Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum

Amyloid-beta (Aβ) plaque formation in Alzheimer's disease (AD) pathology is morphologically diverse. Understanding the association of polymorphic Aβ pathology with AD pathogenesis and progression is critical in light of emerging Aβ-targeting therapies. In this work, functional amyloid microscopy enhanced by deep learning was integrated with mass spectrometry imaging to delineate polymorphic plaques and to identify their associated Aβ make-up. In both sporadic AD (n = 12) and familial AD (n = 6), dense-core plaques showed higher levels of Aβ1-40 and N-terminal pyroglutamated Aβx-42 compared to diffuse plaques and plaques in non-demented, amyloid positive individuals (n = 5). Notably, a distinct dense-core plaque subtype, coarse-grained plaque, was observed in AD but not in non-demented, amyloid positive patients. Coarse-grained plaques were more abundant in early onset AD, showed increased neuritic dystrophy and higher levels of Aβ1-40 and Aβ3pE-40, an Aβ-pattern similar to cerebral amyloid angiopathy. The correlative chemical imaging paradigm presented here allowed to link structural and biochemical characteristics of Aβ plaque polymorphism across various AD etiologies.

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Publication Details

Journal
Nature Communications
Published
2025-04-24
DOI
https://doi.org/10.1038/s41467-025-59085-7
Citations
10
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
11.64
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article

Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum

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10 citations
Nature Communications
Alzheimer's disease research and treatments
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article

Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum

Wojciech Michno, Jörg Hanrieder, Alicja Szadziewska, Kaj Blennow, Meera Srikrishna, Jack I. Wood, Tammaryn Lashley, Jeffrey N. Savas, Michael Schöll, Maciej Dulewicz, Srinivas Koutarapu, Junyue Ge, Henrik Zetterberg, Natalie S. Ryan
article en
10 citations

Abstract

Amyloid-beta (Aβ) plaque formation in Alzheimer's disease (AD) pathology is morphologically diverse. Understanding the association of polymorphic Aβ pathology with AD pathogenesis and progression is critical in light of emerging Aβ-targeting therapies. In this work, functional amyloid microscopy enhanced by deep learning was integrated with mass spectrometry imaging to delineate polymorphic plaques and to identify their associated Aβ make-up. In both sporadic AD (n = 12) and familial AD (n = 6), dense-core plaques showed higher levels of Aβ1-40 and N-terminal pyroglutamated Aβx-42 compared to diffuse plaques and plaques in non-demented, amyloid positive individuals (n = 5). Notably, a distinct dense-core plaque subtype, coarse-grained plaque, was observed in AD but not in non-demented, amyloid positive patients. Coarse-grained plaques were more abundant in early onset AD, showed increased neuritic dystrophy and higher levels of Aβ1-40 and Aβ3pE-40, an Aβ-pattern similar to cerebral amyloid angiopathy. The correlative chemical imaging paradigm presented here allowed to link structural and biochemical characteristics of Aβ plaque polymorphism across various AD etiologies.

Nature CommunicationsVol. 16(1)
Northwestern University (US), Uppsala University (SE), University of Science and Technology of China (CN), University of Wisconsin–Madison (US), King's College London (GB), Sahlgrenska University Hospital (SE), Sorbonne Université (FR), Pitié-Salpêtrière Hospital (FR), UK Dementia Research Institute (GB), MRC Prion Unit (GB), NIHR Queen Square Dementia Biomedical Research Unit (GB), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), University College London (GB), University of Gothenburg (SE)
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Alzheimer's disease research and treatments
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