Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way?

•Cognitive impairment in brain diseases is closely associated with the systemic milieu.•The brain–periphery crosstalk holds the key to better understand and treat cognitive decline.•Cognitive and neuroprotective benefits could be achieved by drugs without brain access.•Future CNS drug discovery may need a holistic approach integrating the peripheral factors.

Cognitive impairment is a devastating condition commonly observed with normal aging and neurodegenerative disorders such as Alzheimer's Disease (AD). Although major efforts to prevent or slow down cognitive decline are largely focused within the central nervous system (CNS), it has become clear that signals from the systemic milieu are closely associated with the dysfunctional brain. In particular, the bidirectional crosstalk between the CNS and peripheral immune system plays a decisive role in shaping neuronal survival and function via neuroimmune, neuroendocrinal and bioenergetic mechanisms. Importantly, it is emerging that some neuroprotective and cognition-strengthening drugs may work by targeting the brain–periphery interactions, which could be intriguingly achieved without entering the CNS. We describe here how recent advances in dissecting cognitive deficits from a systems-perspective have contributed to a non-neurocentric understanding of its pathogenesis and treatment strategy. We also discuss the therapeutic and diagnostic implications of these exciting progresses and consider some key issues in the clinical translation.This article is part of a Special Issue entitled ‘Neuroimmunology and Synaptic Function’.