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1.  Long-Term Exposure to Ambient Air Pollution and Incidence of Cerebrovascular Events: Results from 11 European Cohorts within the ESCAPE Project 
Environmental Health Perspectives  2014;122(9):919-925.
Background: Few studies have investigated effects of air pollution on the incidence of cerebrovascular events.
Objectives: We assessed the association between long-term exposure to multiple air pollutants and the incidence of stroke in European cohorts.
Methods: Data from 11 cohorts were collected, and occurrence of a first stroke was evaluated. Individual air pollution exposures were predicted from land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE). The exposures were: PM2.5 [particulate matter (PM) ≤ 2.5 μm in diameter], coarse PM (PM between 2.5 and 10 μm), PM10 (PM ≤ 10 μm), PM2.5 absorbance, nitrogen oxides, and two traffic indicators. Cohort-specific analyses were conducted using Cox proportional hazards models. Random-effects meta-analysis was used for pooled effect estimation.
Results: A total of 99,446 study participants were included, 3,086 of whom developed stroke. A 5-μg/m3 increase in annual PM2.5 exposure was associated with 19% increased risk of incident stroke [hazard ratio (HR) = 1.19, 95% CI: 0.88, 1.62]. Similar findings were obtained for PM10. The results were robust to adjustment for an extensive list of cardiovascular risk factors and noise coexposure. The association with PM2.5 was apparent among those ≥ 60 years of age (HR = 1.40, 95% CI: 1.05, 1.87), among never-smokers (HR = 1.74, 95% CI: 1.06, 2.88), and among participants with PM2.5 exposure < 25 μg/m3 (HR = 1.33, 95% CI: 1.01, 1.77).
Conclusions: We found suggestive evidence of an association between fine particles and incidence of cerebrovascular events in Europe, even at lower concentrations than set by the current air quality limit value.
Citation: Stafoggia M, Cesaroni G, Peters A, Andersen ZJ, Badaloni C, Beelen R, Caracciolo B, Cyrys J, de Faire U, de Hoogh K, Eriksen KT, Fratiglioni L, Galassi C, Gigante B, Havulinna AS, Hennig F, Hilding A, Hoek G, Hoffmann B, Houthuijs D, Korek M, Lanki T, Leander K, Magnusson PK, Meisinger C, Migliore E, Overvad K, Östenson CG, Pedersen NL, Pekkanen J, Penell J, Pershagen G, Pundt N, Pyko A, Raaschou-Nielsen O, Ranzi A, Ricceri F, Sacerdote C, Swart WJ, Turunen AW, Vineis P, Weimar C, Weinmayr G, Wolf K, Brunekreef B, Forastiere F. 2014. Long-term exposure to ambient air pollution and incidence of cerebrovascular events: results from 11 European cohorts within the ESCAPE project. Environ Health Perspect 122:919–925; http://dx.doi.org/10.1289/ehp.1307301
doi:10.1289/ehp.1307301
PMCID: PMC4153743  PMID: 24835336
2.  Arterial Blood Pressure and Long-Term Exposure to Traffic-Related Air Pollution: An Analysis in the European Study of Cohorts for Air Pollution Effects (ESCAPE) 
Environmental Health Perspectives  2014;122(9):896-905.
Background: Long-term exposure to air pollution has been hypothesized to elevate arterial blood pressure (BP). The existing evidence is scarce and country specific.
Objectives: We investigated the cross-sectional association of long-term traffic-related air pollution with BP and prevalent hypertension in European populations.
Methods: We analyzed 15 population-based cohorts, participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE). We modeled residential exposure to particulate matter and nitrogen oxides with land use regression using a uniform protocol. We assessed traffic exposure with traffic indicator variables. We analyzed systolic and diastolic BP in participants medicated and nonmedicated with BP-lowering medication (BPLM) separately, adjusting for personal and area-level risk factors and environmental noise. Prevalent hypertension was defined as ≥ 140 mmHg systolic BP, or ≥ 90 mmHg diastolic BP, or intake of BPLM. We combined cohort-specific results using random-effects meta-analysis.
Results: In the main meta-analysis of 113,926 participants, traffic load on major roads within 100 m of the residence was associated with increased systolic and diastolic BP in nonmedicated participants [0.35 mmHg (95% CI: 0.02, 0.68) and 0.22 mmHg (95% CI: 0.04, 0.40) per 4,000,000 vehicles × m/day, respectively]. The estimated odds ratio (OR) for prevalent hypertension was 1.05 (95% CI: 0.99, 1.11) per 4,000,000 vehicles × m/day. Modeled air pollutants and BP were not clearly associated.
Conclusions: In this first comprehensive meta-analysis of European population-based cohorts, we observed a weak positive association of high residential traffic exposure with BP in nonmedicated participants, and an elevated OR for prevalent hypertension. The relationship of modeled air pollutants with BP was inconsistent.
