Preclinical AD also represents the boundary condition between two important therapeutic approaches:

the true primary prevention selleck inhibitor of illness and the so-called ‘secondary prevention’ or treatment of the very earliest manifestations of illness. Future trials will need to account for and distinguish between the truly asymptomatic and preclinical AD. Although we have seen remarkable and rapid advances in the ability to diagnose preclinical AD (Weiner et al., 2010), in order to move toward primary prevention we need to advance our ability to predict who is at very high risk for AD and in what time frame they might develop observable pathology and subsequently clinical symptoms. Based on current data, we know that APOE ɛ4 genotype, low CSF Aβ42, and increased PET amyloid tracer binding in the brain, all confer substantially increased risk for the progression of preclinical AD to mild cognitive impairment (MCI) and MCI to AD ( Blennow, 2004, De Meyer et al., 2010, Romas et al., 1999 and Storandt et al., 2009). But these markers do not provide information regarding onset of pathology. Even the presence of an APOE ɛ4 genotype only indicates increased risk or earlier age-of-onset but fails to provide precise information with respect to timing of disease onset. Identification of additional factors that predict more precisely the risk for development

of AD, what are generically referred to as premorbid biomarkers, could be very useful in identifying an at-risk population for a primary buy Lapatinib prevention study. Again, if we make an analogy to

atherosclerotic disease, plasma cholesterol-testing serves as such a premorbid biomarker. Given this reality, there is substantial interest in the Phosphoprotein phosphatase field to test preventive agents in genetic forms of AD where large kindreds, such as one in Antioquia, Colombia, with a deterministic early-onset presenilin 1 mutation (www.dian-info.org), or in individuals who are homozygous for the APOE ɛ4 allele ( Reiman et al., 2010 and Strittmatter and Roses, 1995). Though laudable and perhaps the only way forward at the present time, these studies have some limitations. Even in large kindreds with deterministic AD-causing mutations, the number of asymptomatic mutation carriers who might be predicted to develop or have preclinical AD within a reasonable time frame is relatively small. Thus, the number of different therapies that might be tested in such a setting will probably be very limited and, because of variance in the age of onset, it is unclear how long such studies would need to extend in order to convincingly demonstrate efficacy. Further, it has been shown that some anti-Aβ treatments may have altered efficacy in presenilin mutation carriers ( Weggen et al., 2003). The 1%–2% of the population that is homozygous for the APOE ɛ4 allele represents another at-risk or preclinical sample for clinical trials ( Reiman et al.