ABSTRACT Alzheimer’s disease (AD) and related dementias are heterogeneous multifactorial diseases, in which many etiopathogenic mechanisms are involved, eventually leading to neuronal death and loss of cognitive function. Numerous attempts are made to arrest the disease, or to slow down its progression by directly targeting its major hallmarks - amyloidosis, pathological neurofibrillary tangles, and local neuroinflammation; none have shown major clinical improvement to date. A novel, paradigm-shifting approach for treating AD and other neurodegenerative disorders is to harness the body’s own mechanisms of maintenance and repair. Among such common pathways is the systemic immune response, which has been shown to display supportive effects on brain maintenance, plasticity and repair. Studies initiated by the laboratory of Prof. Michal Schwartz at the Weizmann Institute of Science in Israel and supported by others, over two decades, have illuminated our understanding of the intricate relationships between the brain and the peripheral immune system, and have demonstrated the potential for benefit of leveraging the brain-immune relationship for the treatment of AD and neurodegeneration. ImmunoBrain Checkpoint (IBC) is proposing to conduct a first-in-human (FIH) study in AD using its novel immunotherapy approach of targeting the peripheral immune system by transient blockade of the inhibitory immune checkpoint, Programmed death-ligand 1 (PD-L1). The pre-clinical pharmacological studies with various mouse models for AD and dementia revealed that single antibody administration was sufficient to evoke a cascade of events leading to a reduction in brain pathology and restoration/maintenance of cognitive abilities. These studies indicated that the therapeutic disease-modifying effect of anti-PD-L1 antibody administration requires intermittent repeated injections of a short-lived antibody with long intervals between successive injections. These observations set the basis for IBC’s uniquely engineered antibody, IBC-Ab002, and for the proposed FIH clinical study design. IBC is proposing to conduct a FIH study to evaluate the safety, tolerability and pharmacokinetics and preliminary exploratory activity of IBC-Ab002 in persons with Early AD. The planned study will be a randomized, double-blind, placebo-controlled study of escalating multiple IV doses, combining Single- and Multiple- Ascending Dose components. The study will have an adaptive design and will be carried out in 2 parts. Parts A will comprise a Single-Ascending-Dose (SAD) study and Part B will continue dosing of Part A subjects as a Multiple-Ascending Dose (SAD) study, with 12 weeks interval between administrations. Data emerging from this study will be used to support decisions regarding further clinical development of IBC- Ab002, most importantly the setting of dose, dose interval and biomarker collection strategy for any future Phase 2 studies.