Perspective tein, four are located in the luminal loop between predicted transmembrane domains one and two, two are in the large cytoplasmic loop between predicted transmembrane domains six and seven, and two are in the carboxy-terminal cytoplasmic tail. Three of the four mutations in PSEN2 also reside within predicted transmembrane domains. Thus, even though these mutations are distributed throughout the presenilins, their primary pathogenic effect appears to be elicited in the membrane-spanning or hydrophobic portions of these proteins, perhaps affecting their interactions with other hydrophobic helices (eg within intracellular membranes), where they primarily reside (7). Thus, one common consequence of the presenilin AD mutations may be to alter the conformation of these proteins, perhaps making them more prone to intracellular aggregation, a common feature of a variety of mutated proteins associated with neurodegenerative diseases. How misfolding of FAD-associated mutant presenilins and their increased susceptibility to aggregation might be related to increased production of Aβ42, a major pathogenic consequence of these mutations, remains unresolved. All but one of the PSEN1 mutations are 100% penetrant and are sufficient (but not necessary) to cause AD. The mean age of onset of AD in PSEN1-linked AD families is approximately 45 years with a range of 28 to 60 years. In contrast, the mean age of onset in families for the N141I PSEN2 mutation (the Volga Germans) is 52 years, and individual ages of onset in these kindreds range from 40-85 years. The early-onset AD mutations are associated with disastrous phenotypic consequences that are apparent at a relatively early point in adult life. Such mutations therefore cause a profound biological impact and are virtually 100% penetrant, but they are exceedingly rare.