Amyloid‐ß oligomer Aß*56 is associated with Alzheimer’s dementia independently of amyloid pathology

Abstract Background A current hypothesis of the etiology of Alzheimer’s disease (AD) suggests that soluble amyloid‐ß (Aß) oligomers (Aßo) play a more significant role than amyloid plaques. Among the numerous Aßo discovered in the brain, Aß*56 has been shown to be associated with aging and cognitive dysfunction in mice, dogs, and humans, and impair memory in rodents. Evidence from our recent study indicates that Aß*56 produced from Tg2576 mice modeling AD is a ∼56‐kDa, SDS‐stable, A11 (anti‐amyloid oligomer antibody)‐reactive, water‐soluble oligomer that impairs memory in healthy wild‐type mice; and that there exist at least two Aß*56 variants—Aß(40)*56 and Aß(42)*56—that contain canonical Aß(1‐40) and Aß(1‐42), respectively, in AD mouse models. In addition, Aß*56 appears prior to the formation of amyloid plaques in Tg2576 mice, suggesting that the biogenesis of Aß*56 is independent on plaques. Here, we extend the characterization of this non‐plaque‐dependent oligomer to human AD cases and investigate the relationship between Aß*56 and cognitive dysfunction in AD dementia. Method We analyzed AD‐affected, inferior temporal gyrus (ITG) postmortem specimens from de‐identified elderly individuals enrolled in the Religious Orders Study/Memory and Aging Project. This cohort consisted of cognitively normal (CN) individuals, individuals with mild cognitive impairment (MCI), and individuals with AD dementia ( N = 19‐23 per group) that were age‐matched, sex‐balanced, and contained comparable amyloid plaque loads in the ITG. Using immunoprecipitation/western blotting coupled with densitometry‐based semi‐quantitative analysis, we measured levels of Aß(40)*56 and Aß(42)*56. We then compared levels of Aß*56 variants between different clinical diagnoses and correlated them to cognitive assessments. Result We showed that both levels of Aß(40)*56 and Aß(42)*56 are elevated in individuals with AD dementia compared to CN individuals and individuals with MCI. In addition, we showed that levels of Aß*56 variants are correlated to mini‐mental state examination scores and severity of impairment in global cognitive function, episodic memory, and semantic memory, but not working memory. Conclusion Our data suggest an association between Aß*56 to AD dementia in elderly human brains that is independent of amyloid pathology. Such findings support the use of Aß*56 as a molecular marker for AD diagnosis.