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Recent estimates suggesting that over half of Alzheimer's disease burden worldwide might be attributed to potentially modifiable risk factors do not take into account risk-factor non-independence. We aimed to provide specific estimates of preventive potential by accounting for the association between risk factors. Using relative risks from existing meta-analyses, we estimated the population-attributable risk (PAR) of Alzheimer's disease worldwide and in the USA, Europe, and the UK for seven potentially modifiable risk factors that have consistent evidence of an association with the disease (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment). The combined PAR associated with the risk factors was calculated using data from the Health Survey for England 2006 to estimate and adjust for the association between risk factors. The potential of risk factor reduction was assessed by examining the combined effect of relative reductions of 10% and 20% per decade for each of the seven risk factors on projections for Alzheimer's disease cases to 2050. Worldwide, the highest estimated PAR was for low educational attainment (19·1%, 95% CI 12·3–25·6). The highest estimated PAR was for physical inactivity in the USA (21·0%, 95% CI 5·8–36·6), Europe (20·3%, 5·6–35·6), and the UK (21·8%, 6·1–37·7). Assuming independence, the combined worldwide PAR for the seven risk factors was 49·4% (95% CI 25·7–68·4), which equates to 16·8 million attributable cases (95% CI 8·7–23·2 million) of 33·9 million cases. However, after adjustment for the association between the risk factors, the estimate reduced to 28·2% (95% CI 14·2–41·5), which equates to 9·6 million attributable cases (95% CI 4·8–14·1 million) of 33·9 million cases. Combined PAR estimates were about 30% for the USA, Europe, and the UK. Assuming a causal relation and intervention at the correct age for prevention, relative reductions of 10% per decade in the prevalence of each of the seven risk factors could reduce the prevalence of Alzheimer's disease in 2050 by 8·3% worldwide. After accounting for non-independence between risk factors, around a third of Alzheimer's diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimer's disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression. National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough.

The prevalence of dementia is of interest worldwide. Contemporary estimates are needed to plan for future care provision, but much evidence is decades old. We aimed to investigate whether the prevalence of dementia had changed in the past two decades by repeating the same approach and diagnostic methods as used in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) in three of the original study areas in England. 1989 and 1994, MRC CFAS investigators did baseline interviews in populations aged 65 years and older in six geographically defined areas in England and Wales. A two stage process, with screening followed by diagnostic assessment, was used to obtain data for algorithmic diagnoses (geriatric mental state–automated geriatric examination for computer assisted taxonomy), which were then used to estimate dementia prevalence. Data from three of these areas—Cambridgeshire, Newcastle, and Nottingham—were selected for CFAS I. Between 2008 and 2011, new fieldwork was done in the same three areas for the CFAS II study. For both CFAS I and II, each area needed to include 2500 individuals aged 65 years and older to provide power for geographical and generational comparison. Sampling was stratified according to age group (65–74 years vs ≥75 years). CFAS II used identical sampling, approach, and diagnostic methods to CFAS I, except that screening and assessement were combined into one stage. Prevalence estimates were calculated using inverse probability weighting methods to adjust for sampling design and non-response. Full likelihood Bayesian models were used to investigate informative non-response. 7635 people aged 65 years or older were interviewed in CFAS I (9602 approached, 80% response) in Cambridgeshire, Newcastle, and Nottingham, with 1457 being diagnostically assessed. In the same geographical areas, the CFAS II investigators interviewed 7796 individuals (14 242 approached, 242 with limited frailty information, 56% response). Using CFAS I age and sex specific estimates of prevalence in individuals aged 65 years or older, standardised to the 2011 population, 8·3% (884 000) of this population would be expected to have dementia in 2011. However, CFAS II shows that the prevalence is lower (6·5%; 670 000), a decrease of 1·8% (odds ratio for CFAS II vs CFAS I 0·7, 95% CI 0·6–0·9, p=0·003). Sensitivity analyses suggest that these estimates are robust to the change in response. This study provides further evidence that a cohort effect exists in dementia prevalence. Later-born populations have a lower risk of prevalent dementia than those born earlier in the past century. UK Medical Research Council.

There is evidence to suggest that social isolation is associated with poor cognitive health, although findings are contradictory. One reason for inconsistency in reported findings may be a lack of consideration of underlying mechanisms that could influence this relationship. Cognitive reserve is a theoretical concept that may account for the role of social isolation and its association with cognitive outcomes in later life. Therefore, we aimed to examine the relationship between social isolation and cognition in later life, and to consider the role of cognitive reserve in this relationship. Baseline and two year follow-up data from the Cognitive Function and Ageing Study-Wales (CFAS-Wales) were analysed. Social isolation was assessed using the Lubben Social Network Scale-6 (LSNS-6), cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and cognitive reserve was assessed using a proxy measure of education, occupational complexity, and cognitive activity. Linear regression modelling was used to assess the relationship between social isolation and cognition. To assess the role of cognitive reserve in this relationship, moderation analysis was used to test for interaction effects. After controlling for age, gender, education, and physically limiting health conditions, social isolation was associated with cognitive function at baseline and two year follow-up. Cognitive reserve moderated this association longitudinally. Findings suggest that maintaining a socially active lifestyle in later life may enhance cognitive reserve and benefit cognitive function. This has important implications for interventions that may target social isolation to improve cognitive function.