Citation: Fuks KB, Weinmayr G, Foraster M, Dratva J, Hampel R, Houthuijs D, Oftedal B, Oudin A, Panasevich S, Penell J, Sommar JN, Sørensen M, Tittanen P, Wolf K, Xun WW, Aguilera I, Basagaña X, Beelen R, Bots ML, Brunekreef B, Bueno-de-Mesquita HB, Caracciolo B, Cirach M, de Faire U, de Nazelle A, Eeftens M, Elosua R, Erbel R, Forsberg B, Fratiglioni L, Gaspoz JM, Hilding A, Jula A, Korek M, Krämer U, Künzli N, Lanki T, Leander K, Magnusson PK, Marrugat J, Nieuwenhuijsen MJ, Östenson CG, Pedersen NL, Pershagen G, Phuleria HC, Probst-Hensch NM, Raaschou-Nielsen O, Schaffner E, Schikowski T, Schindler C, Schwarze PE, Søgaard AJ, Sugiri D, Swart WJ, Tsai MY, Turunen AW, Vineis P, Peters A, Hoffmann B. 2014. Arterial blood pressure and long-term exposure to traffic-related air pollution: an analysis in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Environ Health Perspect 122:896–905; http://dx.doi.org/10.1289/ehp.1307725
doi:10.1289/ehp.1307725
PMCID: PMC4154218  PMID: 24835507
3.  Incidence and Predictors of Multimorbidity in the Elderly: A Population-Based Longitudinal Study 
PLoS ONE  2014;9(7):e103120.
Background
We aimed to calculate 3-year incidence of multimorbidity, defined as the development of two or more chronic diseases in a population of older people free from multimorbidity at baseline. Secondly, we aimed to identify predictors of incident multimorbidity amongst life-style related indicators, medical conditions and biomarkers.
Methods
Data were gathered from 418 participants in the first follow up of the Kungsholmen Project (Stockholm, Sweden, 1991–1993, 78+ years old) who were not affected by multimorbidity (149 had none disease and 269 one disease), including a social interview, a neuropsychological battery and a medical examination.
Results
After 3 years, 33.6% of participants who were without disease and 66.4% of those with one disease at baseline, developed multimorbidity: the incidence rate was 12.6 per 100 person-years (95% CI: 9.2–16.7) and 32.9 per 100 person-years (95% CI: 28.1–38.3), respectively. After adjustments, worse cognitive function (OR, 95% CI, for 1 point lower Mini-Mental State Examination: 1.22, 1.00–1.48) was associated with increased risk of multimorbidity among subjects with no disease at baseline. Higher age was the only predictor of multimorbidity in persons with one disease at baseline.
Conclusions
Multimorbidity has a high incidence at old age. Mental health-related symptoms are likely predictors of multimorbidity, suggesting a strong impact of mental disorders on the health of older people.
doi:10.1371/journal.pone.0103120
PMCID: PMC4109993  PMID: 25058497
4.  Relation of multimorbidity to subjective and objective cognitive impairment: a population-based twin study 
Objective
To examine the association of common chronic disease and multimorbidity with subjective cognitive impairment (SCI) and cognitive impairment no-dementia (CIND), and to explore the contribution of genetic background and shared familial environment to these associations.
Design
Population-based twin study.
Setting
Nationwide Swedish twins.
Subjects
11,379 dementia-free individuals aged ≥ 65 from the Swedish Twin Registry.
Main Outcome Measures
SCI was defined as subjective complaint of cognitive change without objective cognitive impairment, and CIND was ascertained according to the standard definition. Chronic diseases were classified based on international criteria, and multimorbidity was assessed as the co-occurrence of at least two chronic diseases in the same individual.
Results
In unmatched, fully-adjusted regression models, musculoskeletal, respiratory, and urological diseases were significantly associated with increased odds ratios (ORs) of both SCI and CIND. Circulatory and gastrointestinal disorders were related to SCI, while endocrine diseases were associated with CIND. The adjusted ORs of multimorbidity were 2.1 [95% Confidence Intervals (95% CI): 1.8–2.3] for SCI and 1.5 for CIND (95% CI: 1.3–1.8). There was a significant dose-dependent relationship between number of chronic diseases and ORs for SCI but not for CIND. In co-twin control analyses, the chronic diseases-SCI association remained significant but the association with CIND was no longer statistically significant.
Conclusion
Chronic diseases are associated with both SCI and CIND and the association is stronger when there is multimorbidity. Genetic and shared environmental factors may partially explain the association of CIND but not that of SCI with chronic diseases.
