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

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium

THE RATE OF BINARY BLACK HOLE MERGERS INFERRED FROM ADVANCED LIGO OBSERVATIONS SURROUNDING GW150914

A transient gravitational-wave signal, GW150914, was identi fi ed in the twin Advanced LIGO detectors on 2015 September 2015 at 09:50:45 UTC. To asse ss the implications of this discovery, the detectors remained in operation with unchanged con fi gurations over a period of 39 days around the time of t he signal. At the detection statistic threshold corresponding to that observed for GW150914, our search of the 16 days of simultaneous two-detector observational data is estimated to have a false-alarm rate ( FAR ) of < ́ -- 4.9 10 yr 61 , yielding a p -value for GW150914 of < ́ - 210 7 . Parameter estimation follo w-up on this trigger identi fi es its source as a binary black hole ( BBH ) merger with component masses ( )( ) = - + - + mm M ,36,29 12 4 5 4 4 at redshift = - + z 0.09 0.04 0.03 ( median and 90% credible range ) . Here, we report on the constraints these observations place on the rate of BBH coalescences. Considering only GW150914, assuming that all BBHs in the universe have the same masses and spins as this event, imposing a search FAR threshold of 1 per 100 years, and assuming that the BBH merger rate is constant in the comoving frame, we infer a 90% credible range of merger rates between – -- 2 53 Gpc yr 31 ( comoving frame ) . Incorporating all search triggers that pass a much lower threshold while accounting for the uncerta inty in the astrophysical origin of each trigger, we estimate a higher rate, ranging from – -- 13 600 Gpc yr 31 depending on assumptions about the BBH mass distribution. All together, our various rate estimat es fall in the conservative range – -- 2 600 Gpc yr 31

Effectiveness of rehabilitation interventions in improving emotional and functional status in hearing or visually impaired older adults: a systematic review with meta-analyses

OBJECTIVE: To assess the effectiveness of non-equipment based rehabilitation interventions for older adults with an age-related hearing or visual impairment. DATA SOURCES: We searched PubMed, EMBASE, PsychInfo, CINAHL, and the Cochrane Central Register of Controlled Trials. REVIEW METHODS: Two authors independently assessed trial eligibility, extracted data and assessed methodological quality. Controlled studies with more than 80% of participants aged >/= 55 years and with rehabilitation interventions either separately or in combination with technical device provision were included. Meta-analyses were undertaken for the primary outcomes: emotional status, functional status, self-efficacy and social participation. All studies were categorized into 3 subgroups of intervention approaches (cognitive restructuring, education, and problem-solving), and subgroup analysis was performed. RESULTS: Fourteen studies were identified: six on hearing impairment and eight on visual impairment, involving 1622 sensory impaired participants (mean age 70). Methodological quality of the studies was modest. Eight studies offered data for meta-analysis. No significant effects in favour of interventions on either emotional or functional status, self-efficacy, or social participation were found. In the subgroup analysis, only the problem-solving approach showed a positive effect on emotional status. CONCLUSIONS: This review found no effects of non-equipment based rehabilitation interventions on emotional and functional status, self-efficacy, and social participation. However, subgroup analysis showed problem-solving as a potential effective approach for positively affecting emotional status

Physical activity and mortality across cardiovascular disease risk groups

OBJECTIVE: To assess the effectiveness of non-equipment based rehabilitation interventions for older adults with an age-related hearing or visual impairment. DATA SOURCES: We searched PubMed, EMBASE, PsychInfo, CINAHL, and the Cochrane Central Register of Controlled Trials. REVIEW METHODS: Two authors independently assessed trial eligibility, extracted data and assessed methodological quality. Controlled studies with more than 80% of participants aged >/= 55 years and with rehabilitation interventions either separately or in combination with technical device provision were included. Meta-analyses were undertaken for the primary outcomes: emotional status, functional status, self-efficacy and social participation. All studies were categorized into 3 subgroups of intervention approaches (cognitive restructuring, education, and problem-solving), and subgroup analysis was performed. RESULTS: Fourteen studies were identified: six on hearing impairment and eight on visual impairment, involving 1622 sensory impaired participants (mean age 70). Methodological quality of the studies was modest. Eight studies offered data for meta-analysis. No significant effects in favour of interventions on either emotional or functional status, self-efficacy, or social participation were found. In the subgroup analysis, only the problem-solving approach showed a positive effect on emotional status. CONCLUSIONS: This review found no effects of non-equipment based rehabilitation interventions on emotional and functional status, self-efficacy, and social participation. However, subgroup analysis showed problem-solving as a potential effective approach for positively affecting emotional status