PSEN1 and Alzheimer disease: In line with these findings, we have previously reported that PS1 shows a ‘closed’ conformation around Aβ plaques in the sporadic AD brain (Wahlster et al., 2013), and that higher Aβ42/40 ratio leads to the pathogenic conformation of PS1/γ-secretase (Zoltowska et al., 2016).