Not all persons who have a high genetic risk for Alzheimer's disease (AD) become symptomatic, even those who reach extreme old age (e.g., 90+ years old). This observation suggests that genetic vulnerability to AD is moderated by other factors. Identifying these factors, particularly those that are modifiable, could lead to effective AD treatments and risk reduction strategies. We conjecture that peripheral chronic low-grade inflammation is a major factor that influences expression of AD-related genes. Further, we hypothesize that AD risk genes affect proinflammatory reactions in both peripheral and central systems that accelerate accumulation of AD-related pathologies in the brain. This idea is supported by our recent Framingham Heart Study (FHS) investigation of longitudinal measurements of C-reactive protein (CRP) from which we derived a threshold to define chronic low-grade inflammation (CLI) as a chronic proinflammatory burden. We found that CLI was associated with increased risk and earlier onset of AD among APOE ?4 carriers [1]. In addition, some AD risk genes influence both AD risk and peripheral inflammation. For example, PLXNA4 variants are associated with AD risk [2] and PlxnA4 also has a role in inflammatory processes. The central hypothesis for this study is that genetic vulnerability in concert with CLI has an important role in AD pathogenesis. To test this hypothesis, we will capitalize on the comprehensively characterized FHS cohort and its associated brain bank and prospective serial AD-related brain MRI and biomarker data to evaluate the correlation of CLI with changes in cognition and brain structure, as well as with incident AD, up to several decades later. Specifically, we will 1) Evaluate the association of genetic variants with AD risk in the presence of chronic peripheral inflammation in the FHS cohort; 2) Identify blood biomarkers associated with AD among FHS participants with AD genetic risk variants and CLI, and evaluate their correlation with AD-related brain pathology; 3) Validate associations established in Aims 1 and 2 between AD-related peripheral and brain inflammation in other datasets including the Alzheimer Disease Genetic Consortium cohorts, the Alzheimer Disease Neuroimaging Initiative, Knight Alzheimer's Disease Research Center at Washington University, and the Korean National Center for Research in Dementia. If we find differences in the incidence of AD based on biomarker profiles between carriers and non-carriers of particular AD-associated genetic variants among persons who have CLI, our study will provide rationale for the mechanisms of AD genetic risk for the disease. We anticipate that results from this study will provide insight for developing a personalized approach for treating and preventing AD.
