BackgroundMen and women experience large disparities in prevalence, detection, and clinical course of neurodegenerative diseases. Inflammation has been implicated in the pathogenesis of neurodegenerative diseases, yet there is a paucity of literature documenting sex differences in this phenomenon in prospective, longitudinal studies.MethodsParticipants were 4217 non-smoking individuals (62.2% female; aged 46-91 at enrollment) enrolled in the Health and Retirement Study who provided dried blood spots and completed a standardized assessment of cognitive function 3 times across 8 years. Inflammation was indexed using C-reactive protein (CRP).ResultsHigher CRP was associated with lower concurrent cognitive function, b = -0.13 (SE = 0.06), p < .05, but less decline in cognitive function over time, b = 0.02 (SE = 0.01), p < .05. Sex moderated the association between CRP and decline in total cognitive function, b = 0.02 (SE = 0.01), p < .05, such that the steepest declines in cognitive function were observed among women with the lowest CRP concentrations.ConclusionsWomen with lower systemic inflammation as measured by CRP may be at risk of going undetected for neurodegenerative disease, especially given their overall higher cognitive scores. This may perpetuate sex-related disparities in prevention and clinical course. Attention to the underlying biological mechanisms explaining the link between lower CRP and risk for cognitive decline for women and its potential clinical implications are needed.