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Cited by 270Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease

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Dani, Melanie, Wood, Melanie, Mizoguchi, Ruth, Fan, Zhen, Walker, Zuzana, Morgan, Richard, Hinz, Rainer, Biju, Maya +3 more·2018·Brain
DOI 10.1093/brain/awy188
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Abstract

Alzheimer's disease is characterized by the histopathological presence of amyloid-β plaques and tau-containing neurofibrillary tangles. Microglial activation is also a recognized pathological component. The relationship between microglial activation and protein aggregation is still debated. We investigated the relationship between amyloid plaques, tau tangles and activated microglia using PET imaging. Fifty-one subjects (19 healthy controls, 16 mild cognitive impairment and 16 Alzheimer's disease subjects) participated in the study. All subjects had neuropsychometric testing, MRI, amyloid (18F-flutemetamol), and microglial (11C-PBR28) PET. All subjects with mild cognitive impairment and Alzheimer's disease and eight of the controls had tau (18F-AV1451) PET. 11C-PBR28 PET was analysed using Logan graphical analysis with an arterial plasma input function, while 18F-flutemetamol and 18F-AV1451 PET were analysed as target:cerebellar ratios to create parametric standardized uptake value ratio maps. Biological parametric mapping in the Statistical Parametric Mapping platform was used to examine correlations between uptake of tracers at a voxel-level. There were significant widespread clusters of positive correlation between levels of microglial activation and tau aggregation in both the mild cognitive impairment (amyloid-positive and amyloid-negative) and Alzheimer's disease subjects. The correlations were stronger in Alzheimer's disease than in mild cognitive impairment, suggesting that these pathologies increase together as disease progresses. Levels of microglial activation and amyloid deposition were also correlated, although in a different spatial distribution; correlations were stronger in mild cognitive impairment than Alzheimer's subjects, in line with a plateauing of amyloid load with disease progression. Clusters of positive correlations between microglial activation and protein aggregation often targeted similar areas of association cortex, indicating that all three processes are present in specific vulnerable brain areas. For the first time using PET imaging, we show that microglial activation can correlate with both tau aggregation and amyloid deposition. This confirms the complex relationship between these processes. These results suggest that preventative treatment for Alzheimer's disease should target all three processes.

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  • Human research indicates that microglia promote beta-amyloids and subsequent tau accumulation, thus having a key role in cognitive decline.

    “Human research indicates that microglia promote beta-amyloids and subsequent tau accumulation, thus having a key role in cognitive decline [90,91].”

    From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [91]

    The Discussion reports correlations between microglial activation and both amyloid deposition and tau aggregation in people with mild cognitive impairment or Alzheimer’s disease. The Figure 6 caption proposes that activated microglia promote amyloid plaques and tangles, but the Discussion says longitudinal studies are needed to establish mechanisms of progression. This cross-sectional human study therefore does not establish the claimed causal sequence or show that microglia drive cognitive decline. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • NFTs are spatially correlated with neuroinflammation in clinical samples from AD patients.

    “NFTs have also been found to be spatially correlated with neuroinflammation in clinical samples from AD patients.45”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [45]

  • In Alzheimer's disease, neuroinflammation correlates spatially with tau aggregation.

    “Here we aim to build on recent in vivo studies of Alzheimer’s disease, which demonstrate that neuroinflammation correlates spatially with tau aggregation (Dani et al., 2018)”

    From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Dani et al., 2018

  • The correlation between regional distributions of neuroinflammation and protein aggregation supports a close relationship between these processes in FTD, mirroring evidence from Alzheimer's disease that neuroinflammation is correlated with tau aggregation, and extending this to TDP-43 associated diseases.

    “The correlation between regional distributions of neuroinflammation and protein aggregation supports a close relationship between these processes in FTD, mirroring recent evidence from Alzheimer’s disease that neuroinflammation is correlated with tau aggregation (Dani et al., 2018), and extending this to TDP-43 associated diseases.”

    From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Dani et al., 2018

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Authors
Dani, M., Wood, M., Mizoguchi, R., Fan, Z., Walker, Z., Morgan, R., Hinz, R., Biju, M., Kuruvilla, T., Brooks, D. J., & Edison, P.
Affiliations
  • Hammersmith Hospital (GB)
  • University College London (GB)
  • Chelsea and Westminster Hospital (GB)
  • University of Manchester (GB)
  • Gether NHS Foundation Trust, Gloucester, UK
  • Aarhus University (DK)
Corresponding author
Edison, Paul
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2018-07-20
Volume
141
Issue
9
Pages
2740-2754
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awy188
OpenAlex
W2806823430
Cited by
270
References
20
Citations by year
2026: 7 · 2025: 34 · 2024: 39 · 2023: 40 · 2022: 51 · 2021: 46 · 2020: 28 · 2019: 23 · 2018: 2
FWCI
17.02
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/about_us/legal/notices (vor, 1 d)
Locations
  • Brain (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Scopus (Elsevier) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion)
Funders
  • Medical Research Council (WMCN_P33428)
  • Alzheimer’s Research UK (WMCN_P23750)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, microglial activation, tau aggregation, amyloid plaques, neurofibrillary tangles, mild cognitive impairment, [11C]PBR28, 18F-flutemetamol, 18F-AV-1451, amyloid PET, tau PET, association cortex, disease progression
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Amyloidosis, Brain, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Microglia, Disease Progression, Positron-Emission Tomography, Plaque, Amyloid, Cognitive Dysfunction

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