The β-amyloid oligomer Aβ*56 is associated with Alzheimer's dementia independently of amyloid pathology

The amyloid cascade hypothesis posits that {beta}-amyloid (A{beta}) oligomers (A{beta}o) play a key role in the pathogenesis of Alzheimers disease (AD). A{beta}o are believed to contribute to dementia in AD, and more than a dozen have been identified. While some oligomers are associated with amyloid plaques, others--such as A{beta}*56--are not. It remains unclear whether these plaque-independent oligomers contribute to dementia. A{beta}*56 is a non-fibrillar, sodium dodecyl sulfate-stable, brain-derived type of A{beta}o that impairs memory in mice. We recently confirmed and extended the characterization of A{beta}*56 in AD mouse models and identified two variants, namely A{beta}(40)*56 and A{beta}(42)*56 containing canonical A{beta}(1-40) and A{beta}(1-42), respectively. To examine the role of A{beta}*56 in dementia, we measured A{beta}*56 in elderly individuals--selected for equivalent levels of amyloid plaques--with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia. Using immunoprecipitation (IP), western blotting (WB), size exclusion chromatography, and conformation-sensitive antibodies, we confirmed the presence of A{beta}(40)*56 and A{beta}(42)*56 in human brains. Using IP/WB coupled with densitometry-based semi-quantitative analysis, we found that levels of both A{beta}*56 variants were elevated in AD dementia compared to NCI and MCI and correlated inversely with various measures of memory and cognition. Furthermore, mediation analyses showed that these associations were mediated by phosphorylated tau at serine 202 and threonine 205 (ptau 202/205)-containing neurofibrillary tangles. These findings support an association between A{beta}*56 and AD dementia independently of amyloid pathology. The results are significant because they suggest that targeting A{beta}*56 in patients could provide additional cognitive benefits beyond those achieved by current anti-A{beta} therapies that focus on removing amyloid plaques.