Bi-directional Association of Cerebrospinal Fluid Immune Markers with Stage of Alzheimer’s Disease Pathogenesis

Immune mechanisms may be important in the pathogenesis of Alzheimer’s disease (AD). Yet, studies comparing cerebrospinal fluid (CSF) and plasma immune marker levels of healthy and demented individuals have yielded conflicting results. We analyzed CSF from 101 members of the parental history-positive PREVENT-AD cohort of healthy aging adults, and 237 participants without dementia from the initial cohort of the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1). Following recent practice, we used the biomarkers total-tau and amyloid-β(1-42) to allocate participants from each study into four stages of AD pathogenesis: Stage 0 (no abnormality), Stage 1 (reduced amyloid-β(1-42)), Stage 2 (reduced amyloid-β(1-42) and increased total-tau), or “Suspected Non-Alzheimer Pathology” (elevated total-tau only). Investigating the PREVENT-AD participants’ CSF assay results for 19 immune/inflammatory markers, we found six that showed a distinct bi-directional relationship with pathogenetic stage. Relative to Stage 0, these were diminished at Stage 1 but strongly increased at Stage 2. Among the ADNI participants (90 healthy controls and 147 with mild cognitive impairment), we found that 23 of 83 available CSF markers also showed this distinct pattern. These results support recent observations that immune activation may become apparent only after the onset of both amyloid and tau pathologies. Unexpectedly, they also suggest that immune marker activity may diminish along with earliest appearance of amyloid-β plaque pathology. These findings may explain discordant results from past studies, and suggest the importance of characterizing the extent of AD pathology when comparing clinical groups.