Aβ propagation and strains: Implications for the phenotypic diversity in Alzheimer's disease

The progressive nature of Alzheimer's disease (AD) is thought to occur, at least in part, by the self-replication and spreading of Aβ and Tau aggregates through a prion mechanism. Evidence now exists that structural variants of Aβ prions can propagate their distinct conformations through template-directed folding of naïve Aβ peptides. This notion implicates that the first self-propagating Aβ assembly to emerge in the brain dictates the conformation, anatomical spread and pace of subsequently formed deposits. It is hypothesized that a prion mechanism defines the molecular basis underlying the diverse clinicopathologic phenotypes observed across the spectrum of AD patients. Thus, distinct AD strains might require further sub-classification based on biochemical and structural characterization of aggregated Aβ. Here, we review the evidence for distinct, self-propagating Aβ strains, and discuss potential cellular mechanisms that might contribute to their manifestation. From this perspective, we also explore the implications of Aβ strains for current FDA-approved medical imaging probes and therapies for amyloid. Ultimately, the discovery of new molecular tools to differentiate Aβ strains and dissect the heterogeneity of AD may lead to the development of more informative diagnostics and strain-specific therapeutics.