SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer's Disease (AD): A Multi-center, Randomized, Double-Blind, Placebo-Controlled Safety and Biomarker Study of Pepinemab Anti-SEMA4D Antibody in Early-AD

• Written informed consent from the participant and legally acceptable representative (trial partner).

• Have a reliable and competent trial partner who must have a close relationship with the participant, who has face to face contact at least three days a week for a minimum of ten waking hours a week and is willing to accompany the participant to all trial visits. The trial partner should understand the nature of the trial and adhere to trial requirements (e.g., dose, visit schedules, receive phone calls, and evaluations).

• Male and female participants between the ages of 55 to 85 (inclusive).

• If female, not be of childbearing potential as indicated by one of the following:

• a. Has reached natural menopause defined as either: i. ≥ 12 months of spontaneous amenorrhea or ii. ≥ 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels \> 40 mIU/ml as determined by the central laboratory; b. Has had a hysterectomy; or c. Has had a bilateral tubal ligation; or d. Has had a bilateral oophorectomy (with or without a hysterectomy) and more than 6 weeks have passed since the surgery.

• If male, must agree to use a reliable method of birth control (condoms with contraceptive forms or sexual abstinence) during the study and for 6 months after the last dose of study drug.

• Must fulfill one of the following:

∙ A documented amyloid PET scan (florbetaben F18, florbetapir F18, or flutametamol F18) determined as positive by the Investigator obtained at any time prior to the Screening visit; or

‣ A documented positive amyloid CSF result obtained at any time prior to the Screening visit; or

‣ Investigator has knowledge of positive amyloid PET scan or positive amyloid CSF result obtained previously; or

‣ A positive amyloid CSF result at screening. The cut-off value for CSF Aβ1-42 or CSF Aβ1-42/Aβ1-40 ratio will be based on the value determined by Vaccinex

• Evidence of cognitive impairment based on history and neuropsychological testing that meet the diagnostic criteria for probable Alzheimer's dementia.

• Global Clinical Dementia Rating (CDR) of 0.5 or 1.0

• MMSE score of 17-26, inclusive.

⁃ Adequate vision, hearing, and motor function to comply with testing.

⁃ If receiving medications for AD (including but not limited to donepezil, rivastigmine, galantamine, tacrine, and memantine), be on a stable dose for at least 8 weeks prior to Screening Visit.

⁃ If on stable doses of centrally-acting medications, be on a stable dose for 8 weeks prior to Screening Visit.

⁃ In the opinion of the Investigator, is in reasonably good health over the last 6 months and any chronic disease is stable based on medical history and screening assessments.