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Dominik Röhr, Baayla D.C. Boon, Martin Schuler, Kristin Kremer, Jeroen J.M. Hoozemans, Femke H. Bouwman, Samir F. El‑Mashtoly, Andreas Nabers, Frederik Großerüschkamp, Annemieke J.M. Rozemuller, Klaus Gerwert

• The neuropathology of Alzheimer's disease (AD) is characterized by hyperphosphorylated tau neurofibrillary tangles (NFTs) and amyloid-beta (A\(\beta\)) plaques. A\(\beta\) plaques are hypothesized to follow a development sequence starting with diffuse plaques, which evolve into more compact plaques and finally mature into the classic cored plaque type. A better molecular understanding of A\(\beta\) pathology is crucial, as the role of A\(\beta\) plaques in AD pathogenesis is under debate. Here, we studied the deposition and fibrillation of A\(\beta\) in different plaque types with label-free infrared and Raman imaging. Fourier-transform infrared (FTIR) and Raman imaging was performed on native snap-frozen brain tissue sections from AD cases and non-demented control cases. Subsequently, the scanned tissue was stained against A\(\beta\) and annotated for the different plaque types by an AD neuropathology expert. In total, 160 plaques (68 diffuse, 32 compact, and 60 classic cored plaques) were imaged with FTIR and the results of selected plaques were verified with Raman imaging. In diffuse plaques, we detect evidence of short antiparallel \(\beta\)-sheets, suggesting the presence of A\(\beta\) oligomers. A\(\beta\) fibrillation significantly increases alongside the proposed plaque development sequence. In classic cored plaques, we spatially resolve cores containing predominantly large parallel \(\beta\)-sheets, indicating A\(\beta\) fibrils. Combining label-free vibrational imaging and immunohistochemistry on brain tissue samples of AD and non-demented cases provides novel insight into the spatial distribution of the A\(\beta\) conformations in different plaque types. This way, we reconstruct the development process of A\(\beta\) plaques in human brain tissue, provide insight into A\(\beta\) fibrillation in the brain, and support the plaque development hypothesis.