doi:10.3233/JAD-122050
PMCID: PMC4079077  PMID: 23603395
Cognitive impairment no-dementia (CIND); chronic diseases; multimorbidity; population-based; subjective cognitive impairment (SCI); twin-study
5.  Differential distribution of subjective and objective cognitive impairment in the population: A nationwide twin-study 
We report the prevalence of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND), their socio-demographic profile, and the contribution of genetic background and shared familial environment to SCI and CIND. Subjects were 11,926 dementia-free twin individuals aged ≥ 65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. Overall prevalence of SCI and CIND was 39% (95% CI 38-39) and 25% (95% CI 24-25). Among those with CIND, 57% had subjective cognitive complaints; 43% did not. In multivariate GEE models, both SCI and CIND were older compared with people without any cognitive impairment. CIND were also less educated, more likely to be unmarried and to have lower socioeconomic status (SES). SCI individuals differed from persons with CIND as they were older, more educated, more likely to be married, and to have higher SES. Co-twin control analysis, which corrects for common genetic and shared environmental background, confirmed that low education was still associated with CIND. Probandwise concordance for SCI and CIND was 63% and 52% in monozygotic twins, 63% and 50% in dizygotic same-sex twins, and 42% and 29% in dizygotic unlike-sex twins. Tetrachoric correlations showed no significant differences between monozygotic and dizygotic same-sex twins. We conclude that subjective and objective cognitive impairment are both highly prevalent among nondemented elderly yet have distinct sociodemographic profiles. Shared environmental influences rather than genetic background play a role in the occurrence of SCI and CIND.
doi:10.3233/JAD-2011-111904
PMCID: PMC4063353  PMID: 22233768
Cognitive impairment no dementia; concordance; population-based; prevalence; socio-demographic; subjective cognitive impairment; twin study
6.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Background
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
doi:10.1371/journal.pone.0094661
PMCID: PMC4055488  PMID: 24922517
7.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
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.
doi:10.1038/ng.2802
PMCID: PMC3896259  PMID: 24162737
8.  A Self-Report Risk Index to Predict Occurrence of Dementia in Three Independent Cohorts of Older Adults: The ANU-ADRI 
PLoS ONE  2014;9(1):e86141.
Background and Aims
The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.
Methods
This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.
Results
For the ANU-ADRI using available data, the MAP study c-statistic was 0·637 (95% CI 0·596–0·678), for the KP study it was 0·740 (0·712–0·768) and for the CVHS it was 0·733 (0·691–0·776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650–0.727), 0.666 (0.628–0.704) and 0.734 (0.707–0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427–0.554) to 0.595 (0.565–0.625).
Conclusion
A composite risk score derived from the ANU-ADRI weights including 8–10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.
doi:10.1371/journal.pone.0086141
PMCID: PMC3900468  PMID: 24465922
9.  The Influence of Multimorbidity on Clinical Progression of Dementia in a Population-Based Cohort 
PLoS ONE  2013;8(12):e84014.
Introduction
Co-occurrence with other chronic diseases may influence the progression of dementia, especially in case of multiple chronic diseases. We aimed to verify whether multimorbidity influenced cognitive and daily functioning during nine years after dementia diagnosis compared with the influence in persons without dementia.
Methods
In the Kungsholmen Project, a population-based cohort study, we followed 310 persons with incident dementia longitudinally. We compared their trajectories with those of 679 persons without dementia. Progression was studied for cognition and activities of daily life (ADLs), measured by MMSE and Katz Index respectively. The effect of multimorbidity and its interaction with dementia status was studied using individual growth models.
Results
The mean (SD) follow-up time was 4.7 (2.3) years. As expected, dementia related to both the decline in cognitive and daily functioning. Irrespective of dementia status, persons with more diseases had significantly worse baseline daily functioning. In dementia patients having more diseases also related to a significantly faster decline in daily functioning. Due to the combination of lower functioning in ADLs at baseline and faster decline, dementia patients with multimorbidity were about one to two years ahead of the decline of dementia patients without any co-morbidity. In persons without dementia, no significant decline in ADLs over time was present, nor was multimorbidity related to the decline rate. Cognitive decline measured with MMSE remained unrelated to the number of diseases present at baseline.
Conclusion
Multimorbidity was related to baseline daily function in both persons with and without dementia, and with accelerated decline in people with dementia but not in non-demented individuals. No relationship of multimorbidity with cognitive functioning was established. These findings imply a strong interconnection between physical and mental health, where the greatest disablement occurs when both somatic and mental disorders are present.
doi:10.1371/journal.pone.0084014
PMCID: PMC3875493  PMID: 24386324
10.  Associations between White Matter Microstructure and Cognitive Performance in Old and Very Old Age 
PLoS ONE  2013;8(11):e81419.
Increasing age is associated with deficits in a wide range of cognitive domains as well as with structural brain changes. Recent studies using diffusion tensor imaging (DTI) have shown that microstructural integrity of white matter is associated with cognitive performance in elderly persons, especially on tests that rely on perceptual speed. We used structural equation modeling to investigate associations between white matter microstructure and cognitive functions in a population-based sample of elderly persons (age ≥ 60 years), free of dementia, stroke, and neurological disorders (n = 253). Participants underwent a magnetic resonance imaging scan, from which mean fractional anisotropy (FA) and mean diffusivity (MD) of seven white matter tracts were quantified. Cognitive functioning was analyzed according to performance in five task domains (perceptual speed, episodic memory, semantic memory, letter fluency, and category fluency). After controlling for age, FA and MD were exclusively related to perceptual speed. When further stratifying the sample into two age groups, the associations were reliable in the old-old (≥78 years) only. This relationship between white matter microstructure and perceptual speed remained significant after excluding persons in a preclinical dementia phase. The observed pattern of results suggests that microstructural white matter integrity may be especially important to perceptual speed among very old adults.
doi:10.1371/journal.pone.0081419
PMCID: PMC3839877  PMID: 24282593
11.  Is Midlife Occupational Physical Activity Related to Disability in Old Age? The SNAC-Kungsholmen Study 
PLoS ONE  2013;8(7):e70471.
