| 1. |
- Coley, Nicola, et al.
(author)
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Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial
- 2024
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In: The Lancet Healthy Longevity. - 2666-7568. ; 5:2
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Journal article (peer-reviewed)abstract
- Background: It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. Methods: This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. Findings: Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7–11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was −0·34 [effect size −0·52; 95% CI −0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [−0·21 to 0·47], 0·03 [−0·30 to 0·36], and 0·10 [−0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was −3·01 pg/mL (−4·45 to −1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). Interpretation: Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required.
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| 2. |
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| 3. |
- De Guio, François, et al.
(author)
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Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease
- 2016
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In: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X. ; 36:8, s. 1319-1337
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Research review (peer-reviewed)abstract
- Brain imaging is essential for the diagnosis and characterization of cerebral small vessel disease. Several magnetic resonance imaging markers have therefore emerged, providing new information on the diagnosis, progression, and mechanisms of small vessel disease. Yet, the reproducibility of these small vessel disease markers has received little attention despite being widely used in cross-sectional and longitudinal studies. This review focuses on the main small vessel disease-related markers on magnetic resonance imaging including: white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and brain volume. The aim is to summarize, for each marker, what is currently known about: (1) its reproducibility in studies with a scan-rescan procedure either in single or multicenter settings; (2) the acquisition-related sources of variability; and, (3) the techniques used to minimize this variability. Based on the results, we discuss technical and other challenges that need to be overcome in order for these markers to be reliably used as outcome measures in future clinical trials. We also highlight the key points that need to be considered when designing multicenter magnetic resonance imaging studies of small vessel disease.
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| 4. |
- Dumanski, Jan P., et al.
(author)
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Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease
- 2016
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 98:6, s. 1208-1219
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Journal article (peer-reviewed)abstract
- Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.
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| 5. |
- Escott-Price, Valentina, et al.
(author)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Journal article (peer-reviewed)abstract
- 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 = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-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.
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| 6. |
- Jansen, Iris E, et al.
(author)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Journal article (peer-reviewed)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 7. |
- Jones, Lesley, et al.
(author)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Journal article (peer-reviewed)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 8. |
- Kerr, John R., et al.
(author)
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Correlates of intended COVID-19 vaccine acceptance across time and countries : Results from a series of cross-sectional surveys
- 2021
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In: BMJ Open. - : BMJ. - 2044-6055. ; 11:8
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Journal article (peer-reviewed)abstract
- Objective Describe demographical, social and psychological correlates of willingness to receive a COVID-19 vaccine. Setting Series of online surveys undertaken between March and October 2020. Participants A total of 25 separate national samples (matched to country population by age and sex) in 12 different countries were recruited through online panel providers (n=25 334). Primary outcome measures Reported willingness to receive a COVID-19 vaccination. Results Reported willingness to receive a vaccine varied widely across samples, ranging from 63% to 88%. Multivariate logistic regression analyses reveal sex (female OR=0.59, 95% CI 0.55 to 0.64), trust in medical and scientific experts (OR=1.28, 95% CI 1.22 to 1.34) and worry about the COVID-19 virus (OR=1.47, 95% CI 1.41 to 1.53) as the strongest correlates of stated vaccine acceptance considering pooled data and the most consistent correlates across countries. In a subset of UK samples, we show that these effects are robust after controlling for attitudes towards vaccination in general. Conclusions Our results indicate that the burden of trust largely rests on the shoulders of the scientific and medical community, with implications for how future COVID-19 vaccination information should be communicated to maximise uptake.
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| 9. |
- Kühnel, Line, et al.
