Thus, of the four loci reported to influence CSF tau/ptau, three show robust evidence for also altering risk for AD. In each instance the direction of effect on CSF tau and ptau, and on risk for

AD, cognitive decline, and tangle pathology was consistent; alleles KU-55933 concentration associated with lower tau and ptau were associated with reduced risk for AD, slower cognitive decline, and reduced neurofibrillary tangle pathology. While this is an exciting piece of work that supports the idea of using endophenotype to understand the basis of disease, there is still much to do. There exist exciting opportunities and challenges in taking the current findings further. GWA studies identify loci, not genes, and as such a critical next step is to identify the pathobiologically relevant gene (or genes) at the Compound Library in vivo 3q28 locus and TREM gene cluster and determine the effect of these risk alleles on that gene. For the most part, the risk alleles associated by GWA are not linked to protein-coding variability, and in all likelihood they confer their effects by altering transcript

expression. While Cruchaga et al. (2013) went some way toward testing this—by examining the effect of the identified alleles on expression of proximal transcripts—this small exploratory study requires further work. Given the recent identification of TREM2 as a risk gene for AD, the identification of multiple independent alleles at this locus that alter CSF tau/ptau is particularly exciting, and further fine-scale investigation of this locus is certainly warranted in AD. Lastly, by Cruchaga et al. (2013)’s own calculations, the four loci linked with CSF tau/ptau levels only explain a minor proportion of the variability in

CSF tau/ptau, indicating that at least some of the remaining variability can be attributed to as-yet-unknown genetic variants. Thus, there are clearly more risk alleles to be found. It is likely that the best route to identify these unknown factors will employ a combination of genetic methods, including GWA and second-generation sequencing. There is certainly great promise in these methods; however, analyzing cohorts of sufficient size will be critical; approximately 1,300 CSF samples are an impressive amount, but making substantive future gains in this area will probably require Adenosine larger cohorts and unified biological measures. In summary, Cruchaga et al. (2013) have taken an exciting step in showing that the endophenotype is a valuable and informative measure for understanding disease. Their work has provided valuable new insight into the basis of AD and promises to be the impetus for addressing a new series of research questions in this field. Given their findings, this effort certainly appears to be a valuable addition to the massive consortium-based case control analyses. “
“Neural activity recorded simultaneously across multiple neurons allows neuroscientists to study the importance of synchronous or correlated activity for the neural code.