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

Cohen et al. identify at least three distinct A beta 42 conformations in post-mortem brain tissue from patients with a rapidly progressive subtype of sporadic Alzheimer's disease. Increased abundance of smaller A beta 42 particles with unique structural characteristics correlates with rapid progression and implies prion-like A beta 42 strains with differing toxicities and propagation rates.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-beta and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-beta 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-beta(42) particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-beta(40) 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-beta(42), with higher levels of distinctly structured amyloid-beta(42) particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-beta(42) 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-beta(42) structural states and imply the existence of prion-like conformational strains.