Within-patient correspondence of amyloid-β and intrinsic network connectivity in Alzheimer’s disease
Open accessAbstract
There is striking overlap between the spatial distribution of amyloid-β pathology in patients with Alzheimer's disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-β and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-β plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-β exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-β on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-β and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-β on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of intrinsic connectivity and amyloid-β distributions. Here we compared spatial patterns of amyloid-β-plaques (measured by Pittsburgh compound B positron emission tomography) and intrinsic functional connectivity (measured by resting-state functional magnetic resonance imaging) in patients with prodromal Alzheimer's disease via spatial correlations in intrinsic networks covering fronto-parietal heteromodal cortices. At the global network level, we found that amyloid-β and intrinsic connectivity patterns were positively correlated in the default mode and several fronto-parietal attention networks, confirming that amyloid-β aggregates in areas of high intrinsic connectivity on a within-network basis. Further, we saw an internetwork gradient of the magnitude of correlation that depended on network plaque-load. After accounting for this globally positive correlation, local amyloid-β-plaque concentration in regions of high connectivity co-varied negatively with intrinsic connectivity, indicating that amyloid-β pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-β-plaque concentration. The local negative association between amyloid-β and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-β on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-β and intrinsic connectivity, with the distribution of amyloid-β pathology following functional connectivity gradients within and across intrinsic networks.
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A certain overlap between the DMN and the distribution of Aβ fibrils in AD has been noted in previous publications.
“A certain overlap between the DMN and the distribution of Aβ fibrils in AD has also been noted in previous publications23–26.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [25]
There is an increased Aβ-PET signal within the central executive network and salience network in the progression of AD.
“There is an increased Aβ-PET signal within the CEN and the SN in the progression of AD.244,245”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [244]
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- Authors
- Myers, N., Pasquini, L., Göttler, J., Grimmer, T., Koch, K., Ortner, M., Neitzel, J., Mühlau, M., Förster, S., Kurz, A., Förstl, H., Zimmer, C., Wohlschläger, A. M., Riedl, V., Drzezga, A., & Sorg, C.
- Affiliations
- TUM Klinikum (DE)
- Technical University of Munich (DE)
- University of Cologne (DE)
- Corresponding author
- Myers, Nicholas
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-04-26
- Volume
- 137
- Issue
- 7
- Pages
- 2052-2064
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4065018
- OpenAlex
- W2031921419
- Cited by
- 132
- References
- 57
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 9 · 2023: 13 · 2022: 9 · 2021: 15 · 2020: 5 · 2019: 10 · 2018: 13 · 2017: 20 · 2016: 11 · 2015: 14 · 2014: 7
- FWCI
- 9.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Wellcome Trust
- Bundesministerium für Bildung und Forschung (01ER0803, 01EV0710)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyloid plaques, intrinsic functional connectivity, Alzheimer's disease, prodromal Alzheimer's disease, default mode network, frontoparietal attention network, within-patient comparison, Pittsburgh compound B PET, resting-state fMRI
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Aniline Compounds, Brain, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neural Pathways, Neuropsychological Tests, Thiazoles, Amyloid beta-Peptides, Positron-Emission Tomography, Plaque, Amyloid
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