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

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

Selection of roughage diets by sheep and goats

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The intake and digestion of a range of temperate forages by sheep and fibre-producing goats

The voluntary intake, digestibility and mean retention time of six temperate forages differing in their chemical composition by 12 adult castrated male Scottish blackface sheep, aged 15 months, and fibre-producing castrated male goats, aged 27 months, and of similar live weight, 40 kg, were described. The creation of a range of chemical compositions was effected through the use of barley straw, and a low- and high-digestibility hay, and the use of ammonia treatment of these forages. A wide range of voluntary intakes (42-78 g DM/kg W⁰·⁷⁵/day), digestibility of dry matter (0.46-0.60) and mean retention times of undigested residues (36-72 h) was achieved through feeding the six forages. Across all the forages fibre-producing goats had higher voluntary intakes, expressed on a metabolic live weight basis, and lower digestibility values than sheep, whereas the mean retention time of the undigested residues was similar for the two species. Within forages goats selected a diet of potentially higher nutritive value, as predicted from chemical composition, with a smaller particle size than sheep. It was concluded that the differences in intake and digestion of temperate forages between sheep and fibre-producing goats are broadly similar to those observed in other experiments between sheep and goats ingesting tropical forages

Comparative preference by sheep and goats for Graminaeae forages varying in chemical composition

The preferences for six Graminaeae forages, differing in chemical composition, by adult castrated male Scottish Blackface sheep and fibre-producing castrated male goats were assessed in paired choice trials. Using barley straw, low and high digestibility grass hay (Lolium perenne) and the use of ammonia treatment of the low quality forages, created the range in chemical composition of the forages. A wide range of voluntary intakes (33.7-82.3 g DM/kg W-0.75/day) was achieved through feeding the paired forages. Sheep and goats had similar preference rankings for the forages with both preferring the high digestibility hay to other forages. Ammonia treatment of the forages had little effect on their preference. For both species the forages' preference rankings were positively correlated with the voluntary intake (P < 0.01) and the in vitro OM digestibility (P < 0.05) of the individual forages, whereas they were negatively related (P < 0.01) to the fibre characteristics (NDF, ADF, AIL) of the feeds. It was concluded that goats and sheep used in this study had similar preferences, for the forages tested, despite differences between species in their intake and digestion of the individual forages

Intake, digestion and selection of roughage with different staple lengths by sheep and goats

The diet selection, ingestive and digestive responses of goats and sheep offered a single forage, which was prepared with three staple lengths: long (L), medium (M) and short (S) (mean particle size (mm): 13.29, 7.26 and 0.69, respectively) were studied in three experiments. The sheep (Scottish Blackface wethers) increased their dry matter intake (sheep DMI: 60.1, 61.1 and 66.2 g DM/(kg W-0.75) per day for L, M and S) and reduced mean retention time (MRT) of the undigested residues (sheep MRT: 54.6, 52.9 and 45.9 h for L, M and S) and digestive efficiency (sheep DM digestibility: 0.524, 0.522 and 0.493 for L, M and S) with the reduction in forage particle size. The respective responses of goats (feral crosses) were not modified with forage staple length (goat DMI: 68.1, 65.9 and 67.3 g DM/(kg W-0.75) per day for L, M and S); (goat MRT: 3 8.7, 39.3 and 41.1 h for L, M and S); (goat DM digestibility: 0.495, 0.475 and 0.480 for L, M and S). However, both species had similar intakes of digestible dry matter (DDMI) on all staple lengths (mean DDMI: 32.0 and 32.6 g DDM/(kg W-0.75) per day for sheep and goats). On the longer staple lengths (L and M) goats masticated the fibre into smaller particles than did sheep and had (P < 0.01) a greater proportion of small particles in their boli (mean: 0.45 and 0.30 for goats and sheep). The selection of components within the forage offered was different for the two species. Goats consumed forage of lower nitrogen (N) (P < 0.01) and in vitro organic matter digestibility (OMD) (P < 0.05) and higher neutral detergent fibre (NDF) (P < 0.01) contents than sheep. This was associated with the residues from sheep having a coarser texture than those of goats. When the forages of different staple lengths were offered in pairs to the animals, there was no evidence for selection of forage types by either species. It would appear that the greater ability of goats to chew efficiently provides a reason for the different responses to staple length in intake, digestibility and MRT by the two species

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.Pattern Recognition and Bioinformatic

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