Objectives
Leisure-time physical activity (PA) has been established to be related to more years lived without disability. However, less is known about the relationship between occupational PA and disability in old age. The aim of the study was 1) to investigate whether midlife occupational PA is related to late-life disability, and 2) to test the hypothesis that the association differs according to the occupational categories of blue and white collar work.
Methods
The study population was derived from the Swedish National Study on Aging and Care, and consisted of a random sample of 1804 subjects aged 72 and above. The association of occupational PA during the longest held occupation with disability in old age was determined using logistic regression.
Results
There was no significant relationship between occupational PA and disability in personal or instrumental activities of daily living (ADL) after controlling for demographic and health-related factors. However, in stratified analyses moderate levels of occupational PA was associated with a lower odds ratio of dependency in personal ADL amongst white collar workers, compared to low level of occupational PA (OR = 0.34 95% C1 0.12–0.98).
Conclusions
Moderate levels of midlife occupational PA were associated with a decreased risk of personal ADL disability in old age among white collar workers, but not among blue collar workers. Our results highlight the importance of encouraging white collar workers to engage in physical activity during or outside work hours.
doi:10.1371/journal.pone.0070471
PMCID: PMC3728023  PMID: 23936209
12.  Association of Cardiovascular Burden with Mobility Limitation among Elderly People: A Population-Based Study 
PLoS ONE  2013;8(5):e65815.
Background
Cardiovascular risk factors (CRFs) such as smoking and diabetes have been associated with mobility limitations among older adults. We seek to examine to what extent individual and aggregated CRFs and cardiovascular diseases (CVDs) are associated with mobility limitation.
Methods
The study sample included 2725 participants (age ≥60 years, mean age 72.7 years, 62% women) in the Swedish National Study on Aging and Care in the Kungsholmen district of central Stockholm, Sweden, who were living either at their own home or in institutions. Data on demographic features, CRFs, and CVDs were collected through interview, clinical examination, self-reported history, laboratory tests, and inpatient register. Mobility limitation was defined as walking speed <0.8 m/s. Data were analyzed using multiple logistic models controlling for potential confounders.
Results
Of the 2725 participants, 581 (21.3%) had mobility limitation. The likelihood of mobility limitation increased linearly with the increasing number of CRFs (i.e., hypertension, high C-reactive protein, obesity, diabetes and smoking) (p for linear trend<0.010) and of CVDs (i.e., ischemic heart disease, atrial fibrillation, heart failure and stroke) (p for linear trend<0.001). There were statistical interactions of aggregated CRFs with age and APOE ε4 allele on mobility limitation (pinteraction<0.05), such that the association of mobility limitation with aggregated CRFs was statistically evident only among people aged <80 years and among carriers of the APOE ε4 allele.
Conclusion
Aggregations of multiple CRFs and CVDs are associated with an increased likelihood of mobility limitation among older adults; however the associations of CRFs with mobility limitation vary by age and genetic susceptibility.
doi:10.1371/journal.pone.0065815
PMCID: PMC3669202  PMID: 23741513
13.  Work-Related Stress May Increase the Risk of Vascular Dementia 
OBJECTIVES
We examined job control, job demands, social support at work, and job strain (ratio of demands to control) in relation to risk of any dementia, Alzheimer’s disease (AD), and vascular dementia (VaD).
DESIGN
A cohort study.
SETTING
The population-based Study of Dementia in Swedish Twins.
PARTICIPANTS
A total of 257 dementia cases (167 AD, 46 VaD) and 9,849 non-demented individuals.
MEASUREMENTS
Dementia diagnoses were based on telephone screening for cognitive impairment followed by in-person clinical work-up. An established job exposure matrix was matched to main occupation categories to measure work characteristics.
RESULTS
In generalized estimating equations (adjusted for the inclusion of complete twin pairs), lower job control was associated with greater risk of any dementia (odds ratio [OR]=1.17, 95% confidence interval [95%CI] 1.04-1.31) and VaD specifically (OR=1.39, 95% CI 1.07-1.81). Lower social support at work was associated with increased risk of dementia (OR=1.15, 95% CI 1.03-1.28), AD (OR=1.14, 95% CI 1.00-1.31), and VaD (OR=1.28, 95% CI=1.02-1.60). Greater job strain was associated with increased risk of VaD only (OR=1.28, 95% CI 1.02-1.60), especially in combination with low social support (OR=1.35, 95% CI 1.11-1.64). Age, gender, education, and cardiovascular disease were controlled. Results were not explained by work complexity or manual work. No differences in work-related stress scores were observed in the 54 twin pairs discordant for dementia, although only two pairs included a twin with VaD.
