Increasing evidence suggests that Alzheimer’s disease (AD) is not restricted to the aggregated proteins (amyloid and tau), but strongly proposes that immunological mechanisms have a key role in the pathogenesis. The study of the neuroinflammation surrounding this hypothesis is leading to novel findings that genes for brain resident immune cell receptors—microglia—including TREM2 and CD33, are associated with AD. Neuroinflammation not only relies on the innate immune cells that permanently reside in the brain, but also on the peripheral immune cells. Under specific circumstances, peripheral immune cells can enter the brain and have disease-modulating functions. However, little is known about the potential contribution of the immune system outside the brain to AD pathophysiology. Targeting leukocyte trafficking to the brain could, thereby, represent novel therapeutics and diagnostic approaches in AD. Here we propose to use microphysiological systems (also called organs-on-chips) to investigate the relevance of circulating peripheral immune cells trafficking in AD, and investigate the crosstalk between the brain, vascular and peripheral immune system.