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

Srinivas Koutarapu, Junyue Ge, Maciej Dulewicz, Meera Srikrishna, Alicja Szadziewska, Jack Wood, Kaj Blennow, Henrik Zetterberg, Wojciech Michno, Natalie S. Ryan, Tammaryn Lashley, Jeffrey N. Savas, Michael Schöll and Jörg Hanrieder ()
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Srinivas Koutarapu: University of Gothenburg
Junyue Ge: University of Gothenburg
Maciej Dulewicz: University of Gothenburg
Meera Srikrishna: University of Gothenburg
Alicja Szadziewska: University of Gothenburg
Jack Wood: University of Gothenburg
Kaj Blennow: University of Gothenburg
Henrik Zetterberg: University of Gothenburg
Wojciech Michno: University of Gothenburg
Natalie S. Ryan: University College London
Tammaryn Lashley: University College London
Jeffrey N. Savas: Northwestern University Feinberg School of Medicine
Michael Schöll: University of Gothenburg
Jörg Hanrieder: University of Gothenburg

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59085-7

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