The effect of Syt1 KD is also in agreement with the proposed γ-secretase loss-of-function due to familial AD mutations in PS1, which also display “closed” conformation and biochemically result in a partial loss of the γ-secretase activity due to inability of ‘complete digestion’ of the APP substrate, generating fewer but longer Aβs (for review see [37]). This evidence concerns the gene PSEN1 and Alzheimer disease.