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Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the A\u03b2 aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the individual underlying microscopic steps. We apply this work-flow to the disease-associated A\u03b242-A2V variant and to a variation in pH as examples of an intrinsic and an extrinsic perturbation. In both cases, our data reveal a shift towards a mechanism in which a larger fraction of the reactive flux goes via a pathway that generates potentially toxic oligomeric species in a fibril-catalyzed reaction. This is in agreement with the finding that A\u03b242-A2V leads to early-onset Alzheimer\u2019s disease and enhances neurotoxicity.<\/jats:p>","DOI":"10.1038\/srep18728","type":"journal-article","created":{"date-parts":[[2016,1,13]],"date-time":"2016-01-13T11:40:57Z","timestamp":1452685257000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated A\u03b2-peptide"],"prefix":"10.1038","volume":"6","author":[{"given":"Georg","family":"Meisl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitta","family":"Frohm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas P. 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