Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

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Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

The Association Between Midlife Physical Activity and Depressive Symptoms in Late Life: Age Gene/Environment Susceptibility-Reykjavik Study.

BACKGROUND: There is little evidence on the long-term association between physical activity (PA) and depressive symptoms in old age. We examined the association of midlife PA and depressive symptoms in late life. METHODS: A large community-based population residing in Reykjavik, Iceland, participated in a longitudinal study with an average of 25 years of follow up. Midlife PA was categorized as active and inactive groups (n = 4,140, Active = 1,292, Inactive = 2,848, mean age 52±7 years). The main outcome had six or higher depressive symptoms assessed by the 15-item Geriatric Depression scale. Participants who had a history of depression (n = 226), and were diagnosed with dementia (n = 393), and had incomplete cognitive data (n = 595) and incomplete analytical data (n = 422) were excluded. Level of weekly PA was ascertained by a questionnaire at midlife. Depressive symptoms were assessed on average 25 (±4) years later. RESULTS: After controlling for demographic and health-related risk factors, those who were active at midlife were less likely to have high level of depressive symptomatology (6 or higher Geriatric Depression scale scores, odds ratio = 0.58, 95% confidence interval: 0.41-0.83, p < .005) compared with those who were inactive in midlife. After full adjustment of three domains of late-life cognitive function the results remained significant (odds ratio = 0.61, 95% confidence interval: 0.43-0.86, p = .005). CONCLUSION: Our study shows that midlife PA is associated with lower depressive symptoms 25 years later. Participating in regular PA in midlife may improve mental health in late life.

Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease.

We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10(-15)).

Midlife physical activity preserves lower extremity function in older adults: age gene/environment susceptibility-Reykjavik study.

OBJECTIVES: To examine the long-term association between midlife physical activity (PA) and lower extremity function (LEF) in late life. DESIGN: Longitudinal study with an average of 25 years of follow-up. SETTING: Community-dwelling old population in Reykjavik, Iceland. PARTICIPANTS: Four thousand seven hundred fifty-three community-dwelling men and women (mean age 76 ± 6) in Reykjavik, Iceland. MEASUREMENTS: On the basis of weekly hours of regular PA reported at the midlife examination, participants were classified as active or inactive. Measures of LEF in late life were gait speed on a 6-m walk, Timed Up and Go (TUG), and knee extension (KE) strength tests. Linear regression analysis was used to examine the association. RESULTS: Participants who were active in midlife had significantly better LEF (faster gait speed, ß = 0.50, P ≤ .001; faster TUG time, ß = -0.53 P ≤ .001; stronger KE strength, ß = 1.3, P ≤ .001) in late life than those who were not active in midlife after adjusting for sociodemographic and cardiovascular risk factors. After adjustment for cognitive function in late life (speed of processing, memory, and executive function), participants who were active in midlife had significantly faster gait speed (ß = 0.04, P ≤ .001), faster TUG time (ß = -0.34, P ≤ .001), and greater KE strength (ß = 0.87, P ≤ .001) in old age than those who were not active in midlife. CONCLUSION: Regular PA in midlife is associated with better performance of LEF in later life, even after controlling for late-life cognitive function.

Variant of TREM2 associated with the risk of Alzheimer's disease.

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.).

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-ß precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease ß-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the ß-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.

The effect of midlife physical activity on cognitive function among older adults: AGES--Reykjavik Study.

BACKGROUND: There are few studies on the long-term associations of physical activity (PA) to cognition. Here, we examine the association of midlife PA to late-life cognitive function and dementia. METHODS: The sample consisted of a population-based cohort of men and women (born in 1907-1935) participating in the Age Gene/Environment Susceptibility-Reykjavik Study. The interval between the midlife ascertainment of PA and late-life cognitive function was 26 years. Composite scores of speed of processing, memory, and executive function were assessed with a battery of neuropsychological tests, and dementia was diagnosed according to international guidelines. There were 4,761 nondemented participants and 184 (3.7%) with a diagnosis of dementia, with complete data for the analysis. RESULTS: Among the participants, no midlife PA was reported by 68.8%, ≤ 5 hours PA by 26.5%, and >5 hours PA by 4.5%. Excluding participants with dementia compared with the no PA group, both PA groups had significantly faster speed of processing (≤ 5 hours, ß = .22; >5 hours, ß = .32, p trend < .0001), better memory (≤ 5 hours, ß = .15; >5 hours, ß = .18, p trend < .0001), and executive function (≤ 5 hours, ß = .09; >5 hours, ß = .18, p trend< .0001), after controlling for demographic and cardiovascular factors. The ≤ 5 hours PA group was significantly less likely to have dementia in late life (odds ratio: 0.6, 95% confidence interval: 0.40-0.88) after adjusting for confounders. CONCLUSION: Midlife PA may contribute to maintenance of cognitive function and may reduce or delay the risk of late-life dementia.

Evaluating differences in linkage disequilibrium between populations.

We propose two methods to evaluate the statistical significance of differences in linkage disequilibrium (LD) between populations, where LD is measured by the standardised parameter D'. The first method is based on bootstrapping individuals within populations in order to test LD differences for each pair of loci. Using this approach we propose a solution to the problem of testing multiple locus-pairs by means of a single test for the number of pairs that exhibit significant LD differences among populations. The second method provides the Bayesian posterior probability that one population has greater LD than the other for each locus pair. Both methods can handle genotypes with unknown phase, and are demonstrated using two data sets. For the purpose of demonstration, we apply the methods to two different sets of data from humans. First, we explore the issue of LD differences between reproductively isolated populations using a new data set of twelve Xq25 microsatellites, typed in four European populations. Second, we examine evidence for LD differences between Alzheimer cases and controls from the Icelandic population using 19 single nucleotide polymorphisms (SNPs) from a 97 kb region flanking the Apolipoprotein E (APOE) gene on chromosome 19.

Vitamin D deficiency and nutritional status in elderly hospitalized subjects in Iceland.

OBJECTIVE: Poor nutrition and limited sunlight exposure (season) can be related to reduced serum 25-hydroxyvitamin D (25(OH)D) concentrations. Thus, elderly people in the Nordic countries might be at high risk for vitamin D deficiency. The aims of the study were to describe the prevalence of vitamin D deficiency in elderly hospitalized patients in Reykjavik, Iceland, and to investigate the effects of nutritional status and season on serum 25(OH)D. DESIGN: Cross-sectional study. Nutritional status was assessed and fasting blood was drawn and analysed for serum 25(OH)D and other clinical routine measurements. SETTING: Departments of Geriatrics, Landspitali-University Hospital, Reykjavik, Iceland. SUBJECTS: Sixty hospitalized patients (mean age 83.0 (SD 7.9) years) were randomly assigned. RESULTS: Of the patients, 12.3% suffered from vitamin D deficiency (serum 25(OH)D < 25 nmol/l) and 71.9% suffered from hypovitaminosis D (serum 25(OH)D = 25-75 nmol/l). There were no significant effects of gender or nutritional status on serum 25(OH)D. Anthropometric variables correlated significantly with serum 25(OH)D, but on stepwise linear regression modelling for the prediction of serum 25(OH)D, BMI remained the only predictor variable (B = -1.454, 95% CI -2.535, -0.373, P = 0.009). CONCLUSIONS: BMI was significantly negatively associated with serum 25(OH)D in hospitalized elderly patients. Neither nutritional status nor season significantly affected serum 25(OH)D in our patient group. Higher levels of serum 25(OH)D in elderly subjects with lower BMI are most likely explained by volume of distribution rather than by mobilization of vitamin D from its storage in adipose tissue due to age and disease-related catabolism.

Anemia, nutritional status, and inflammation in hospitalized elderly.

OBJECTIVE: Anemia (hemoglobin <120 g/L) in elderly patients is a health problem. The aim of this study was to investigate the prevalence of anemia and associations of anemia with nutritional status and inflammation in hospitalized elderly. METHODS: Sixty patients from the Department of Geriatrics were randomly assigned to participate. Blood samples were drawn and analyzed at the laboratory of the University Hospital in Reykjavik. Nutritional status was assessed using anthropometric and hematologic parameters. RESULTS: The prevalence of anemia was 36.7%. Female participants were more frequently anemic than male participants (47.4% versus 18.2%, P = 0.024). Anemic patients had a lower albumin level (31.3 versus 33.4 g/L, P = 0.019) and a higher erythrocyte sedimentation rate (29.6 versus 16.0 mm/h, P = 0.005) and were more often malnourished (81.8% versus 44.7%, P = 0.005) than non-anemic patients. Hemoglobin correlated with prealbumin (rho = 0.338, P = 0.008) and albumin (rho = 0.250, P = 0.054) levels, but negatively with age (rho = -0.310, P = 0.016) and erythrocyte sedimentation rate (rho = -0.412, P < 0.001). In the multivariate analysis, erythrocyte sedimentation rate and nutritional status were significant predictors of hemoglobin (R(2) = 34.0%). CONCLUSION: This cross-sectional analysis provides evidence of anemia in 36.7% of patients hospitalized at the Landspitali-University Hospital in Reykjavik and shows an association among anemia, deteriorated nutritional status, and inflammation. Future prospective studies are needed to assess the efficacy of adjuvant nutritional support to stabilize or improve nutritional status including anemia in hospitalized elderly.

Differences in the glomerular filtration rate calculated by two creatinine-based and three cystatin-C-based formulae in hospitalized elderly patients.

BACKGROUND: Reduced renal function is a health problem in elderly patients. Different creatinine- and cystatin-C-based formulae have been used to estimate glomerular filtration rate (GFR). AIMS: To investigate individual and group differences of GFR estimates derived from five different formulae. METHODS: 60 patients were randomly assigned to participate in this cross-sectional study. Nutrition status was assessed, blood samples were drawn and GFR was calculated using two creatinine- and three cystatin-C-based formulae. RESULTS: Four of five formulae indicate reduced GFR in >70% of the participants, GFR was significantly less in malnourished patients according to one creatinine formula. Estimates from the formulae were highly correlated (r = 0.607-0.863, p < 0.001), but individual differences were between -36.1 and 79.9 ml/min/1.73 m(2). The formulae grouped 38.3-60.0% of the subjects differently into the five stages of chronic kidney disease. BMI, total cholesterol, age and gender were significant predictors for the calculated GFR differences between the formulae. CONCLUSION: The prevalence of reduced renal function is high in elderly hospitalized patients. BMI, age and/or gender can affect GFR estimates depending on the formula used, and there is an association between total cholesterol and calculated GFR differences between formulae. Different formulae can result in a different grouping of patients into the five stages of chronic renal disease.

Total plasma homocysteine in hospitalized elderly: associations with vitamin status and renal function.

AIMS: To describe the prevalence of hyperhomocystein- emia (>15 micromol/l) in hospitalized elderly and to investigate whether nutrition status and other factors are related to total plasma homocysteine (tHcy). METHODS: Sixty hospitalized elderly patients (age 83.0 +/- 7.9 years) participated in this cross-sectional study. Blood was drawn in fasting state and analyzed for albumin, prealbumin, lymphocytes, tHcy, cystatin C, folic acid, and vitamin B(12). The nutritional status was assessed. Statistical analyses included multivariate regression. RESULTS: The prevalence of hyperhomocysteinemia was 31.7%, increased cystatin C was observed in 38.3% of the subjects. tHcy correlated positively with cystatin C, but negatively with vitamin B(12) and folic acid. Neither age nor nutritional status were related to tHcy. In multivariate analysis, folic acid and cystatin C remained significant predictors of tHcy (adjusted R(2) = 60.6%). According to the regression model, serum folic acid concentrations >30.3 nmol/l are required to achieve a mean tHcy <15.0 micromol/l in patients with reduced renal function. CONCLUSIONS: Hyperhomocysteinemia is frequent in hospitalized elderly. Cystatin C and folic acid explain most of the tHcy variance. Higher folic acid levels within the normal range might further decrease tHcy. The current lower folic acid cutoff value (7 nmol/l) might not be sufficient in preventing homocysteinemia in hospitalized elderly with reduced renal function.