On the Possible Relevance of Bottom-up Pathways in the Pathogenesis of Alzheimer's Disease

Dementia is an increasing health problem in older aged populations worldwide. Age-related changes in the brain can be observed decades before the first symptoms of cognitive decline appear. Cognitive impairment has chronic inflammatory components, which can be enhanced by systemic immune activation. There exist mutual interferences between inflammation and cognitive deficits. Signs of an activated immune system i.e. increases in the serum concentrations of soluble biomarkers such as neopterin or accelerated tryptophan breakdown along the kynurenine axis develop in a significant proportion of patients with dementia and correlate with the course of the disease, and they also have a predictive value. Changes in biomarker concentrations are reported to be associated with systemic infections by pathogens such as cytomegalovirus (CMV) and bacterial content in saliva. More recently, the possible influence of microbiome composition on Alzheimer's disease (AD) pathogenesis has been observed. These observations suggest that brain pathology is not the sole factor determining the pathogenesis of AD. Interestingly, patients with AD display drastic changes in markers of immune activation in the circulation and in the cerebrospinal fluid. Other data have suggested the involvement of factors extrinsic to the brain in the pathogenesis of AD. However, currently, neither the roles of these factors nor their importance has been clearly defined.