Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults

Abstract

Introduction: Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aβ), remains unclear.

Methods: We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aβ. We next examined associations between cytokine levels and neuroimaging biomarkers of Aβ/tau/neurodegeneration.

Results: Higher IL-12p70 was associated with slower cognitive decline in the setting of higher Aβ (false discovery rate [FDR] = 0.0023), whereas higher IFN-γ was associated with slower cognitive decline independent of Aβ (FDR = 0.013). Higher IL-12p70 was associated with less tau and neurodegeneration in participants with higher Aβ.

Discussion: Immune dysregulation is implicated in early-stage cognitive decline, and greater IL-12/IFN-γ axis activation may be protective against cognitive decline and early-stage AD progression.

Keywords: Alzheimer's disease; IFN-γ; IL-12; biomarker; cognitive decline; neuroimaging; preclinical Alzheimer's disease.

Figure 1.. Plasma IL-12p70 predicts Aβ-related longitudinal cognition in clinically normal older adults.

(A) Predicted PACC5 trajectory according to baseline Αβ (PiB DVR at baseline) and baseline plasma IL-12p70, from a linear mixed model. Modeled value for the mean baseline age (72.0) was plotted. Higher IL-12p70 was associated with less decline in PACC5 only in the Aβ(+) subgroup. Blue dashed line: PiB DVR=1.08, IL-12p70 −1 s.d.; blue solid line: PiB DVR=1.08, IL-12p70 +1 s.d.; red dashed line: PiB DVR=1.46, IL-12p70 −1 s.d.; red solid line: PiB DVR=1.46, IL-12p70 +1 s.d. (B) Spaghetti plot of longitudinal plasma IL-12p70 measures (log-standardized). Plasma IL-12p70 levels from subsequent years were largely stable compared to baseline levels (year 3: r=0.84, year 5: r=0.85).

Figure 2.. Plasma IFN-γ predicts longitudinal cognition independent of amyloid-β in clinically normal older adults.

(A) Predicted PACC5 trajectory according to baseline Αβ (PiB DVR at baseline) and baseline plasma IFN-γ, from a linear mixed model. Modeled value for the mean baseline age (72.0) was plotted. Higher IFN-γ was associated with less decline in PACC5 in both Aβ(+) and Aβ(−) subgroups. Blue dashed line: PiB DVR=1.08, IFN-γ −1 s.d.; blue solid line: PiB DVR=1.08, IFN-γ +1 s.d.; red dashed line: PiB DVR=1.46, IFN-γ −1 s.d.; red solid line: PiB DVR=1.46, IFN-γ +1 s.d. (B) Spaghetti plot of longitudinal plasma IFN-γ measures (log-standardized). Plasma IFN-γ levels from subsequent years were largely stable compared to the baseline levels (year 3: r=0.51, year 5: r=0.49). PiB DVR= Pittsburgh compound B PET distribution volume ratio from a neocortical composite region of interest (cerebellar gray reference).

Figure 3.. Plasma IL-12p70 and Aβ are interactively associated with lower ITC tau and smaller hippocampal volume

(A) Correlation between plasma IL-12p70 (log-standardized) and IT tau at Year 4 visit (3 years from baseline) in high PiB (PiB DVR>1.324; red solid line) and low PiB (PiB DVR<1.186; blue solid line) subgroups. (B) Predicted HV trajectory according to baseline Αβ (PiB DVR at baseline) and baseline plasma IL-12p70, from a linear mixed model. Modeled value for the mean baseline age (72.0) and mean ICV was plotted. Although individuals with high PiB, high IL-12p70 had smaller baseline hippocampal volume, the rate of longitudinal change was not significantly different compared to individuals with lower PiB or lower IL-12p70. Blue dashed line: PiB DVR=1.08, IL-12p70 −1 s.d.; blue solid line: PiB DVR=1.08, IL-12p70 +1 s.d.; red dashed line: PiB DVR=1.46, IL-12p70 −1 s.d.; red solid line: PiB DVR=1.46, IL-12p70 +1 s.d. HV=hippocampal volume; ICV=intracranial volume; PiB DVR= Pittsburgh compound B PET distribution volume ratio from a neocortical composite region of interest (cerebellar gray reference).