(author)
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Personalized prediction of progression in pre-dementia patients based on individual biomarker profile : A development and validation study
- 2021
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:12, s. 1938-1949
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Journal article (peer-reviewed)abstract
- Introduction: The prognosis of patients at the pre-dementia stage is difficult to define. The aim of this study is to develop and validate a biomarker-based continuous model for predicting the individual cognitive level at any future moment. In addition to personalized prognosis, such a model could reduce trial sample size requirements by allowing inclusion of a homogenous patient population. Methods: Disease-progression modeling of longitudinal cognitive scores of pre-dementia patients (baseline Clinical Dementia Rating ≤ 0.5) was used to derive a biomarker profile that was predictive of patient's cognitive progression along the dementia continuum. The biomarker profile model was developed and validated in the MEMENTO cohort and externally validated in the Alzheimer's Disease Neuroimaging Initiative. Results: Of nine candidate biomarkers in the development analysis, three cerebrospinal fluid and two magnetic resonance imaging measures were selected to form the final biomarker profile. The model-based prognosis of individual future cognitive deficit was shown to significantly improve when incorporating biomarker information on top of cognition and demographic data. In trial power calculations, adjusting the primary analysis for the baseline biomarker profile reduced sample size requirements by ≈10%. Compared to conventional cognitive cut-offs, inclusion criteria based on biomarker-profile cut-offs resulted in up to 28% reduced sample size requirements due to increased homogeneity in progression patterns. Discussion: The biomarker profile allows prediction of personalized trajectories of future cognitive progression. This enables accurate personalized prognosis in clinical care and better selection of patient populations for clinical trials. A web-based application for prediction of patients’ future cognitive progression is available online.
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| 10. |
- Le Guen, Yann, et al.
(author)
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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
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Journal article (peer-reviewed)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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| 11. |
- Luo, Jiao, et al.
(author)
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Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease
- 2023
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In: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 6:5
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Journal article (peer-reviewed)abstract
- IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022.EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors.RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]).CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
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| 12. |
- Söderlund, Hedvig, et al.
(author)
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Cerebral changes on MRI and cognitive function: The CASCADE Study.
- 2006
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 27:1, s. 16-23
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Journal article (peer-reviewed)abstract
- The aging, non-demented brain undergoes several physiological changes, some of which may and some of which may not affect cognitive function. The goal of the present study was to examine the effects of subcortical and periventricular white matter hyperintensities (WMHs), and cortical and subcortical atrophy on cognitive function (episodic and semantic memory, attention, and perceptual, cognitive, and motor speed). This was done within a European collaborative study, CASCADE (Cardiovascular Determinants of Dementia), in which Magnetic Resonance Imaging (MRI) was performed on community-dwelling individuals. The study includes 1,254 persons from eight European study centers, ranging between 64 and 76 years of age (M 69.4 + 3.3; 55% men). When demographics (age, education, and sex), study center, and concurrent brain changes had been adjusted for, periventricular WHMS predicted lower performance in motor speed and Stroop (errors). The findings are consistent with findings from lesion and functional neuroimaging studies.
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| 13. |
- Weuve, Jennifer, et al.
(author)
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Guidelines for reporting methodological challenges and evaluating potential bias in dementia research.
- 2015
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 11:9, s. 1098-109
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Journal article (peer-reviewed)abstract
- Clinical and population research on dementia and related neurologic conditions, including Alzheimer's disease, faces several unique methodological challenges. Progress to identify preventive and therapeutic strategies rests on valid and rigorous analytic approaches, but the research literature reflects little consensus on "best practices." We present findings from a large scientific working group on research methods for clinical and population studies of dementia, which identified five categories of methodological challenges as follows: (1) attrition/sample selection, including selective survival; (2) measurement, including uncertainty in diagnostic criteria, measurement error in neuropsychological assessments, and practice or retest effects; (3) specification of longitudinal models when participants are followed for months, years, or even decades; (4) time-varying measurements; and (5) high-dimensional data. We explain why each challenge is important in dementia research and how it could compromise the translation of research findings into effective prevention or care strategies. We advance a checklist of potential sources of bias that should be routinely addressed when reporting dementia research.
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| 14. |
- Wolters, Frank J, et al.
(author)
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Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.
- 2020
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In: Neurology. - 1526-632X. ; 95:5
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Journal article (peer-reviewed)abstract
- To determine changes in the incidence of dementia between 1988 and 2015.This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]).The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
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