Cortical neurons derived from patients carrying fAD mutations or more complex forms of AD, including TS21, faithfully reproduce pathological changes in disease-relevant proteins reported in vivo, without the need for artificial overexpression or exogenous toxic insult (Israel et al., 2012, Moore et al., 2015, Shi et al., 2012b, Yagi et al., 2011). Here, PSEN1 is linked to Alzheimer disease.