The Effects of Estrogen on the Risk of Developing Dementia: A Cohort Study Using the UK Biobank Data.

OBJECTIVES: The protective role of estrogen in the development of dementia remains uncertain. We investigated the role of lifetime cumulative exposure to estrogen in dementia in the UK Biobank. METHODS: Reproductive characteristics, including estrogen length and history of surgery (hysterectomy/oophorectomy), were used as exposure variables. Cox Proportional Hazard models were used to estimate hazard ratios (HR) for the development of dementia. RESULTS: A total of 273,260 female participants were included in this study. Compared to women with the shortest estrogen length, women with the longer estrogen length (38-42) had a 28% decreased risk of dementia (HR = 0.718, 95% confidence interval [CI] = 0.651-0.793). Women with later last age at estrogen exposure (50-52) had a 24% decreased risk for dementia (HR = 0.763, 95% CI = 0.695-0.839) compared to women with younger age at last estrogen exposure (≤45). Later age at menarche (≥15) was associated with a 12% increased risk for dementia (HR = 1.121, 95% CI = 1.018-1.234) compared to women with earlier age at menarche (≤12). Women with a history of surgery had an 8% increased risk of dementia (HR = 1.079, 95% CI = 1.002-1.164) compared to women without a history of surgery. CONCLUSION: This study found that more prolonged exposure to estrogen (longer estrogen length and later age at last estrogen exposure) had a decreased risk for dementia, and shorter exposure to estrogen (later age at menarche and history of reproductive surgery) had an increased risk for dementia. Based on the results of this study, estrogen might have a protective role in women in the development of dementia.

Population-level interventions for the primary prevention of dementia: a complex evidence review.

BACKGROUND: Dementia is a leading, global public health challenge. Recent evidence supporting a decrease in age-specific incidence of dementia in high-income countries (HICs) suggests that risk reduction is possible through improved life-course public health. Despite this, efforts to date have been heavily focused on individual-level approaches, which are unlikely to significantly reduce dementia prevalence or inequalities in dementia. In order to inform policy, we identified the population-level interventions for dementia risk reduction with the strongest evidence base. METHODS: We did this complex, multistage, evidence review to summarise the empirical, interventional evidence for population-level interventions to reduce or control each of the 12 modifiable life-course risk factors for dementia identified by the Lancet commission. We conducted a series of structured searches of peer-reviewed and grey literature databases (eg, Medline, Trip database, Cochrane library, Campbell Collaboration, the WHO, and Google Scholar), in January, March, and June, 2023. Search terms related to risk factors, prevention, and population-level interventions, without language restrictions. We extracted evidence of effectiveness and key contextual information to aid consideration and implementation of interventions by policymakers. We performed a narrative synthesis and evidence grading, and we derived a population-level dementia risk reduction intervention framework, structured by intervention type. This study is registered with PROSPERO, ID:CRD42023396193. FINDINGS: We identified clear and consistent evidence for the effectiveness of 26 population-level interventions to reduce the prevalence of nine of the risk factors, of which 23 have been empirically evaluated in HICs, and 16 in low-income and middle-income countries. We identified interventions that acted through fiscal levers (n=5; eg, removing primary school fees), marketing or advertising levers (n=5; eg, plain packaging of tobacco products), availability levers (n=8; eg, cleaner fuel replacement programmes for cooking stoves), and legislative levers (n=8; eg, mandated provision of hearing protective equipment at noisy workplaces). We were not able to recommend any interventions for diabetes (other than indirectly through action on obesity and physical inactivity), depression, or social isolation. INTERPRETATION: This complex evidence review provides policymakers and public health professionals with an evidence-based framework to help develop and implement population-level approaches for dementia risk reduction that could significantly reduce the population's risk of dementia and reduce health inequalities. FUNDING: None.

Risk factors, ethnicity and dementia: A UK Biobank prospective cohort study of White, South Asian and Black participants.

