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. 2021 May:94:299-307.
doi: 10.1016/j.bbi.2021.01.010. Epub 2021 Jan 22.

Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults

Daniel S Albrecht  1 , Abhay Sagare  2 , Maricarmen Pachicano  2 , Melanie D Sweeney  2 , Arthur Toga  1 , Berislav Zlokovic  2 , Helena Chui  3 , Elizabeth Joe  3 , Lon Schneider  3 , John C Morris  4 , Tammie Benzinger  4 , Judy Pa  5
Affiliations

Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults

Daniel S Albrecht et al. Brain Behav Immun. 2021 May.

Abstract

CNS inflammation is a key factor in Alzheimer's Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults. Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [18F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [18F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions. Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF-Aβ/tau relationships. Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate.

Keywords: Amyloid-β; Chemokine; Cytokine; Glial activation; Neuroinflammation; PET imaging; Tau.

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Conflict of interest statement

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Aβ PET is negatively correlated with inflammatory markers. Clusters shown in blue colorscale depict significant negative correlations between FBP SUVR and CSF IL-6 (A) and IL-8 (B). For visualization, average FBP SUVR was extracted from significant clusters and plotted against CSF IL-6/IL-8, after correcting for age, sex, and APOE4 status. PFC: prefrontal cortex; SMG: supramarginal gyrus; S1/M1: primary somatosensoiy/motor cortex; IFG: inferior frontal gyrus. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2.
Fig. 2.
Tau PET is negatively correlated with CSF inflammatory markers. Clusters shown in blue colorscale depict significant negative correlations between FTP SUVR and CSF TNFα (A) and IL-8 (B). For visualization, average FTP SUVR was extracted from significant clusters and plotted against CSF TNFα/IL-8, after correcting for age, sex, and APOE4 status. MTL: medial temporal lobe; EC: entorhinal cortex; ITG/MTG/STG: inferior/middle/superior temporal gyrus; IPL: inferior parietal lobule; dlPFC: dorsolateral prefrontal cortex; ACC: anterior cingulate cortex; OFC: orbitofrontal cortex; R: right; LA: left anterior; LP: left posterior. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3.
Fig. 3.
Significant interactions between APOE4 and IL-8 on Aβ and tau PET. Clusters shown in blue colorscale depict significant interactions between APOE4 status and IL-8 on FBP SUVR (A) and FTP SUVR (B). For visualization, average FBP/FTP SUVR was extracted from significant clusters and plotted against CSF IL-8, after correcting for age, sex, and APOE4 status. APOE4 carriers are shown in orange, non-carriers are shown in blue. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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