Peripheral immune system in aging and Alzheimer's disease

Abstract

Alzheimer's disease (AD) represents an urgent public health mandate. AD is no longer considered a neural-centric disease; rather, a plethora of recent studies strongly implicate a critical role played by neuroinflammation in the pathogeneses of AD and other neurodegenerative conditions. A close functional connection between the immune system and central nervous system is increasingly recognized. In late-onset AD, aging represents the most significant risk factor. Here, from an immunological perspective, we summarize the prominent molecular and cellular changes in the periphery of aging individuals and AD patients. Moreover, we review the knowledge gained in the past several years that implicate specific arms of the peripheral immune system and other types of immune responses in modulating AD progression. Taken together, these findings collectively emphasize a dynamic role of a concert of brain-extrinsic, peripheral signals in the aging and degenerative processes in the CNS. We believe that a systematic view synthesizing the vast amounts of existing results will help guide the development of next-generation therapeutics and inform future directions of AD investigation.

Keywords: Adaptive immune response; Aging; Alzheimer’s disease; Humoral immune response; Immunosignature; Peripheral immune response; Senescence; T cells; T regulatory cells.

Fig. 1

Multifactorial systemic changes are associated with chronological aging and linked to diminished health status. Peripheral aging is promoted by inflammaging, immune cell skewing, senescence, and depletion of youth protective factors. The broad outcome of aging includes increased incidences of infection, autoimmune diseases, and decline of memory and cognitive functions.

Fig. 2

AD pathogenesis is influenced by multiple systemic factors. Aging-induced systemic changes, surveillance by various immune cell populations, and influence of altered systemic immune responses all influence the onset and progression of AD. Understanding the interplay between these elements and AD pathogenesis is crucial for the successful intervention of the disease.