Neurodegenerative disorders are characterized by increasing deterioration and destruction of neurons in the CNS. Immune system failure is the hallmark of neurodegenerative disorders. There is substantial evidence that pathogenic alterations occur gradually in both the central and peripheral immune responses. It has been commonly assumed that the BBB establishes an immunologically favoured surrounding in the CNS via preventing peripheral immune cells and humoral immune components from entering the CNS. Peripheral-produced cytokines can penetrate the BBB, give rise to the stimulation of microglia and astrocytes, and induce direct neurotoxicity. Additionally, peripheral immune cells can invade the brain and contribute in evaluation of neuroinflammation, leading to neurodegenerative disorders. In recent years, neuroinflammation has attracted considerable interest as a therapeutic target for a variety of such conditions. This book chapter focuses on the growing roles of PIS and CIS in neurodegenerative disorders, as well as interconnections. A deeper awareness of the immune system’s increasing significance in neurological disorders could enhance therapeutic options. Through this chapter, an effort has been made to emphasize the interplay between peripheral and central immunological alterations to combat neurodegenerative disorders.