Background: Both Alzheimer's disease (AD) and the inflammatory response are under strong genetic control. Accumulating evidence suggests that inflammatory risk factors are associated with AD. However, it remains to be established whether these inflammatory risk factors lead to AD or are a consequence of AD. In subjects with AD, markers of inflammation are found in and around amyloid plaques. Moreover subjects with cognitive impairment and AD exhibit a pro-inflammatory cytokine response upon stimulation in whole blood samples. However, causal inference on these data is troublesome. Apart from genetic studies or prospective studies with a very long follow-up, it is not possible to tackle the problem of reversed causality, i.e. that a pro- inflammatory response leads to AD or is a consequence of AD. Although very appealing, the current strategy to find inflammatory polymorphisms involved in AD, has not been able to identify these polymorphisms effectively. We can circumvent the problem of reversed causality, by using a unique family design in which the inflammatory response of the patient will be estimated in first-degree relatives. Such an analysis favors a causal interpretation of the association, as the cytokine response cannot be the result of disease. Objective: To determine inflammatory profiles in the offspring of subjects with AD and in the offspring of old subjects with optimal cognitive function, to test if an innate pro-inflammatory reaction contributes to the development of AD.
Specific aims : Whether pro-inflammatory cytokines and chemokines are higher in children of subjects with AD compared to children of subjects without AD, and whether anti- inflammatory markers are lower. Methods: Inflammatory cytokines and chemokines are measured in children (n=230) of subjects with AD and in children (n=230) of subjects with optimal cognitive function. Subjects with AD are recruited from nursing homes. Subjects with optimal cognitive function are recruited from two Dutch population-based studies. Cytokine production levels are assessed with an ex vivo whole blood assay. Relevance: By studying the inflammatory response in the offspring of subjects with Alzheimer's disease (AD), we can answer whether inflammatory risk factors lead to AD or are a consequence of AD. Identification of critical inflammatory pathways resulting in AD opens the way for innovative preventive strategies. ? ?