Brain amyloid-β oligomers in ageing and Alzheimer's disease

Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-beta aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-beta in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-beta aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-beta aggregates, including soluble amyloid-beta oligomers. Different soluble amyloid-beta oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-beta oligomers previously described in mouse models-amyloid-beta trimers, A beta*56 and amyloid-beta dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-beta trimers appear to be the fundamental amyloid-beta assembly unit of A beta*56 and are present in young mice prior to memory decline, amyloid-beta trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. A beta*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-beta dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between A beta*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between A beta*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-beta dimers or amyloid-beta trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-beta dimers, but the lowest levels of A beta*56 and amyloid-beta trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults A beta*56 increased ahead of amyloid-beta dimers or amyloid-beta trimers, and pathological tau proteins and postsynaptic proteins correlated with A beta*56, but not amyloid-beta dimers or amyloid-beta trimers. We propose that A beta*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.