CONCLUSION
Work-related stress including low job control and low social support at work may increase the risk of dementia, particularly VaD. Modification to work environment that includes attention to social context and provision of meaningful roles for the workers may contribute to the efforts to promote cognitive health.
doi:10.1111/j.1532-5415.2011.03777.x
PMCID: PMC3258308  PMID: 22175444
Work-related stress; job strain; dementia; vascular dementia
14.  The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age 
Mitochondrial dysfunction is implicated in neurodegenerative disorders, such as Alzheimer's disease (AD). Translocase of outer mitochondrial membrane 40 (TOMM40) may be influential in this regard by influencing mitochondrial neurotoxicity. Little is known about the influence of the TOMM40 gene on hippocampal (HC) volume and episodic memory (EM), particularly in healthy older adults. Thus, we sought to discern the influence of TOMM40 single nucleotide polymorphisms (SNPs), which have previously been associated with medial temporal lobe integrity (rs11556505 and rs2075650), on HC volume and EM. The study sample consisted of individuals from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) who were free of dementia and known neurological disorders, and 60–87 years of age (n = 424). EM was measured by using a 16-item word list with a 2-min free recall period and delineation of the HC was performed manually. The influence of Apolipoprotein E (APOE) and TOMM40 was assessed by 2 × 2 ANOVAs and partial correlations. There was no effect of APOE and TOMM40 on EM performance and HC volume. However, partial correlations revealed that HC volume was positively associated with free recall performance (r = 0.21, p < 0.01, r2 = 0.04). When further stratified for TOMM40, the observed association between HC volume and free recall in APOE ε4 carriers was present in combination with TOMM40 rs11556505 any T (r = 0.28, p < 0.01, R2 = 0.08) and rs2075650 any G (r = 0.28, p < 0.01, R2 = 0.08) “risk” alleles. This pattern might reflect higher reliance on HC volume for adequate EM performance among APOE ε4 carriers with additional TOMM40 “risk” alleles suggesting that the TOMM40 gene cannot merely be considered a marker of APOE genotype. Nevertheless, neither APOE nor TOMM40 influenced HC volume or EM in this population-based sample of cognitively intact individuals over the age of 60.
doi:10.3389/fnhum.2013.00198
PMCID: PMC3660657  PMID: 23734114
APOE; TOMM40; episodic memory; hippocampus; cognitive aging
15.  Dementia prevention: current epidemiological evidence and future perspective 
Dementia, a major cause of disability and institutionalization in older people, poses a serious threat to public health and to the social and economic development of modern society. Alzheimer's disease (AD) and cerebrovascular diseases are the main causes of dementia; most dementia cases are attributable to both vascular and neurodegenerative brain damage. No curative treatment is available, but epidemiological research provides a substantial amount of evidence of modifiable risk and protective factors that can be addressed to prevent or delay onset of AD and dementia. Risk of late-life dementia is determined by exposures to multiple factors experienced over the life course, and the effect of specific risk/protective factors depends largely on age. Moreover, cumulative and combined exposure to different risk/protective factors can modify their effect on dementia/AD risk. Multidisciplinary research involving epidemiology, neuropathology, and neuroimaging has provided sufficient evidence that vascular risk factors significantly contribute to the expression and progression of cognitive decline (including dementia) but that active engagement in social, physical, and mentally stimulating activities may delay the onset of dementia. However, these findings need to be confirmed by randomized controlled trials (RCTs). A promising strategy for preventing dementia is to implement intervention programs that take into account both the life-course model and the multifactorial nature of this syndrome. In Europe, there are three ongoing multidomain interventional RCTs that focus on the optimal management of vascular risk factors and vascular diseases. The RCTs include medical and lifestyle interventions and promote social, mental, and physical activities aimed at increasing the cognitive reserve. These studies will provide new insights into prevention of cognitive impairment and dementia. Such knowledge can help researchers plan larger, international prevention trials that could provide robust evidence on dementia/AD prevention. Taking a step in this direction, researchers involved in these European RCTs recently started the European Dementia Prevention Initiative, an international collaboration aiming to improve strategies for preventing dementia.
doi:10.1186/alzrt104
PMCID: PMC3471409  PMID: 22339927
16.  Work-Related Exposure to Extremely Low-Frequency Magnetic Fields and Dementia: Results from the Population-Based Study of Dementia in Swedish Twins 
Background.
We examined the association between extremely low-frequency magnetic fields (EMF) and the risk of dementia and Alzheimer’s disease using all 9,508 individuals from the Study of Dementia in Swedish Twins (HARMONY) with valid occupational and diagnostic data.
Methods.
Dementia diagnoses were based on telephone screening followed by in-person clinical workup. Main lifetime occupation was coded according to an established EMF exposure matrix. Covariates were age, gender, education, vascular risk factors, and complexity of work. Based on previous research, data were also analyzed separately for cases with disease onset by age 75 years versus later, men versus women, and those with manual versus nonmanual main occupation. We used generalized estimating equations with the entire sample (to adjust for the inclusion of complete twin pairs) and conditional logistic regression with complete twin pairs only.
