Alzheimer's disease (AD) is characterized by a progressive memory loss and cognitive decline [For review see (Caselli et al., 2006)]. Hippocampus-dependent memory (Rosen et al., 1984; Haxby et al., 1992; Jacobs et al., 1995) and olfaction-dependent memory (Warner et al., 1986; Albers et al., 2006; Serby, 1987; Kesslak et al., 1988;Bacon et al., 1998) are severely impaired in the disease. The vast majority of AD cases are the late onset sporadic form of the disease. While aging is the greatest environmental risk factor for the sporadic form, apolipoprotein E (apoE) genotype is the greatest known genetic risk factor [For review see (Ashford, 2004; Bu, 2009)]. Rare, familial, early- onset autosomal dominant forms of Alzheimer's disease (FAD) are caused by mutations in genes encoding amyloid precursor protein (APP), presenilin-1 (PS1) and presenilin-2 (PS2). PS play a central role in the function of the aspartyl protease γ-secretase complex that cleaves numerous membrane proteins intramembranously, including APP [(De Strooper, 2003) for review see (Selkoe and Wolfe, 2007)]. APP can undergo regulated intramembrane proteolysis (RIP) in at least two pathways known as the non-amyloidogenic
