GSIs were originally developed to block amyloid precursor protein cleavage to generate the Abeta peptide, which aggregates in Alzheimer's disease, but Notch toxicity (including diarrhoea from goblet cell metaplasia and immunological problems) was a severe side effect observed after long-term use in Alzheimer's research clinical trials [140,141]. Here, APP is linked to early-onset autosomal dominant Alzheimer disease.