Background Timely recognition of the end of life allows patients to discuss preferences and make advance plans, and clinicians to introduce appropriate care. We examined changes in frailty over 1 year, with the aim of identifying trajectories that could indicate where an individual is at increased risk of all-cause mortality and may require palliative care. Methods Electronic health records from 13,149 adults (cases) age 75 and over who died during a 1-year period (1 January 2015 to 1 January 2016) were age, sex and general practice matched to 13,149 individuals with no record of death over the same period (controls). Monthly frailty scores were obtained for 1 year prior to death for cases, and from 1 January 2015 to 1 January 2016 for controls using the electronic frailty index (eFI; a cumulative deficit measure of frailty, available in most English primary care electronic health records, and ranging in value from 0 to 1). Latent growth mixture models were used to investigate longitudinal patterns of change and associated impact on mortality. Cases were reweighted to the population level for tests of diagnostic accuracy. Results Three distinct frailty trajectories were identified. Rapidly rising frailty (initial increase of 0.022 eFI per month before slowing from a baseline eFI of 0.21) was associated with a 180% increase in mortality (OR 2.84, 95% CI 2.34–3.45) for 2.2% of the sample. Moderately increasing frailty (eFI increase of 0.007 per month, with baseline of 0.26) was associated with a 65% increase in mortality (OR 1.65, 95% CI 1.54–1.76) for 21.2% of the sample. The largest (76.6%) class was stable frailty (eFI increase of 0.001 from a baseline of 0.26). When cases were reweighted to population level, rapidly rising frailty had 99.1% specificity and 3.2% sensitivity (positive predictive value 19.8%, negative predictive value 93.3%) for predicting individual risk of mortality. Conclusions People aged over 75 with frailty who are at highest risk of death have a distinctive frailty trajectory in the last 12 months of life, with a rapid initial rise from a low baseline, followed by a plateau. Routine measurement of frailty can be useful to support clinicians to identify people with frailty who are potential candidates for palliative care, and allow time for intervention.

AbstractObjectivesTo estimate the association between the duration and level of exposure to different classes of anticholinergic drugs and subsequent incident dementia.DesignCase-control study.SettingGeneral practices in the UK contributing to the Clinical Practice Research Datalink.Participants40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia.InterventionsDaily defined doses of anticholinergic drugs coded using the Anticholinergic Cognitive Burden (ACB) scale, in total and grouped by subclass, prescribed 4-20 years before a diagnosis of dementia.Main outcome measuresOdds ratios for incident dementia, adjusted for a range of demographic and health related covariates.Results14 453 (35%) cases and 86 403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was associated with an increasing average ACB score. When considered by drug class, gastrointestinal drugs with an ACB score of 3 were not distinctively linked to dementia. The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3. This result was also observed for exposure 15-20 years before a diagnosis.ConclusionsA robust association between some classes of anticholinergic drugs and future dementia incidence was observed. This could be caused by a class specific effect, or by drugs being used for very early symptoms of dementia. Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure.Trial registrationRegistered to the European Union electronic Register of Post-Authorisation Studies EUPAS8705.

Dementia is receiving increasing attention from governments and politicians. Epidemiological research based on western European populations done 20 years ago provided key initial evidence for dementia policy making, but these estimates are now out of date because of changes in life expectancy, living conditions, and health profiles. To assess whether dementia occurrence has changed during the past 20–30 years, investigators of five different studies done in western Europe (Sweden [Stockholm and Gothenburg], the Netherlands [Rotterdam], the UK [England], and Spain [Zaragoza]) have compared dementia occurrence using consistent research methods between two timepoints in well-defined geographical areas. Findings from four of the five studies showed non-significant changes in overall dementia occurrence. The only significant reduction in overall prevalence was found in the study done in the UK, powered and designed explicitly from its outset to detect change across generations (decrease in prevalence of 22%; p=0·003). Findings from the study done in Zaragoza (Spain) showed a significant reduction in dementia prevalence in men (43%; p=0·0002). The studies estimating incidence done in Stockholm and Rotterdam reported non-significant reductions. Such reductions could be the outcomes from earlier population-level investments such as improved education and living conditions, and better prevention and treatment of vascular and chronic conditions. This evidence suggests that attention to optimum health early in life might benefit cognitive health late in life. Policy planning and future research should be balanced across primary (policies reducing risk and increasing cognitive reserve), secondary (early detection and screening), and tertiary (once dementia is present) prevention. Each has their place, but upstream primary prevention has the largest effect on reduction of later dementia occurrence and disability.

