74 RESULTS
COMMENT Replications are important in medical science, and this study essentially replicates the paper from deCode on this Alzheimer-protective mutation published five years ago. This replication is particularly important because its result points at a therapeuti
COMMENT This paper from the De Strooper lab convincingly shows that there is not a clear effect of PLD3 on APP biology and reignites the debate on whether PLD3 is an AD gene (Cruchaga et al., 2013). Genetic analysis looking for rare variants is subject to difficu
COMMENT It is clear that neuroimmune response is key to the genetics of Alzheimer’s disease, not just because of the identification of TREM2 as a risk locus but also from the systematic analysis of the GWAS hits (Jones et al., 2010). Interestingly, transgenic mou
COMMENT De Strooper and Karran’s thoughtful review takes us past the initiating events in AD, to think about the entirety of the pathogenesis. With all the new genetic risk factors we have discovered, this is an entirely appropriate development. We have been thin
COMMENT I agree with Sam Sisodia that assessing the structure of other mutations would be useful. An obvious one is the D9 mutation which has a clear effect on function (Perez-Tur et al., 1995; Thinakaran et al., 1996). J.Hardy 0 A mutation in Alzheimer's di
COMMENT This study by Bai and colleagues resolves the γ-secretase structure to an atomic level (resolution of 3.4Ǻ). This type of detail allows the authors to map and analyze some of the reported PSEN1 disease-associated mutations and to start to develop clearer
COMMENT (and as De Strooper comments, these genetic definitions are moot now we know precisely, for APP at
COMMENT It is vexing to be set up as the straw man suggesting that PSEN1 mutations act as a gain of function. In fact, not only did our quoted review (Hardy and Selkoe, 2002) not say this anywhere, but I have always thought that PSEN1 mutations were a subtle loss
COMMENT This paper is an undoubted step forward in the extent of both amyloid and tau pathology. It is not correct, however, to say that this is entirely novel. Shi et al., 2012, showed both Aβ deposition and tau pathology in iPSC-derived neuron cultures derived
COMMENT We (Guerreiro et al., 2013) and others (Jonsson et al., 2013) have previously described a significant association between the TREM2 p.R47H variant and an increased risk for the development of Alzheimer's disease. Additionally, Trem2 expression was fo
COMMENT These studies are very important. They are filling in the jigsaw of Alzheimer risk loci and, perhaps most importantly, they continue to point to four pathways which are of interest: the innate immune system, cholesterol metabolism, endosomal vesicle recyc
COMMENT Potter and colleagues demonstrate clearly, in vivo, two phenomena we, as a field, have suspected for 10-15 years: Presenilin mutations cause an increase in Aβ42 in the human CNS, and some compartment, presumably early deposits, start to extract Aβ42 from
COMMENT Clearly, the 1000 Genomes Project and related projects are very important for those of us who are interested in the genetic determinants of all diseases. These projects give us the background information for disease association studies. One of the major g
COMMENT It is very difficult to carry out a genetic analysis of African-Americans for locus discovery purposes. This population is genetically about 30 percent European in ancestry (but very variable), and the 70 percent African ancestry is far more variable than
COMMENT Sperling and colleagues cite three possible reasons why amyloid-targeted therapies may not yet have shown efficacy: 1) wrong mechanism, 2) right mechanism, but drug not hitting target, and 3) right mechanism, right target, but too late. That pretty much c
