Siponimod to slow brain shrinkage in early Alzheimer's

Inclusion Criteria:

1. Male or female at least 50 years of age, but less than 85 (84 at time of screening)
2. Females must be of non-childbearing potential or have negative pregnancy test at time of screening. Women of non-childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for \>12 months prior to the planned date of enrollment.
3. Must have a diagnosis of mild Alzheimer's Dementia determined by medical record review.
4. Vision and hearing must be sufficient to comply with study procedures.
5. Be able to take oral medications.
6. Must be able to attend all study visits indicated in the schedule of visits.
7. Must have a collateral informant/study partner who has significant direct contact with the patient at least 10 hours per week and who is willing to accompany the patient to specified clinic visits, supervise administration of all study medication, and be available for telephone visits/interviews.
8. Documented Mini Mental State Exam (MMSE) score between 20-26 at Screening Visit Day 1.
9. CT or MRI scan of the brain within 12 months of Screening Visit Day 1 showing no evidence of significant focal lesions or other pathology which could contribute to dementia. If neither a CT or a MRI scan is available from the past 12 months, a scan fulfilling the requirements must be obtained before randomization.
10. Hachinski ischemic score must be \< 4.
11. Geriatric depression scale must be \< 10.
12. Prior to dosing all randomized study subjects must show proof they have received immunization to varicella (VZV IgG).
13. Each patient must be assessed for capacity to consent by the principal or sub-investigators in order to provide informed consent. If the patient is deemed unable to provide informed consent, they must have a legally authorized representative (LAR), and the LAR must review and sign the informed consent form. If the patient does not have a LAR, the patient must appear able to provide informed consent and must review and sign the informed consent form. If the patient is deemed unable to provide informed consent and does not have a LAR, they cannot participate in the study. In addition, the patient's study partner/informant (as defined in the study inclusion criteria) must sign the informed consent form. If the LAR and the patient's study partner/informant are the same individual, he/she should sign under both.
14. No active suicidality identified on Columbia-Suicide Severity Rating Scale (C-SSRS).
15. Patients with stable prostate cancer may be included at the discretion of the Medical Monitor.
16. Patients who are on monoclonal antibody medication for the treatment of Alzheimer's (ex. lecanemab, donanemab) for \> 6 months or have discontinued monoclonal antibody medication for the treatment of Alzheimer's for \> 6 months may be included if all other criteria has been met.

Exclusion Criteria:

1. Taking one of the following medications: Medications for treatment of cancer or other drugs that weaken the immune system (ex. Natalizumab and Rituximab), Amiodarone, Bishydroxycoumarin, Chloramphenicol, Cimetidine, Fluconazole, Fluvastatin, Miconazole, Phenylbutazone, Sulphinpyrazone, Sulphadiazine, Sulphamethizole, Sulfamethoxazole, Sulphaphenazole, Trimethoprim, and Zafirlukast.
2. Current active infection in participants including, but not limited to, herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection and fungal skin infection. Siponimod may increase the risk in participants with active infections.
3. If participant received mRNA COVID-19 vaccination, must have received last dose at least 3 months prior to first dose of study drug/placebo.
4. Current evidence or history within the last 3 years of a neurological or psychiatric illness that could contribute to dementia, including (but not limited to) epilepsy, focal brain lesion, Parkinson's disease, seizure disorder, or head injury with loss of consciousness.
5. Meets DSM IV criteria for any major psychiatric disorder including psychosis, major depression and bipolar disorder.
6. Known history of or self-reported active alcohol and/ or substance abuse within the past three years.
7. Isolated living circumstances which would prohibit a study partner from providing sufficient and credible information about the participant.
8. Poorly controlled hypertension
9. Known Atrioventricular heart block, known heart block type I-III.
10. History of myocardial infarction or signs or symptoms of unstable coronary artery disease within the last year (including revascularization procedure/angioplasty).
11. Severe pulmonary disease (including chronic obstructive pulmonary disease) requiring more than 2 hospitalizations within the past year.
12. Untreated obstructive sleep apnea.
13. Any thyroid disease (unless euthyroid on treatment for at least 6 months prior to screening).
14. Active neoplastic disease (except for skin tumors other than melanoma) within five years.
15. Absolute lymphocytopenia of \<1,000/mm3, or a history of lymphocytopenia within the past two years.
16. Absolute neutropenia of \<1,000/mm3, or a history of neutropenia within the past two years.
17. History of/ or current thromboembolism (including deep venous thrombosis).
18. Any clinically significant hepatic or renal disease (including presence of Hepatitis B or C surface antigen or an elevated transaminase levels of greater than 2x the upper limit of normal (ULN) or creatinine greater than 1.5 x upper limit of normal (ULN)).
19. Clinically significant hematologic or coagulation disorder including any unexplained anemia, or a platelet count less than 100,000/µL at screening.
20. Use of any investigational drug within 30 days or within five half-lives of the investigational agent, whichever is longer.
21. Unwilling or unable to undergo CT or MRI imaging.
22. In the opinion of the investigator, participation would not be in the best interest of the subject.
23. Subjects with CYP2C9\*3/\*3 genotyping