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

Vitamin D, vitamin D binding protein, lung function and structure in COPD

SummaryRationaleVitamin D and vitamin D binding protein (DBP) have been associated with COPD and FEV1. There are limited data regarding emphysema and vitamin D and DBP.ObjectiveThis is a pilot study of a portion of the subjects in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study designed to examine the relationship between vitamin D status, DBP, FEV1 and emphysema in COPD patients.MethodsWe measured serum 25(OH)D and DBP in 498 ECLIPSE subjects. Subjects were distributed amongst smoker controls, non-smoker controls, and GOLD stages 2, 3 and 4. Within each GOLD stage, the subjects were equally divided amongst high and low emphysema burden. The associations between 25(OH)D, DBP, and free vitamin D with FEV1, CT-defined emphysema, biomarkers and clinical data including CT-measured bone attenuation were assessed.Measurements25(OH)D and DBP were measured using tandem mass spectroscopy and competitive enzyme-linked immunosorbent assay, respectively,Main result25(OH)D was correlated with FEV1 (p = 0.01) and with severity of emphysema (p < 0.01). 25(OH)D was also associated with six-minute walk (p = 0.02), bronchodilator response (p = 0.04), and Clara cell secretory protein (CC-16) (p = 0.01). 25(OH)D levels were not associated with CT-measured bone attenuation, however DBP was associated with bone attenuation in subjects with emphysema. DBP was not associated with FEV1 or emphysema. 25(OH)D and DBP were inversely associated (p = 0.01).ConclusionThis is the first study to demonstrate a relationship between emphysema and vitamin D. We also provide further evidence for a relationship between vitamin D and FEV1