Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β

Mark L. Cohen, Chae Kim, Tracy Haldiman, Mohamed ElHag, Prachi Mehndiratta, Termsarasab Pichet, Frances Lissemore, Michelle Shea, Yvonne Cohen, Wei Chen, Janis Blevins, Brian S. Appleby, Krystyna Surewicz, Witold K. Surewicz, Martha Sajatovic, Curtis Tatsuoka, Shulin Zhang, Ping Mayo, Mariusz Butkiewicz, Jonathan L. HainesAlan J. Lerner, Jiri G. Safar

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer's disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer's disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer's disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer's disease phenotypes. These findings indicate that Alzheimer's disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.

Original languageEnglish (US)
Pages (from-to)1009-1022
Number of pages14
Issue number4
StatePublished - Apr 1 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 The Author.


  • Alzheimer
  • progression rate
  • structure
  • β-amyloid


Dive into the research topics of 'Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β'. Together they form a unique fingerprint.

Cite this