Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults
Open accessAbstract
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 [18 F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [18 F]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.
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Early neuroinflammation has been shown to be an adaptive mechanism by microglia that protects against AD pathology by reducing the levels of Aβ and tau.
“Furthermore, early neuroinflammation has been shown to be an adaptive mechanism by microglia that protects against AD pathology by reducing the levels of Aβ and tau.118–120”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [118]
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- Authors
- Albrecht, D. S., Sagare, A., Pachicano, M., Sweeney, M. D., Toga, A., Zlokovic, B., Chui, H., Joe, E., Schneider, L., Morris, J. C., Benzinger, T., & Pa, J.
- Affiliations
- University of Southern California (US)
- Washington University in St. Louis (US)
- Corresponding author
- Pa, Judy
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 94
- Pages
- 299-307
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC8793040
- OpenAlex
- W3125717937
- Cited by
- 37
- References
- 71
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 13 · 2022: 4 · 2021: 2
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P01AG03991, P01AG052350, P50AG05681, R01AG054617, P01AG026276)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neuroinflammation, Alzheimer's disease, amyloid-beta, tau protein, APOE ε4, interleukin-6, interleukin-8, TNF-α, IL-10, 18F-flortaucipir, 18F-florbetapir, positron emission tomography, cognitively normal older adults, medial temporal lobe, frontal lobe
- MeSH terms
- Aged, Alzheimer Disease, Cross-Sectional Studies, Humans, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Cognitive Dysfunction
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