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.

Rapid replication in vitro implicates distinct populations of misfolded hippocampal 4R TAU protein in accelerated progression of Alzheimer’s disease.

Objective: To study the dynamics of clustering semantic fluency responses and switching between clusters.Methods: We conducted a cross-sectional study of participants (N = 60) in a study of patient reported outcomes who were given the Saint Louis University Mental Status test. Sixty-second animal naming tests were scored for the timing of responses as well as the clustering of responses into semantic categories. Time scores were detrended to correct for exponential exhaustion and normalize the time scale across individuals.Results: Grouped by number of responses given, low performers (LP; Carter et al., 2012) switched between clusters fewer times than medium performers (MP) and high performers (HP). Prior to detrending, LP showed increased intracluster response times when compared to the other groups, but no differences were shown in intercluster response times. After detrending, however, the difference in intracluster response times disappeared and LP showed significantly faster detrended intercluster response times compared to both MP and HP.Conclusion: Prior to detrending, slower intracluster response times appear to be driving poorer performance. When time scores are detrended, our findings suggest that LP participants have quicker intercluster response times but exhaust more quickly as well. Detrending can help describe the interplay between the structure-loss and retrieval-slowing models of declining semantic fluency by isolating the component mechanisms involved in each.