The present invention is directed to recombinantly engineered mice that are deficient in the expression of both presenilin-1 and presenilin-2. The mice exhibit characteristics of age-dependent cognitive impairments and neurodegeneration similar to those seen in Alzheimer's disease patients. This presenilin-deficient mouse model can be used to screen compounds capable of slowing, preventing or reversing the progression of cognitive impairments and neurodegeneration. The invention is also directed to the development of treatments for Alzheimer's disease based on augmentation or restoration of presenilin function in the brain. On the basis of the findings described herein, the invention is further directed to the development of assays to detect functional presenilin deficiency in human individuals, preferably through analysis of presenilin substrates, which may provide biomarkers useful in the diagnosis of Alzheimer's disease.