Mice with targeted knock-in of single London mutation in the App gene displayed only mild cognitive impairment without obvious AD pathology.21 When two or three familial AD mutations were introduced into mice, typical AD phenotypes including Aβ plaques, neuroinflammation (gliosis), synaptic loss and cognitive impairment have been observed.19 However, two critical features are lacking in this model: the tau pathology and neuronal death/brain atrophy.18,19 These shortcomings may hamper its utility in basic research and drug development. This evidence concerns the gene MAPT and Brain atrophy.