Neuroimmune contributions to Alzheimer's disease: a focus on human data

The past decade has seen the convergence of a series of new insights that arose from genetic and systems analyses of Alzheimer's disease (AD) with a wealth of epidemiological data from a variety of fields; this resulted in renewed interest in immune responses as important, potentially causal components of AD. Here, we focus primarily on a review of human data which has recently yielded a set of robust, reproducible results that exist in a much larger universe of conflicting reports stemming from small studies with important limitations in their study design. Thus, we are at an important crossroads in efforts to first understand at which step of the long, multiphasic course of AD a given immune response may play a causal role and then modulate this response to slow or block the pathophysiology of AD. We have a wealth of new experimental tools, analysis methods, and capacity to sample human participants at large scale longitudinally; these resources, when coupled to a foundation of reproducible results and novel study designs, will enable us to monitor human immune function in the CNS at the level of complexity that is required while simultaneously capturing the state of the peripheral immune system. This integration of peripheral and central perturbations in immune responses results in pathologic responses in the central nervous system parenchyma where specialized cellular microenvironments composed of multiple cell subtypes respond to these immune perturbations as well as to environmental exposures, comorbidities and the impact of the advancing life course. Here, we offer an overview that seeks to illustrate the large number of interconnecting factors that ultimately yield the neuroimmune component of AD.