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 braineperiphery 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.