Emergence of distinct and heterogeneous strains of amyloid beta as Alzheimer s disease progresses in Down syndrome

Abstract

0.Amyloid beta (A{beta}) is thought to play a critical role in the pathogenesis of Alzheimers disease (AD). Prion-like A{beta} polymorphs, or "strains", can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of A{beta} that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and A{beta} strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various A{beta} and tau species and used conformation-sensitive fluorescent probes to detect differences in A{beta} strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of A{beta} emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sAD.