The Association of Circulating Immune Cells with Cognitive Function, Brain Imaging, and Incident All-cause and Alzheimer's Dementia: The Framingham Offspring Study

Emerging evidence supports the central role of the immune system in brain health, yet little is known about the role of circulating immune cells and cognitive function or brain health in dementia-free populations. We investigated the association of 43 immune cells with cognitive function, structural brain imaging, and incident dementia in Framingham Heart Study Offspring participants. Immune cells were phenotyped by flow cytometry. Linear mixed effects models were used for cross-sectional associations between immune cells and 4 cognitive domain scores and 13 brain magnetic resonance imaging measurements. Cox proportional hazards regression models tested the relationship between immune cells and time to dementia. Models were adjusted for age, sex, education, cytomegalovirus status, and APOE genotype, with further adjustment for cardiovascular risk factors. Data was further stratified by cytomegalovirus status. Among 795 participants with cellular phenotyping, cognitive testing and brain imaging data (mean age 61, 52% women), there were no associations between immune cells and cognitive test scores. Several significant associations between immune cells and regional brain magnetic resonance imaging measurements were observed. Higher CD8+ cells [CD8+CD45RO-CCR7-CD27-(Teff), CD8+CD45RA+CD28-CD57+(TEMRA), CD8+CD27-CD28-] associated with greater cerebrum gray and frontal gray matter volumes and inclusion of cardiovascular risk factors strengthened the association. Among CMV+ participants, CD8+TEMRA and CD8+Teff cells were significantly associated with higher total gray and frontal gray matter volumes. No significant associations were observed between immune cells and incident all-cause or Alzheimer's disease dementia. The pathobiology underpinning the associations between immune cells and brain volumes require further study and validation in diverse samples.