Results.
Level of EMF exposure was not significantly associated with dementia or Alzheimer’s disease. However, in stratified analyses, medium and high levels of EMF exposure were associated with increased dementia risk compared with low level in cases with onset by age 75 years (odds ratio: 1.94, 95% confidence interval: 1.07–3.65 for medium, odds ratio: 2.01, 95% confidence interval: 1.10–3.65 for high) and in participants with manual occupations (odds ratio: 1.81, 95% confidence interval: 1.06–3.09 for medium, odds ratio: 1.75, 95% confidence interval: 1.00–3.05 for high). Results with 42 twin pairs discordant for dementia did not reach statistical significance.
Conclusions.
Occupational EMF exposure appears relevant primarily to dementia with an earlier onset and among former manual workers.
doi:10.1093/gerona/glq112
PMCID: PMC2954236  PMID: 20622138
Dementia; Magnetic fields; Occupation; Alzheimer’s disease
17.  Accelerated Progression From Mild Cognitive Impairment to Dementia in People With Diabetes 
Diabetes  2010;59(11):2928-2935.
OBJECTIVE
The effect of diabetes on mild cognitive impairment (MCI) and its conversion to dementia remains controversial. We sought to examine whether diabetes and pre-diabetes are associated with MCI and accelerate the progression from MCI to dementia.
RESEARCH DESIGN AND METHODS
In the Kungsholmen Project, 963 cognitively intact participants and 302 subjects with MCI (120 with amnestic MCI [aMCI ] and 182 with other cognitive impairment no dementia [oCIND]) age ≥75 years were identified at baseline. The two cohorts were followed for 9 years to detect the incident MCI and dementia following international criteria. Diabetes was ascertained based on a medical examination, hypoglycemic medication use, and random blood glucose level ≥11.0 mmol/l. Pre-diabetes was defined as random blood glucose level of 7.8–11.0 mmol/l in diabetes-free participants. Data were analyzed using standard and time-dependent Cox proportional-hazards models.
RESULTS
During the follow-up period, in the cognitively intact cohort, 182 people developed MCI (42 aMCI and 140 oCIND), and 212 developed dementia. In the MCI cohort, 155 subjects progressed to dementia, the multi-adjusted hazard ratio (95% CI) of dementia was 2.87 (1.30–6.34) for diabetes, and 4.96 (2.27–10.84) for pre-diabetes. In a Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 years. Diabetes and pre-diabetes were neither cross-sectionally nor longitudinally associated with MCI.
CONCLUSIONS
Diabetes and pre-diabetes substantially accelerate the progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI. The association of diabetes with the development of MCI is less evident in old people.
doi:10.2337/db10-0539
PMCID: PMC2963552  PMID: 20713684
18.  Midlife Fruit and Vegetable Consumption and Risk of Dementia in Later Life in Swedish Twins 
Objective:
Diet may be associated with risk of dementia and Alzheimer's disease (AD). We examined the association between fruit and vegetable consumption in midlife and risk for all types of dementia and AD.
Methods:
Participants were 3,779 members of the Swedish Twin Registry who completed a diet questionnaire approximately 30 years prior to cognitive screening and full clinical evaluation for dementia as part of the HARMONY study. Among the participants, 355 twins were diagnosed with dementia. Among these, 81 twin pairs were discordant for dementia (50 discordant for AD). Data were analyzed with logistic regression for the entire sample using generalized estimating equations to adjust for relatedness of twins, and with conditional logistic regression for the co-twin control design.
Results:
In fully-adjusted models, a medium or great proportion of fruits and vegetables in the diet, compared to no or small, was associated with a decreased risk of dementia and AD. This effect was observed among women and those with angina. Similar, but non-significant, odds ratios were found in the co-twin control analyses.
Conclusion:
Our findings suggest that higher fruit and vegetable consumption may reduce the risk of dementia, especially among women and those with angina pectoris in midlife.
doi:10.1097/JGP.0b013e3181c65250
PMCID: PMC2860006  PMID: 19910881
dementia; Alzheimer's disease; diet; fruits and vegetables
19.  Global prevalence of dementia: a Delphi consensus study 
Lancet  2005;366(9503):2112-2117.
Summary
Background
100 years after the first description, Alzheimer's disease is one of the most disabling and burdensome health conditions worldwide. We used the Delphi consensus method to determine dementia prevalence for each world region.
Methods
12 international experts were provided with a systematic review of published studies on dementia and were asked to provide prevalence estimates for every WHO world region, for men and women combined, in 5-year age bands from 60 to 84 years, and for those aged 85 years and older. UN population estimates and projections were used to estimate numbers of people with dementia in 2001, 2020, and 2040. We estimated incidence rates from prevalence, remission, and mortality.
Findings
Evidence from well-planned, representative epidemiological surveys is scarce in many regions. We estimate that 24·3 million people have dementia today, with 4·6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to 81·1 million by 2040. Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040). Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours.
