism), including abnormally high or low serum levels of thyroid stimulating hormone (TSH), where this is thought to be the cause of, or to contribute to the severity of the subject's dementia. 4. History of alcohol or other substance abuse, according to the DSM-IV criteria, or recent or remote history of the same if that could be a contributing factor to dementia. 5. History of intra cerebral haemorrhage due to any of the following causes: cerebral amyloid angiopathy, uncontrolled hypertension, cerebral arteriovenous malformation, coagulopathy, CNS vasculitis or any other condition that the investigator and/or medical monitor considers as a relevant risk factor for intracerebral haemorrhage 6. Recent (i.e.,\<6 months from Screening Visit) cardiovascular event defined as: 1. ST-elevation MI or non-ST-elevation MI, confirmed by cardiac enzyme elevation and ECG changes 2. coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft ) 3. stroke of any etiology 4. resuscitated sudden death 5. prior carotid surgery or stenting procedure 7. Poorly controlled hypertension despite lifestyle modifications and pharmacotherapy (either systolic blood pressure \>160mmHg or diastolic blood pressure \>110mmHg) 8. QTcB interval \>450 msec; or QTcB \> 480 msec in subjects with bundle branch block based on ECG assessment at the Screening visit. 9. HbA1c \>12.0 at Screening, or uncontrolled diabetes in the opinion of the investigator. 10. History of glaucoma or any other findings in the baseline eye exam that, in the opinion of the investigator, would exclude the subject from participation in the study. 11. History of adult asthma (or reactive airway disease) manifested by bronchospasm in the past 6 months, or currently taking regular anti-asthmatic medication(s). 12. Previous history of anaphylaxis, severe allergic reaction or history of hypersensitivity to any of the components of the formulation. 13. Significant abnormalities on clinical chemistry, haematology or urinalysis at Screening, including clinically significant anaemia. 14. History of chronic viral hepatitis (including presence of B surface antigen or hepatitis C antibody), or other chronic hepatic disorders. 15. Abnormal Screening blood tests exceeding any of the limits defined below: 1. Alanine transaminase (ALT) or aspartate transaminase (AST) \>1.5 x the upper limit of normal (ULN) 2. Alkaline phosphatase (AP) and bilirubin \>1.5X ULN (isolated bilirubin \>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). 3. Calculated creatinine clearance \< 30 ml/min (per Cockcroft \& Gault) at Screening 16. Other clinically significant abnormality on physical (including neurological), laboratory or ECG examination that could be detrimental to the subject in the opinion of the Investigator or could compromise the integrity of the study. 17. Planned major surgery within the study period. 18. Use of systemic steroids or other immunosuppressants within the last 30 days prior to screening. 19. Current treatment with barbiturates, MAO inhibitors, butyrophenones, phenothiazines and other "conventional" antipsychotic within 30 days or 5 half-lives prior to Screening, whichever is longer. 20. Treatment with antidepressants, (other than MAO inhibitors), thyroid hormones, atypical antipsychotics (e.g. risperidone), benzodiazepines and other sedatives / hypnotics unless prescribed at a stable dose for at least 2 months prior to Screening. Note: Benzodiazepines or other sedatives/hypnotics (including antihistamines) with half-life less than 6 hours can be taken on a prn (as needed) basis but must not be taken within 5 half lives prior to cognitive testing. 21. Current treatment with known potent inhibitors of CYP3A4 (e.g. ketoconazole, rifampin, modafinil). 22. Current treatment with known potent Pgp inhibitors (itraconazole, ketoconazole, cyclosporin, loperamide, diltiazem, verapamil, spironolactone, quinidine, bepridil, quinine, carvedilol) 23. Cognitive tasks prescribed for cognitive rehabilitation and performed under medical supervision in the 6 months prior to screening and/or during study 24. Investigational medications or devices including symptomatic AD treatment during the 60 days prior to the Screening visit, or within 5 half-lives of use of the investigational drug prior to the Screening Visit, whichever is longer. 25. Participation in another investigational drug (with the exception of anti-amyloid monoclonal antibodies \[mAbs\]) or device study where subject was treated chronically (i.e. \> 1 single dose) with a study agent intended to impact AD progression during the 12 months prior to the Screening visit. 1. Subjects who participated in an investigational drug study that involved chronic dosing with a monoclonal antibody at any time in the past are excluded from this study, unless it is known that they received placebo during the previous study. 2. Subjects who participated in previous single-dose studies of anti-amyloid mAbs will be permitted provided the subject's dose of the mAb is at least 5 half-lives removed; the subjects did not experience any moderate adverse events classified as possibly drug-related or any serious adverse event during that study; the subject did not drop out of the previous study (i.e. completed all safety assessments) 26. Subjects, who in the investigator's judgement, pose a significant suicide risk (e.g. history of suicidal behaviour in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months). 27. Subject or caregiver is an immediate family member or employee of the participating Investigator, any of the participating site staff or GSK staff. 28. Any contraindication to lumbar puncture or insertion of CSF catheter, including but not limited to 1. Thrombocytopenia or other coagulation disorders (including subjects receiving coumarin-derived anti-coagulants or low-molecular-weight heparin). 2. The presence of cutaneous or soft tissue infection overlying or adjacent to the site of lumbar puncture. 3. Previous spinal surgery that could complicate access to the subarachnoid space. 4. Suspicion of increased intracranial pressure due to a cerebral mass.