Alzheimer’s disease (AD) is associated with accumulation of amyloid-β plaques and aggregation of tau tangles. In previous reports we have shown that, in both murine models of amyloidosis, AD (5XFAD) and of tauopathy (DM-hTAU), that targeting of the Programmed Death (PD)-1/PD-L1 axis improves the cognitive performance during assessment of short-term spatial and working memory by harnessing the immune system through blocking of the inhibitory immune checkpoint-mediated. Here we performed a full kinetic and dynamic characterisation of resident versus systemic cells recruited into the CNS, which could potentially mediate an important function in disease modification, unravelling their molecular signature by single-cell mass cytometry (CyTOF). CyTOF has enabled us unbiased simultaneous analysis, providing high-resolution proteomic profiles of states and dynamics of microglia and peripheral recruited leukocytes, revealing a remodeling of blood and brain immune compartments in a time-dependent manner upon immunotherapy in AD and dementia. This study provides an approach for deep immune profiling across disease progression after immunotherapy, covering identity, function and immune regulation, while delving deeper in our overall comprehension of the immune landscape in neurodegenerative diseases.