Interpretation
We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.
doi:10.1016/S0140-6736(05)67889-0
PMCID: PMC2850264  PMID: 16360788
20.  Mid- and Late-Life Diabetes in Relation to the Risk of Dementia 
Diabetes  2009;58(1):71-77.
OBJECTIVE—We aimed to verify the association between diabetes and the risk of dementia, Alzheimer's disease, and vascular dementia in twins and to explore whether genetic and early-life environmental factors could contribute to this association.
RESEARCH DESIGN AND METHODS—This study included 13,693 twin individuals aged ≥65 years. Dementia was diagnosed according to DSM-IV (Diagnostic Manual of Mental Disorders, 4th ed.) criteria. Information on diabetes was collected from the inpatient registry and self- or informant-reported history of diabetes. Data were analyzed following two strategies: 1) unmatched case-control analysis for all participants using generalized estimating equation (GEE) models and 2) cotwin matched case-control analysis for dementia-discordant twin pairs using conditional logistic regression.
RESULTS—Of all participants, 467 were diagnosed with dementia, including 292 with Alzheimer's disease and 105 with vascular dementia, and an additional 170 were diagnosed with questionable dementia. Diabetes was present in 1,396 subjects. In GEE models, diabetes was associated with adjusted odds ratios (ORs) (95% CI) of 1.89 (1.51–2.38) for dementia, 1.69 (1.16–2.36) for Alzheimer's disease, and 2.17 (1.36–3.47) for vascular dementia. Compared with late-life diabetes (onset age ≥65 years), the risk effect of mid-life diabetes (onset age <65 years) on dementia was stronger. Conditional logistic analysis of 210 dementia-discordant twin pairs led to ORs of 2.41 (1.05–5.51) and 0.68 (0.30–1.53) for dementia related to mid- and late-life diabetes, respectively.
CONCLUSIONS—Diabetes increases the risk of Alzheimer disease and vascular dementia. The risk is stronger when diabetes occurs at mid-life than in late life. Genetic and early-life environmental factors might contribute to the late-life diabetes–dementia association but could not account for the mid-life diabetes–dementia association.
doi:10.2337/db08-0586
PMCID: PMC2606895  PMID: 18952836
21.  Depression as a Risk Factor or Prodomal Feature for Dementia? Findings in a Population-Based Sample of Swedish Twins 
Psychology and aging  2009;24(2):373-384.
This study tested whether history of depression is associated with an increased likelihood of having dementia, and to verify whether a first depressive episode earlier in life is associated with an increased likelihood of dementia, or whether only depressive episodes occurring close in time to dementia diagnosis are related to dementia. Depression information was collected from national hospital discharge registries, medical history, and medical records. Dementia was clinically diagnosed using DSM-IV criteria. Case-control results showed that individuals with recent registry-identified depression were 3.9 times more likely than those with no registry-identified depression history to have dementia, while registry-identified depression earlier in life was not associated with an increased dementia risk. Each 1-year increase in the difference between depression onset and dementia onset or censored age decreased the likelihood of dementia by 8.4%. Co-twin control analyses found that individuals with prior depression were 3.0 times more likely to have dementia than their non-depressed twin partner, with a similar gradient of age of depression onset. Taken together, these findings suggest that after partially controlling for genetic influences, late-life depression for many individuals may be a prodrome rather than a risk factor for dementia.
doi:10.1037/a0015713
PMCID: PMC2713179  PMID: 19485655
dementia; depression; risk factor; twin study
22.  Accounting for the relationship between low education and dementia: A twin study 
Physiology & behavior  2007;92(1-2):232-237.
We evaluated whether the association between low education and greater risk of dementia is explained by genetic influences, using three different types of analyses. The HARMONY study (Swedish for “health” (Hälsa), “genes” (ARv), “environment” (Miljö), “and” (Och), and “new” (NY)) includes members of the Swedish Twin Registry who were aged 65 and older and alive in 1998, and who were screened and clinically assessed for dementia. There were 394 cases with dementia and 7786 unrelated controls. Analyses included co-twin control, tests for association between education and a measured genotype, and bivariate twin modeling. Low education was a significant risk factor for dementia both in case-control analyses (odds ratio=1.77, 95% confidence interval 1.38 to 2.28) and co-twin control analyses with monozygotic twin pairs (odds ratio=3.17, 95% confidence interval 1.26 to 7.93). Apolipoprotein E genotype was not associated with education and did not account for the relationship between education and dementia. Bivariate twin modeling showed that the association between education and dementia was not mediated by genetic influences in common between education and dementia. The association was mediated by shared environmental influences that were related to both dementia and to education. Low education is confirmed as a risk factor for dementia. Findings from three different analytic approaches showed that genetic influences did not explain this association.
doi:10.1016/j.physbeh.2007.05.042
PMCID: PMC2225456  PMID: 17597169
Dementia; Education; Risk factors; Twin studies
23.  Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study 
BMJ : British Medical Journal  2004;329(7465):539.
Objective To evaluate the relation between midlife alcohol consumption and mild cognitive impairment and dementia in old age, and the possible modification of this relation by apolipoprotein E.
Design Prospective, population based study.
