New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Atorvastatin induces associated reductions in platelet P-selectin, oxidized low-density lipoprotein, and interleukin-6 in patients with coronary artery diseases.

The development and progression of atherosclerosis comprises various processes, such as endothelial dysfunction, chronic inflammation, thrombus formation, and lipid profile modification. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that have pleiotropic effects in addition to cholesterol-lowering properties. However, the mechanisms of these effects are not completely understood. Here, we investigated whether atorvastatin affects the levels of malondialdehyde-modified low-density lipoprotein (MDALDL), an oxidized LDL, the proinflammatory cytokine interleukin-6 (IL-6), or platelet P-selectin, a marker of platelet activation, relative to that of LDL cholesterol (LDL-C). Forty-eight patients with coronary artery disease and hyperlipidemia were separated into two groups that were administered with (atorvastatin group) or without (control group) atorvastatin. The baseline MDA-LDL level in all participants significantly correlated with LDL-C (r = 0.71, P < 0.01) and apolipoprotein B levels (r = 0.66, P < 0.01). Atorvastatin (10 mg/day) significantly reduced the LDL-C level within 4 weeks and persisted for a further 8 weeks of administration. Atorvastatin also reduced the MDA-LDL level within 4 weeks and further reduced it over the next 8 weeks. Platelet P-selectin expression did not change until 4 weeks of administration and then significantly decreased at 12 weeks, whereas the IL-6 level was gradually, but not significantly, reduced at 12 weeks. In contrast, none of these parameters significantly changed in the control group within these time frames. The reduction (%) in IL-6 between 4 and 12 weeks after atorvastatin administration significantly correlated with that of MDALDL and of platelet P-selectin (r = 0.65, P < 0.05 and r = 0.70, P < 0.05, respectively). These results suggested that the positive effects of atorvastatin on the LDL-C oxidation, platelet activation and inflammation that are involved in atherosclerotic processes are exerted in concert after lowering LDL-C

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

These authors contributed equally: Gail Davies, Max Lam. These authors jointly supervised this work: Todd Lencz, Ian J. Deary

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease