Association between occupational solvent exposure and cognitive performance in the French CONSTANCES study.

OBJECTIVE: The objective of this study was to evaluate the association between occupational exposure to solvents and cognitive performance in middle-aged and early-ageing participants, taking into account the working environment. METHODS: In the French Cohorte des consultants des Centres d'examens de santé (CONSTANCES) cohort, 41 854 participants aged 45-69 years completed a self-reported, lifetime occupational exposure questionnaire. Exposure to solvents (gasoline for hand washing, trichloroethylene, white spirit, cellulosic thinner) was first considered as a binary variable (exposed/not exposed). We computed number of solvent types to which participants were exposed, solvent exposure time and delay since last exposure. Cognitive performance was assessed and analysed in reference to norms of neuropsychological battery previously established in CONSTANCES according to age, sex and education. Multiple linear and modified Poisson regression were used to estimate the associations between solvent exposure and cognitive performance adjusting for individual and environmental characteristics, and working conditions (night shift, repetitive and noisy work). RESULTS: Men had a greater risk of global cognitive impairment when they were exposed to gasoline (relative risk (RR)=1.12, 95% CI 1.03 to 1.22), white spirit (RR=1.14, 95% CI 1.05 to 1.25) or cellulosic thinner (RR=1.17, 95% CI 1.06 to 1.31) at the workplace, even after adjusting for confounders. Women exposed to white spirit or exposed for more than 20 years had poorer global cognitive performance. CONCLUSION: These findings strengthen our understanding of the detrimental effect of solvent exposure on cognitive health not only in men but also in women for the first time, in a large general population middle-aged and early-ageing sample from France, taking into account working conditions.

Norms for standard neuropsychological tests from the French CONSTANCES cohort.

BACKGROUND AND PURPOSE: Neuropsychological testing plays a key role in various clinical contexts. Even though a substantial number of adults suffer neurological disorders such as early-onset dementia, stroke, traumatic brain injury or multiple sclerosis, most normative data do not include persons below 65. The aim of this study was to produce updated norms for the Mini-Mental State Examination, the Free and Cued Selective Reminding Test, the Trail Making Test, verbal fluency tasks and the Digit Symbol Substitution Test for middle-aged and older adults. METHODS: The sample consisted of 51 879 participants aged 45-70 years from the CONSTANCES study. Norms are presented in percentiles stratified on age, education and gender. RESULTS: The results illustrated the effect of age in all tests considered. For tests involving speed processing, the impact of age was observed including in tight age range categories (5 years). The results also showed the well-known effect of education and an effect of gender in tests involving verbal memory and speed processing. CONCLUSIONS: The norms provided allow the variability of the cognitive performances of middle-aged to older populations to be understood, with a high precision in age categories. The tests considered are broadly used in neuropsychological practice and should be helpful in a variety of clinical contexts.

MACVIA-LR (Fighting Chronic Diseases for Active and Healthy Ageing in Languedoc-Roussillon): A Success Story of the European Innovation Partnership on Active and Healthy Ageing.

The Région Languedoc Roussillon is the umbrella organisation for an interconnected and integrated project on active and healthy ageing (AHA). It covers the 3 pillars of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA): (A) Prevention and health promotion, (B) Care and cure, (C) and (D) Active and independent living of elderly people. All sub-activities (poly-pharmacy, falls prevention initiative, prevention of frailty, chronic respiratory diseases, chronic diseases with multimorbidities, chronic infectious diseases, active and independent living and disability) have been included in MACVIA-LR which has a strong political commitment and involves all stakeholders (public, private, patients, policy makers) including CARSAT-LR and the Eurobiomed cluster. It is a Reference Site of the EIP on AHA. The framework of MACVIA-LR has the vision that the prevention and management of chronic diseases is essential for the promotion of AHA and for the reduction of handicap. The main objectives of MACVIA-LR are: (i) to develop innovative solutions for a network of Living labs in order to reduce avoidable hospitalisations and loss of autonomy while improving quality of life, (ii) to disseminate the innovation. The three years of MACVIA-LR activities are reported in this paper.

Effect size for the main cognitive function determinants in a large cross-sectional study.

BACKGROUND AND PURPOSE: The aim of our study was to examine the effect sizes of different cognitive function determinants in middle and early old age. METHODS: Cognitive functions were assessed in 11 711 volunteers (45 to 75 years old), included in the French CONSTANCES cohort between January 2012 and May 2014, using the free and cued selective reminding test (FCSRT), verbal fluency tasks, digit-symbol substitution test (DSST) and trail making test (TMT), parts A and B. The effect sizes of socio-demographic (age, sex, education), lifestyle (alcohol, tobacco, physical activity), cardiovascular (diabetes, blood pressure) and psychological (depressive symptomatology) variables were computed as omega-squared coefficients (ω2 ; part of the variation of a neuropsychological score that is independently explained by a given variable). RESULTS: These sets of variables explained from R2 = 10% (semantic fluency) to R2 = 26% (DSST) of the total variance. In all tests, socio-demographic variables accounted for the greatest part of the explained variance. Age explained from ω2 = 0.5% (semantic fluency) to ω2 = 7.5% (DSST) of the total score variance, gender from ω2 = 5.2% (FCSRT) to a negligible part (semantic fluency or TMT) and education from ω2 = 7.2% (DSST) to ω2 = 1.4% (TMT-A). Behavioral, cardiovascular and psychological variables only slightly influenced the cognitive test results (all ω2 < 0.8%, most ω2 < 0.1%). CONCLUSION: Socio-demographic variables (age, gender and education) are the main variables associated with cognitive performance variations between 45 and 75 years of age in the general population.

Are migraine and non-migrainous headache risk factors for stroke in the elderly? Findings from a 12-year cohort follow-up.

BACKGROUND AND PURPOSE: There is evidence that migraine is a risk factor for stroke but little is known about this association in elderly people. Furthermore, non-migrainous headache (NMH) has received little attention despite being the most frequently reported type of headache. Late-life migraine and NMH were examined as candidate risk factors for stroke in a community-dwelling elderly sample over a 12-year follow-up. METHODS: One thousand nine hundred and nineteen non-institutionalized subjects aged 65+, without dementia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, DSM-IV criteria) and with no stroke history at baseline, were drawn from the Three-City Montpellier cohort (recruitment 1999-2001) for longitudinal analysis. Ischaemic and haemorrhagic stroke was reported at baseline and at each of the five follow-ups, with cases validated by a panel of experts, according to ICD-10 criteria (International Classification of Diseases, 10th revision). Migraine and NMH were determined at baseline during a neurological interview and examination using 1988 International Headache Society criteria. RESULTS: A total of 110 (5.4%) cases of migraine and 179 (8.9%) cases of NMH were identified at baseline. During the median 8.8-year follow-up, incident stroke was observed in 1.9% of baseline migrainers, 6.2% of NMH and 3.6% of those with no lifetime history of headache. Cox proportional hazard models indicated that migraine was not a risk factor for stroke; however, NMH sufferers were twice as likely to have a stroke (hazard ratio 2.00, 95% confidence interval 1.00-3.93, P = 0.049). CONCLUSIONS: This study is one of the first to suggest that late-life NMH rather than migraine could be an independent risk factor for stroke and a warning sign. The incidence of stroke in elderly migrainers, seldom reported, is particularly low.

Primary Prevention of Dementia: An Epidemiological Point of View.

From an epidemiological perspective, in order to increase the level of evidence, it is necessary to refer to data from longitudinal studies to validate the temporal relationship between exposure (e.g. the behavior or modifying factor) and the disease. Findings from such studies are useful for defining risk factors and laying the groundwork for proposing interventions for prevention. This step is crucial in order to define the periods (life-course approach) and groups at risk, which will then become the targets of interventions designed to modify behaviors or lifestyle. Specifying the underlying mechanisms of these risk factors is one of the objectives of etiological epidemiology which focuses on the origin of diseases but is not essential for a more pragmatic interventional approach. These questions are essential for dementia prevention and are discussed in this paper. Furthermore, timing interventions is a major problem even if we identify primary prevention pathways in dementia. Another important concern for epidemiologists is the need to make projections to estimate the number of dementia cases in the next decades considering different intervention scenarios. These models require adequate descriptive indicators of dementia, demography and mortality and precise estimations of the impact of potential interventions in terms of delaying disease onset for instance.

A novel Alzheimer disease locus located near the gene encoding tau protein.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

How to optimize the use of biobanks from population-based cohorts in aging research.

In epidemiological cohorts, there is an increased interest for the implementation of biobanks. The potential role of biological determinants of diseases needs to be investigated before the onset of the event of interest in order to limit the problems encountered when examining biological determinants in classical case-control studies. Biobank is now a very sophisticated system that consists of a programmed storage of biological material and related data. Our aim in this paper is to document how biobank constitution is useful for studying biological determinants of aging and to give some indications on methodological issues that can be helpful to optimize the constitution and use of biobanks in aging cohorts. Optimization of sampling through two-phase designs (nested case control or case-cohort studies) allows better efficiency. These elements are, for most of them, not specific to aging populations but are useful more generally for the epidemiology of chronic diseases. Our purpose will be illustrated with some examples and results obtained in an ongoing aging cohort, the Three-City Study.

Operational Definition of Active and Healthy Ageing (AHA): A Conceptual Framework.

Health is a multi-dimensional concept, capturing how people feel and function. The broad concept of Active and Healthy Ageing was proposed by the World Health Organisation (WHO) as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal Active and Healthy Ageing definition is not available and it may differ depending on the purpose of the definition and/or the questions raised. While the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact, a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier, France, October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (Contre les Maladies Chroniques pour un Vieillissement Actif en Languedoc Roussillon) to propose an operational definition of Active and Healthy Ageing including tools that may be used for this. The current paper describes the rationale and the process by which the aims of the meeting will be reached.

Diagnostic use of facial image analysis software in endocrine and genetic disorders: review, current results and future perspectives.

Cushing's syndrome (CS) and acromegaly are endocrine diseases that are currently diagnosed with a delay of several years from disease onset. Novel diagnostic approaches and increased awareness among physicians are needed. Face classification technology has recently been introduced as a promising diagnostic tool for CS and acromegaly in pilot studies. It has also been used to classify various genetic syndromes using regular facial photographs. The authors provide a basic explanation of the technology, review available literature regarding its use in a medical setting, and discuss possible future developments. The method the authors have employed in previous studies uses standardized frontal and profile facial photographs for classification. Image analysis is based on applying mathematical functions evaluating geometry and image texture to a grid of nodes semi-automatically placed on relevant facial structures, yielding a binary classification result. Ongoing research focuses on improving diagnostic algorithms of this method and bringing it closer to clinical use. Regarding future perspectives, the authors propose an online interface that facilitates submission of patient data for analysis and retrieval of results as a possible model for clinical application.

Poor nutritional status is associated with a higher risk of falling and fracture in elderly people living at home in France: the Three-City cohort study.

UNLABELLED: Falling and fractures are a public health problem in elderly people. The aim of our study was to investigate whether nutritional status is associated with the risk of falling or fracture in community-dwelling elderly. Poor nutritional status was significantly associated with a higher risk of both falling and fractures. INTRODUCTION: Nutrition could play a role to prevent falls and fractures. The purpose of this study is to investigate whether a poor nutritional status is associated with the risk of falling and of fracture in community dwelling elderly. METHODS: Baseline nutritional status of participants was assessed using the Mini Nutritional Assessment (MNA). After a follow-up of 12 years, 6040 individuals with available data for falls and 6839 for fracture were included. People who presented the outcomes at baseline were excluded. Cox models were used to evaluate the associations between nutritional status and the risks of fall or fracture. RESULTS: The frequency of poor nutritional status (MNA ≤ 23.5), at baseline, was respectively 12.0% in the "fall study sample" and 12.8% in the "fracture study sample." Incident fall and fracture over 12 years were reported in 55.8 and 18.5% of the respective samples, respectively. In multivariate models controlled for sociodemographic data and several baseline health indicators, poor nutritional status was significantly associated with a higher risk of falling (hazard ratio (HR) = 1.66, 95% confidence interval (95% CI) 1.35-2.04 in men and HR = 1.20, 95% CI 1.07-1.34 in women) and with a higher risk of fracture (HR = 1.28, 95% CI 1.09-1.49). CONCLUSION: Poor nutritional status was associated with a higher risk of both falling and fractures in French elderly community-dwellers. Early screening and management of the nutritional status may be useful to reduce the frequency of these events in older people.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Developmental determinants in non-communicable chronic diseases and ageing.

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.

Hierarchical structure of the activities of daily living scale in dementia.

OBJECTIVES: To describe the sequence of basic activities of daily living (ADL) loss to determine whether there is a hierarchical structure of ADL in dementia in two epidemiological prospective studies: the Paquid study and the Three City Study (3C). DESIGN: Two prospective population-based cohort studies: Paquid (over 22 years of follow-up) and 3C (over 10 years of follow-up). SETTING: Paquid Study, Gironde, Dordogne, France; The Three Cities Study, Bordeaux, Montpellier, Dijon, France. MAIN OUTCOMES MEASURES: We analyzed four ADL of the Katz scale: bathing, dressing, transferring and feeding. The a priori hierarchical relationship of the 4 activities tested was 1) no ADL-disability at all four activities; 2) moderate ADL-disability, or disability at bathing and/or dressing (and no disability in transferring nor feeding); and 3) severe ADL-disability, or disability in bathing and/or dressing and transferring and/or feeding. We performed a Guttman scale analysis to establish the hierarchical properties scale. RESULTS: In total, 845 incident cases of dementia were included, among which 838 cases (99.2%) were without any missing data for ADL. Upon diagnosis of dementia, 564 subjects (67.3%) had no ADL-disability, 236 (26.2%) had moderate ADL-disability, and 38 subjects (4.5%) had severe disability. The a priori hierarchy was respected with non-discordance. CONCLUSION: We defined 3 simple relevant stages of ADL functional decline in dementia that would be easy to collect in clinical practice: stage 1, subjects with no major ADL disabilities; stage 2, subjects with complete disability in bathing and/or dressing; and stage 3, subjects with complete disability in all 4 tasks.

Impact of a premature menopause on cognitive function in later life.

OBJECTIVE: To determine whether premature menopause (≤40 years) can have long-lasting effects on later-life cognition and investigate whether this association varies depending on the type of menopause and use of hormone treatment (HT). DESIGN: Population-based cohort study. SETTING: The French Three-City Study. POPULATION: Four thousand eight hundred and sixty-eight women aged at least 65 years. METHODS: Multivariable-adjusted logistic regression models were used to determine the association between age at menopause, type of menopause (surgical, natural), and the use of menopausal HT and later-life cognitive function. MAIN OUTCOME MEASURES: Performance on a cognitive test battery (at baseline and over 7 years) and clinical dementia diagnosis. RESULTS: Menopause at or before the age of 40 years, both premature bilateral ovariectomy and premature ovarian failure (non-surgical loss of ovarian function), was associated with worse verbal fluency (OR 1.56, 95%CI 1.12-1.87, P=0.004) and visual memory (OR 1.39, 95%CI 1.09-1.77, P=0.007) in later life. HT at the time of premature menopause appeared beneficial for later-life visual memory but increased the risk of poor verbal fluency. Type of menopause was not significantly associated with cognitive function. Premature menopause was associated with a 30% increased risk of decline in psychomotor speed and global cognitive function over 7 years. CONCLUSION: Both premature surgical menopause and premature ovarian failure were associated with long-term negative effects on cognitive function, which are not entirely offset by menopausal HT. In terms of surgical menopause, these results suggest that the potential long-term effects on cognitive function should form part of the risk/benefit ratio when considering ovariectomy in younger women.

Perception of Alzheimer's disease in the French population.

OBJECTIVE: The aim of this study was to investigate the perception, knowledge, opinions and beliefs about AD in the French population to improve care for patients with Alzheimer's disease. DESIGN: A cross-sectional telephone survey in 2008. SETTING: French "Alzheimer Plan 2008-2012". PARTICIPANTS: 2013 respondents, representative of the French population. MEASUREMENTS: The respondents answered a questionnaire in which they were presented with a series of attitudinal statements about health in general and AD. RESULTS: Main results are summarized as followed: (a) Respondents think that AD can be devastating for a family (93%). This devastating feeling prevails in the population >75 years old and in people who know patient with AD. (b) General population has a reasonable knowledge about AD, but is still unable to recognize early stages: 95% of respondents considered that difficulties to manage administrative papers and find their way back home suggest early AD. (c) 91% of the population would like to know the diagnosis if they had AD. (d) 38% of the population know or have known at least one patient within their social circle. People think that the care of AD's patient can be better but they trust in the French government to improve it. CONCLUSION: General representation of AD is changing in a positive way and, even though AD is perceived as a calamity, people are confident that solutions will be found in the future.

A genome-wide association meta-analysis of plasma Aß peptides concentrations in the elderly.

Amyloid beta (Aß) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aß peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aß peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aß-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aß1-40 and Aß1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aß1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aß1-42 secretion. In conclusion, our study results suggest that plasma Aß peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

Measuring cognitive change in subjects with prodromal Alzheimer's disease.

OBJECTIVE: To investigate the sensitivity of a large set of neuropsychological tests to detect cognitive changes due to prodromal Alzheimer's disease(AD); to compare their metrological properties in order to select a restricted number of these tests for the longitudinal follow-up of subjects with prodromal AD. PARTICIPANTS: 212 patients with mild cognitive impairment were tested at baseline by a standardised neuropsychological battery, which included: the Free and Cued Selective Reminding test (FCSRT), the Benton Visual Retention test, the Deno100, verbal fluency, a serial digit learning test, the double task of Baddeley, the Wechsler Adult Intelligence Scale (WAIS) similarities, the Trail-Making Test and the WAIS digit symbol test. Patients were monitored every 6 months for up to 3 years in order to identify those who converted to AD (retrospectively classified as prodromal AD). Statistical analyses were performed using a nonlinear multivariate mixed model involving a latent process. This model assumes that the psychometric tests are nonlinear transformations of a common latent cognitive process, and it captures the metrological properties of tests. RESULTS: 57 patients converted to AD. The most sensitive tests in the detection of cognitive changes due to prodromal AD were the FCSRT, the semantic verbal fluency and the Deno100. Some tests exhibited a higher sensitivity to cognitive changes for subjects with high levels of cognition, such as the free recall, delayed free recall scores of the FCSRT and the semantic verbal fluency, whereas others showed a higher sensitivity at low levels of cognition, such as the total recall score of the FCSRT. CONCLUSIONS: Tests used for the follow-up of prodromal AD subjects should be chosen among those that actually decline in this stage of the disease and should be selected according to the subject's initial scores.

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

A simple score to predict survival with dementia in the general population.

BACKGROUND/AIMS: This study was designed to develop a practical risk score for predicting 5-year survival after the diagnosis of dementia. METHODS: Using the Paquid Study (prospective, population-based, long-term cohort study), we created a prognosis score with incident cases of dementia and validated it in another prospective, population-based, long-term cohort study, the Three City Study. - RESULTS: Among the 3,777 subjects enrolled in the Paquid Study, 454 incident cases of dementia were included in this study. After a 5-year follow-up period, 319 (70.3%) were deceased. The score was constructed from three independent prognostic variables (gender, age at diagnosis and number of ADL restricted). The discriminant ability of the score was good with a c index of 0.754. Sensitivity was 64.7% and specificity 76.3%. In the validation cohort, the discriminant ability of the prognostic score with c statistics was 0.700. Sensitivity was 26.3% and specificity 95.4%. CONCLUSIONS: The prognostic factors selected in the predictive model are easily assessable, so this simple score could provide helpful information for the management of dementia, particularly to identify patients with duration of the disease greater than 5 years.