Setting Populations of Kuopio and Joensuu, eastern Finland.
Participants Of 1464 men and women aged 65-79 years randomly selected from population based samples studied in 1972 or 1977, 1018 (70%) were re-examined in 1998 (after an average follow up of 23 years).
Main outcome measures Mild cognitive impairment and dementia in old age.
Results Participants who drank no alcohol at midlife and those who drank alcohol frequently were both twice as likely to have mild cognitive impairment in old age as those participants who drank alcohol infrequently. The risk of dementia related to alcohol drinking was modified by the presence of the apolipoprotein e4 allele. The carriers of apolipoprotein e4 had an increased risk of dementia with increasing alcohol consumption: compared with non-carriers who never drank, the odds ratio for carriers who never drank was 0.6, for infrequent drinkers it was 2.3, and for frequent drinkers was 3.6 (the overall interaction term “drinking frequency*apolipoprotein e4” was significant (P = 0.04), as were the interactions “infrequent drinking*apolipoprotein e4” (P = 0.02) and “frequent drinking*apolipoprotein e4” (P = 0.03)). Non-carriers of apolipoprotein e4 had similar odds ratios for dementia irrespective of alcohol consumption.
Conclusion Alcohol drinking in middle age showed a U shaped relation with risk of mild cognitive impairment in old age. Risk of dementia increased with increasing alcohol consumption only in those individuals carrying the apolipoprotein e4 allele.
doi:10.1136/bmj.38181.418958.BE
PMCID: PMC516103  PMID: 15304383
24.  Detection of Alzheimer's disease and dementia in the preclinical phase: population based cohort study 
BMJ : British Medical Journal  2003;326(7383):245.
Objectives
To evaluate a simple three step procedure to identify people in the general population who are in the preclinical phase of Alzheimer's disease and dementia.
Design
Three year population based cohort study.
Setting
Kungsholmen cohort, Stockholm, Sweden.
Participants
1435 people aged 75-95 years without dementia.
Assessments
Single question asking about memory complaints, assessment by mini-mental state examination, and neuropsychological testing.
Main outcome measure
Alzheimer's disease and dementia at three year follow up.
Results
None of the three instruments was sufficiently predictive of Alzheimer's disease and dementia when administered separately. After participants had been screened for memory complaints and global cognitive impairment, specific tests of word recall and verbal fluency had positive predictive values for dementia of 85-100% (95% confidence intervals range from 62% to 100%). However, only 18% of future dementia cases were identified in the preclinical phase by this three step procedure. Memory complaints were the most sensitive indicator of Alzheimer's disease and dementia in the whole population, but only half the future dementia cases reported memory problems three years before diagnosis.
Conclusion
This three step procedure, which simulates what might occur in clinical practice, has a high positive predictive value for dementia, although only a small number of future cases can be identified.
What is already known on this topicAlzheimer's disease is characterised by a preclinical phase, during which cognitive deficits are seen before diagnosisElderly people with subjective memory complaints and objective global cognitive impairment have a high risk of developing Alzheimer's disease and dementiaWhat this study addsThis three step procedure (self report of memory complaints, test of global cognitive functioning, and then domain specific cognitive tests) has a positive predictivity of 85-100% for Alzheimer's disease and dementia at three yearsHowever, only 18% of people in the preclinical phase can be identified using this procedureAbout half of the people in the preclinical phase of Alzheimer's disease and dementia do not report problems with their memory three years before diagnosis
PMCID: PMC140758  PMID: 12560271
25.  Lifestyle, social factors, and survival after age 75: population based study 
Objective To identify modifiable factors associated with longevity among adults aged 75 and older.
Design Population based cohort study.
Setting Kungsholmen, Stockholm, Sweden.
Participants 1810 adults aged 75 or more participating in the Kungsholmen Project, with follow-up for 18 years.
Main outcome measure Median age at death. Vital status from 1987 to 2005.
Results During follow-up 1661 (91.8%) participants died. Half of the participants lived longer than 90 years. Half of the current smokers died 1.0 year (95% confidence interval 0.0 to 1.9 years) earlier than non-smokers. Of the leisure activities, physical activity was most strongly associated with survival; the median age at death of participants who regularly swam, walked, or did gymnastics was 2.0 years (0.7 to 3.3 years) greater than those who did not. The median survival of people with a low risk profile (healthy lifestyle behaviours, participation in at least one leisure activity, and a rich or moderate social network) was 5.4 years longer than those with a high risk profile (unhealthy lifestyle behaviours, no participation in leisure activities, and a limited or poor social network). Even among the oldest old (85 years or older) and people with chronic conditions, the median age at death was four years higher for those with a low risk profile compared with those with a high risk profile.
Conclusion Even after age 75 lifestyle behaviours such as not smoking and physical activity are associated with longer survival. A low risk profile can add five years to women’s lives and six years to men’s. These associations, although attenuated, were also present among the oldest old (≥85 years) and in people with chronic conditions.
doi:10.1136/bmj.e5568
PMCID: PMC3431442  PMID: 22936786

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