Diseases that cause progressive dysfunction of the brain and neuronal death are truly devastating as they are associated with memory loss, depression, and altered personalities. Most neurodegenerative diseases are associated with the accumulation and misfolding of proteins in specific regions of the CNS, for example amyloid beta in the cortex and hippocampus in Alzheimer’s disease (AD) and alpha-synuclein in the substantia nigra in Parkinson’s disease (PD) and it is generally believed that deposition of these misfolded proteins are causative in the pathogenesis. However, aggregates have also been detected in brain tissue from cognitively normal individuals , suggesting that other factors can drive neural dysfunction and/or loss. While age is the largest risk factor for the development of neurodegenerative diseases, in many cases the disease is influenced by environmental and genetic factors, and experimental, imaging and post-mortem studies of human brains have shown a correlation between microglial activation and behavioural, and cognitive changes prior to neuronal loss . In addition, older patients with comorbidities such as atherosclerosis, type II diabetes or those suffering from repeated or chronic systemic bacterial and viral infections show earlier onset and progression of clinical symptoms [3-6] and recent GWAS studies have identified a number of susceptibility genes linked to both innate and adaptive immunity (e.g. TREM2, CD33, LRRK2, HLA-DR) [7-9]. Collectively these studies provide evidence for a critical role of inflammation in the pathogenesis of a range of neurodegenerative diseases, but the factors that drive or initiate inflammation remain largely elusive. In this chapter we will discuss if, and how, ageing affects immune regulation in the CNS, which additional risk factor(s) contribute to the underlying mechanisms leading to neuronal dysfunction or -loss and whether intervention or immune modulation may be beneficial for those at risk of developing a devastating neurodegenerative disease.