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Studies have shown that the diversity of \u03b2 sheet-rich protein deposits (such as amyloid \u03b2 plaques and neurofibrillary tangles), present across different brain regions, might underlie different disease phenotypes and only certain types of aggregates might be associated with cognitive decline. Conformationally sensitive fluorescent amyloid probes have the ability to report different structures of protein aggregates by virtue of their shifting emission spectra. Here we defined the binding affinity of the fluorescent amyloid probes BSB and MCAAD to disease-relevant protein aggregates, and combined the two probes to examine formalin-fixed paraffin-embedded mouse and human brain samples. Coupled with quantitative spectral phasor analysis, the dual-probe staining approach revealed remarkable heterogeneity of protein aggregates across the samples. Distinct emission spectra were consistent with certain types of deposits present in the mouse and human brain sections. The sensitivity of this staining, imaging and analysis approach outperformed conventional immunohistochemistry with the detected spectral differences between the greater parenchyma of cognitively normal and AD cases indicating a subtle yet widespread proteopathy associated with disease. Our method offers more sensitive, objective, and quantitative examination of protein misfolding pathology using conventional tissue sections.<\/jats:p>","DOI":"10.1186\/s40478-022-01456-y","type":"journal-article","created":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T11:06:19Z","timestamp":1666955179000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Dual-probe fluorescence spectroscopy for sensitive quantitation of Alzheimer\u2019s amyloid pathology"],"prefix":"10.1186","volume":"10","author":[{"given":"Anastasiia A.","family":"Stepanchuk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan L.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey T.","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0326-4194","authenticated-orcid":false,"given":"Peter K.","family":"Stys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"1456_CR1","doi-asserted-by":"publisher","unstructured":"Aliyan A, Cook NP, Mart\u00ed AA (2019) Interrogating Amyloid Aggregates using Fluorescent Probes. 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