Inflammatory co-morbidities damage the brain. Severe (that is, severe sepsis) or prolonged systemic inflammation (that is, diabetes, atherosclerosis, obesity, arthritis), even when superimposed on the normal healthy brain (left: intact synaptic integrity and normal ramified microglia shown), can activate microglia and contribute to changes deleterious for cognitive function and thus increase dementia risk. Strength of induction of inflammatory mediators is shown in the dashed box and echoed by the red gradient. Similarly, when superimposed upon the already pathological brain (right: comprising β-amyloidosis, synaptic loss, neuronal death (green apoptotic nuclei in red-labelled neurons) and microglial activation), even relatively mild/moderate acute systemic inflammation can switch the phenotype of primed microglial cells to produce robust exacerbation of central nervous system (CNS) inflammation and to produce damage in the brain, which can contribute to long-term cognitive decline. Severe or prolonged inflammation superimposed on the already pathological brain is predicted to have even more deleterious consequences for trajectory of decline. Figure adapted from  and used with permission of Cambridge University Press. BDNF, brain-derived neurotrophic factor.