Pálmi V. Jónsson

BACKGROUND: Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. METHODS: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, The Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. RESULTS: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003). CONCLUSIONS: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.).

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.

OBJECTIVES: To examine the frequency distributions and interrater reliability of individual items of the interRAI Acute Care instrument. DESIGN: Observational study of a representative sample of older inpatients; duplicate assessments conducted on a subsample by independent assessors to examine interrater reliability. SETTING: Acute medical, acute geriatric and orthopedic units in 13 hospitals in nine countries. PARTICIPANTS: Five hundred thirty-three patients aged 70 and older (mean age 82.4, range 70-102) with an anticipated stay of 48 hours or longer of whom 161 received duplicate assessments. MEASUREMENTS: Sixty-two clinical items across 11 domains. Premorbid (3-day observation period before onset of the acute illness) and admission (the first 24 hours of hospital stay) assessments were conducted. RESULTS: The frequency of deficits exceeded 30% for most items, ranging from 1% for physically abusive behavior to 86% for the need for support in activities of daily living after discharge. Common deficits were in cognitive skills for daily decision-making (38% premorbid, 54% at admission), personal hygiene (37%, 65%), and walking (39%, 71%). Interrater reliability was substantial in the premorbid period (average kappa=0.61) and admission period (average kappa=0.66). Of the 69 items tested, less than moderate agreement (kappa<0.4) was recorded for six (9%), moderate agreement (kappa=0.41-0.6) for 14 (20%), substantial agreement (kappa=0.61-0.8) for 40 (58%), and almost perfect agreement (kappa>0.8) for nine (13%). CONCLUSION: Initial assessment of the psychometric properties of the interRAI Acute Care instrument provided evidence that item selection and interrater reliability are appropriate for clinical application. Further studies are required to examine the validity of embedded scales, diagnostic algorithms, and clinical protocols.