Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-β in cognitively unimpaired older adults

Abstract

Introduction: Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults.

Methods: A large sample of 139 CU older adults (mean age (range) = 85.4 (82-95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations.

Results: At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions.

Discussion: In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.

Keywords: Amyloid-beta; Cognition; Pittsburgh compound-B PET; Preclinical Alzheimer’s disease; Systemic inflammation.

Figure 1.

A) The relationship between IL-6 and global Aβ was moderated by hippocampal volume, such that higher levels of IL-6 predicted elevated Aβ burden among those with smaller hippocampal volume; B) Interaction between sTNFr2 and hippocampal volume on global Aβ. Hippocampal volume stratified by 1 standard deviation for visualization purposes. Low = > 1 SD below the mean (N = 20), average = within 1 SD (N = 96) high = > 1 SD above the mean (N = 23).

Figure 2.

All variables standardized; Δ global Aβ reflects change in global PiB-PET retention from T₁ to T₂. Abbreviations: Δ = change; Aβ = β-amyloid; PiB = Pittsburgh compound-B

Figure 3.

Scatterplot of associations between Interleukin-6 (log transformed and z-scored) and change in standardized regional PiB-PET retention from T1 to T2. Data stratified by baseline PiB-PET status (PiB-/PiB+). Individual scatterplots depict significant interaction effects for ROI’s, showing that elevated IL-6 predicts greater regional amyloid accumulation among those with pathologic Aβ status at baseline, while change in PiB-PET retention remained stable across varying levels of cytokine expression among those that were PiB-negative. Abbreviations: Δ = change; PiB = Pittsburgh compound-B