Background Autism prevalence in the West is approximately 1% of school age children. Autism prevalence in China has been reported to be lower than in the West. This is likely due to at least two reasons: (1) most studies in China only included the special school population, overlooking the mainstream school population; and (2) most studies in China have not used contemporary screening and diagnostic methods. To address this, we tested total autism prevalence (mainstream and special schools) in Jilin City, and mainstream school autism prevalence in Jiamusi and Shenzhen cities. Methods The study included a three-step process: (1) screening; (2) clinical assessment of ‘screen positives’ plus controls; and (3) research diagnostic assessment of those meeting clinical threshold for concerns at step 2. Prevalence estimates per 10,000 children aged 6–10 years old were weighted for study design using diagnostic criteria applied at the research assessment stage. Results In Jilin City, 77 cases of autism were identified from a total population of 7258, equating to a prevalence of 108 per 10,000 (95% confidence interval (CI) 89, 130). In Shenzhen City: 21,420 children were screened and 35 cases of autism were identified, resulting in a mainstream prevalence of 42 per 10,000 (95% CI 20–89). In Jiamusi City, 16,358 children were screened, with 10 autism cases being identified, with a mainstream prevalence of 19 per 10,000 (95% CI 10–38). Conclusions Results from Jilin City, where both mainstream and special school data were available, revealed a similar prevalence of autism in China to the West, at around 1%. Results from Shenzhen and Jiamusi cities, where only mainstream data were available, prevalence is also in line with Western estimates. In all three cities, new cases of autism were identified by the study in mainstream schools, reflecting current under-diagnosis. Non-significant variation across different cities is seen indicating the need to explore potential variation of autism across diverse Chinese regions with large sample sizes to achieve a fully robust national picture.

Background The concept of reserve was established to account for the observation that a given degree of neurodegenerative pathology may result in varying degrees of symptoms in different individuals. There is a large amount of evidence on epidemiological risk and protective factors for neurodegenerative diseases and dementia, yet the biological mechanisms that underpin the protective effects of certain lifestyle and physiological variables remain poorly understood, limiting the development of more effective preventive and treatment strategies. Additionally, different definitions and concepts of reserve exist, which hampers the coordination of research and comparison of results across studies. Discussion This paper represents the consensus of a multidisciplinary group of experts from different areas of research related to reserve, including clinical, epidemiological and basic sciences. The consensus was developed during meetings of the working groups of the first International Conference on Cognitive Reserve in the Dementias (24–25 November 2017, Munich, Germany) and the Alzheimer’s Association Reserve and Resilience Professional Interest Area (25 July 2018, Chicago, USA). The main objective of the present paper is to develop a translational perspective on putative mechanisms underlying reserve against neurodegenerative disease, combining evidence from epidemiological and clinical studies with knowledge from animal and basic research. The potential brain functional and structural basis of reserve in Alzheimer’s disease and other brain disorders are discussed, as well as relevant lifestyle and genetic factors assessed in both humans and animal models. Conclusion There is an urgent need to advance our concept of reserve from a hypothetical model to a more concrete approach that can be used to improve the development of effective interventions aimed at preventing dementia. Our group recommends agreement on a common dictionary of terms referring to different aspects of reserve, the improvement of opportunities for data sharing across individual cohorts, harmonising research approaches across laboratories and groups to reduce heterogeneity associated with human data, global coordination of clinical trials to more effectively explore whether reducing epidemiological risk factors leads to a reduced burden of neurodegenerative diseases in the population, and an increase in our understanding of the appropriateness of animal models for reserve research.

Whether rises in life expectancy are increases in good-quality years is of profound importance worldwide, with population ageing. We investigate how various health expectancies have changed in England between 1991 and 2011, with identical study design and methods in each decade. Baseline data from the Cognitive Function and Ageing Studies in populations aged 65 years or older in three geographically defined centres in England (Cambridgeshire, Newcastle, and Nottingham) provided prevalence estimates for three health measures: self-perceived health (defined as excellent–good, fair, or poor); cognitive impairment (defined as moderate–severe, mild, or none, as assessed by Mini-Mental State Examination score); and disability in activities of daily living (defined as none, mild, or moderate–severe). Health expectancies for the three regions combined were calculated by the Sullivan method, which applies the age-specific and sex-specific prevalence of the health measure to a standard life table for the same period. Between 1991 and 2011, gains in life expectancy at age 65 years (4·5 years for men and 3·6 years for women) were accompanied by equivalent gains in years free of any cognitive impairment (4·2 years [95% CI 4·2–4·3] for men and 4·4 years [4·3–4·5] for women) and decreased years with mild or moderate–severe cognitive impairment. Gains were also identified in years in excellent or good self-perceived health (3·8 years [95% CI 3·5–4·1] for men and 3·1 years [2·7–3·4] for women). Gains in disability-free years were much smaller than those in excellent–good self-perceived health or those free from cognitive impairment, especially for women (0·5 years [0·2–0·9] compared with 2·6 years [2·3–2·9] for men), mostly because of increased mild disability. During the past two decades in England, we report an absolute compression (ie, reduction) of cognitive impairment, a relative compression of self-perceived health (ie, proportion of life spent healthy is increasing), and dynamic equilibrium of disability (ie, less severe disability is increasing but more severe disability is not). Reasons for these patterns are unknown but might include increasing obesity during previous decades. Our findings have wide-ranging implications for health services and for extension of working life. UK Medical Research Council.

Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from cross-sectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods. Data are from 30,372 individuals and comprise 102,583 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade. Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population. Please see later in the article for the Editors' Summary.