APP and dementia: In CSF, toxic effects of Aβ42 oligomerization at synapses independent of amyloid plaque formation have been studied (Ringman et al., 2012d), and Ringman et al. (2012e) found elevated oligomers and low levels of Aβ42 in asymptomatic individuals with a history of variants in PSEN1 (including A431E) and APP. Of the seven participants, five were carriers, with a significant elevation of ring protofibrils with a progressive reduction identified 20 years before to age of onset of dementia.