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

Enquiries to the UK National Poisons Information Service regarding dextromethorphant toxicity [Abstract]

Objective: Dextromethorphan is a readily accessible antitussive agent. Recreational abuse has been associated with dissociative effects, and deaths have been reported after ingestion of very large doses.1,2 This study examined the clinical features associated with dextromethorphan ingestion in the United Kingdom.  Methods:  The National Poisons Information Service is commissioned by the Health Protection Agency to provide clinical advice on the management of poisoned patients in the United Kingdom. Enquiries concerning dextromethorphan were examined retrospectively.  Results: Data were available between 2004 to 2007. There were data concerning 354 patients with median age 7 years (95% CI 4 to 14 years) of whom 194 were female (55.0%). Cases involved accidental ingestion in 261 (73.9%), deliberate overdose in 87 (24.6%), and adverse effects of therapeutic dose in 5 (1.4%). Median dose was 45 mg (range 3 to 2750 mg). Commonest co-ingested agents were paracetamol in 147 (41.6%), promethazine in 132 (37.4%), diphenhydramine in 73 (20.7%), pseudoephedrine in 67 (19.0%), triprolidine in 53 (15.0%), and menthol in 32 (9.1%). There were no symptoms or signs of toxicity in 257 patients (72.8%). The dose was higher in patients with symptoms; 120 mg (IQR 50 to 225 mg) versus 30 mg (IQR 8 to 90 mg), p<0.0001 by Mann Whitney test. Dextromethorphan dose was predictive of toxicity; receiver operating characteristic AUC 72.5% (95% CI 67.1 to 77.4%). Clinical features were drowsiness in 50 (14.2%), minor haemodynamic effects in 14 (4.0%), nausea or vomiting in 13 (3.7%), dizziness and ataxia in 10 (2.8%), agitation in 7 (2.0%), non-specific abdominal pain in 4 (1.1%), mydriasis in 3 (0.8%), dry mouth in 3 (0.8%), blurred vision in 2 (0.6%), headache in 2 (0.6%), and tremor in 1 (0.3%). None had features of severe poisoning. Conclusion: Dextromethorphan enquiries to the National Poisons Information Service often concern accidental exposures in children. The majority of patients had no clinical features or only minor symptoms