Unexpected cognitive worsening, as well as other potential adverse effects (e.g., hepatotoxicity, weight loss or neuropsychiatric symptoms), with BACE inhibitors in phase 2/3 trials have halted their therapeutic development in AD [11, 12, 151], but the model targeting the amyloid pathway at different stages remains a viable strategy, and may be facilitated by next generation gamma secretase modulators [152, 153]. The gene discussed is BACE1; the disease is Alzheimer disease.