Inflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer's Disease, dementia, and cognitive disorders. We examined the association of 11 plasma proteins (CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO) related to immune and inflammatory responses with measures of cognitive function, brain MRI and dementia risk. We identified Framingham Heart Study Offspring participants who underwent neuropsychological testing (n = 2358) or brain MRI (n = 2100) within five years of the seventh examination where a blood sample for quantifying the protein biomarkers was obtained; and who were followed for 10 years for incident all-cause dementia (n = 1616). We investigated the association of inflammatory biomarkers with neuropsychological test performance and brain MRI volumes using linear mixed effect models accounting for family relationships. We further used Cox proportional hazards models to examine the association with incident dementia. False discovery rate p-values were used to account for multiple testing. Participants included in the neuropsychological test and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (average 68 years old at baseline) included 124 participants with incident dementia. In addition to CD14, which has an established association, we found significant associations between higher levels of CD40L and myeloperoxidase (MPO) with executive dysfunction. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher levels of sRAGE were associated with larger TCBV. Associations persisted after adjustment for APOE ε4 carrier status and additional cardiovascular risk factors. None of the studied inflammatory biomarkers were significantly associated with risk of incident all-cause dementia. Higher circulating levels of soluble CD40L and MPO, markers of immune cell activation, were associated with poorer performance on neuropsychological tests, while higher CD5L, a key regulator of inflammation, was associated with smaller total brain volumes. Higher circulating soluble RAGE, a decoy receptor for the proinflammatory RAGE/AGE pathway, was associated with larger total brain volume. If confirmed in other studies, this data indicates the involvement of an activated immune system in abnormal brain aging.