AbstractWe sought to determine whether the biomarkers of chronic inflammation predict cognitive decline in a prospective observational study. We measured baseline serum soluble urokinase plasminogen activator receptor (suPAR) and high sensitivity C‐reactive protein (hs‐CRP) levels in 282 participants of the University of Michigan Memory and Aging Project. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and the Clinical Dementia Rating (CDR) scale for up to five time points. SuPAR and hs‐CRP levels were not significantly higher in participants with mild cognitive impairment (n = 97) or dementia (n = 59), compared to those with normal cognitive function (n = 126). Overall, 14% of participants experienced significant cognitive decline over the study period. The change in MoCA or CDR scores over time did not differ significantly according to baseline suPAR or hs‐CRP levels. Chronic systemic inflammation, as measured by serum suPAR or hs‐CRP levels, is unlikely to contribute significantly to cognitive decline.