Role of Systemic Inflammation in Cognitive Decline: Rheumatoid Arthritis as a Prototype

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PROJECT SUMMARY/ABSTRACT Age-related increase in the burden of systemic inflammation is a key player and potential treatment target in Alzheimer’s disease (AD) and other age-related dementias. Rheumatoid arthritis (RA) is an autoimmune hyper- inflammatory disease and an excellent model for understanding the role of chronic inflammation and autoimmunity in cognitive decline and the modulating effects of anti-rheumatic therapies. Longitudinal studies on the magnitude of the risk and timing of dementia in chronic inflammatory conditions such as RA are lacking, resulting in a substantial knowledge gap. Chronic inflammation precedes the onset of dementia. Furthermore, growing evidence suggests a protective effect of anti-rheumatic medications on AD. We propose to utilize data from existing cohorts of patients with RA and matched comparators without RA (R01 AR046849) to quantify and compare the risk of dementia in RA vs. non-RA participants and to define the role of chronic systemic inflammation in cognitive decline using RA as a prototype. We will determine the impact of chronic systemic inflammation and anti-rheumatic treatments on dementia in RA patients, adjusting for important confounders (age, sex, education, socio-economic status, smoking, obesity, cardiovascular disease, depression). Additionally, using the Mayo Clinic Study of Aging resources (U01 AG006786), we will define change of cognitive function and neuroimaging markers in patients with RA according to the level of inflammation and use of anti-rheumatic treatments. Successful completion of the proposed series of studies will be a key step towards understanding whether chronic exposure to systemic inflammation has adverse cognitive effects and whether tight control of systemic inflammation with anti-rheumatic treatments has protective effects. Our existing cohorts offer a rare opportunity to efficiently address this knowledge gap. Potential downstream effects are significant, including new strategies for prevention and management of dementia in patients with RA and new insights for future studies on prevention of dementia in the general population.