BACKGROUND: Our knowledge of the effect of potentially modifiable risks factors on people developing dementia is mostly from European origin populations. We aimed to explore if these risk factors had similar effects in United Kingdom (UK) White, South Asian and Black UK Biobank participants recruited from 2006-2010 and followed up until 2020. METHODS: We reviewed the literature to 25.09.2020 for meta-analyses identifying potentially modifiable risk factors preceding dementia diagnosis by ≥10 years. We calculated prevalence of each identified risk factor and association with dementia for participants aged ≥55 at registration in UK Biobank. We calculated hazard ratios using Cox regression for each risk factor, stratified by ethnic group, and tested for differences using interaction effects between each risk factor and ethnicity. FINDINGS: We included education, hearing loss, hypertension, obesity, excess alcohol consumption, physical inactivity, smoking, high total cholesterol, depression, diabetes, social isolation, and air pollution as risks. Out of 294,162 participants, there were 287,806 White, 3590 South Asian and 2766 Black people, followed up for up to 14.8 years, with a total follow-up time of 3,392,095 years. During follow-up, 5,972 people (2.03%) developed dementia. Risk of dementia was higher in Black participants than White participants (HR for dementia compared to White participants as reference 1.43, 95% CI 1.16-1.77, p = 0.001) but South Asians had a similar risk. Association between each risk factor and dementia was similar in each ethnic group with no evidence to support any differences. INTERPRETATION: We find that Black participants were more likely to develop dementia than White participants, but South Asians were not. Identified risk factors in White European origin participants had a similar effect in Black and South Asian origin participants. Volunteers in UK Biobank are not representative of the population and interaction effects were underpowered so further work is needed.

A systematic review of the cost-effectiveness of community and population interventions to reduce the modifiable risk factors for dementia.

Dementia is a leading global cause of morbidity and mortality. Evidence suggests that tackling modifiable lifecourse risk factors could prevent or delay a significant proportion of cases. Population- and community-based approaches change societal conditions such that everyone across a given community is more likely to live more healthily. We systematically reviewed economic studies of population- and community-based interventions to reduce modifiable lifecourse risk factors for dementia. We searched Medline, EMBASE, Web of Science, CINAHL, PsycInfo, Scopus, Econlit, ERIC, the British Education Index, and Google, on 03/03/2022. We included cost-effectiveness, cost-benefit, and cost-utility studies, provided that the direct outcome of the intervention was a modifiable risk factor for dementia, and was measured empirically. Quality appraisal was completed using the Consensus on Health Economic Criteria checklist. A narrative synthesis was performed. We included 45 studies, from 22,749 records identified. Included studies targeted smoking (n = 15), education (n = 10), physical inactivity (n = 9), obesity (n = 5), air pollution (n = 2), traumatic brain injury (n = 1), and multiple risk factors (n = 3). Intervention designs included changing the physical/food environment (n = 13), mass media programmes (n = 11), reducing financial barriers or increasing resources (n = 10), whole-community approaches (n = 6), and legislative change (n = 3). Overall, interventions were highly cost-effective and/or cost-saving, particularly those targeting smoking, educational attainment, and physical inactivity. Effects were observed in high- (e.g. USA and UK) and low- and middle-income (e.g. Mexico, Tanzania, Thailand) countries. Further research into the direct effects of targeting these risk factors on future dementia prevalence will have important economic, social and policy implications.

Protection against discrimination in national dementia guideline recommendations: A systematic review.

BACKGROUND: National dementia guidelines provide recommendations about the most effective approaches to diagnosis and interventions. Guidelines can improve care, but some groups such as people with minority characteristics may be disadvantaged if recommended approaches are the same for everyone. It is not known if dementia guidelines address specific needs related to patient characteristics. The objectives of this review are to identify which countries have national guidelines for dementia and synthesise recommendations relating to protected characteristics, as defined in the UK Equality Act 2010: age, disability, gender identity, marriage and civil partnership, pregnancy and maternity, race, religion or belief, sex, and sexual orientation. METHODS AND FINDINGS: We searched CINAHL, PsycINFO, and Medline databases and the Guideline International Network library from inception to March 4, 2020, for dementia guidelines in any language. We also searched, between April and September 2020, Google and the national health websites of all 196 countries in English and in each country's official languages. To be included, guidelines had to provide recommendations about dementia, which were expected to be followed by healthcare workers and be approved at a national policy level. We rated quality according to the iCAHE guideline quality checklist. We provide a narrative synthesis of recommendations identified for each protected characteristic, prioritising those from higher-quality guidelines. Forty-six guidelines from 44 countries met our criteria, of which 18 were rated as higher quality. Most guidelines (39/46; 85%) made at least one reference to protected characteristics, and we identified recommendations relating to age, disability, race (or culture, ethnicity, or language), religion, sex, and sexual orientation. Age was the most frequently referenced characteristic (31/46; 67%) followed by race (or culture, ethnicity, or language; 25/46; 54%). Recommendations included specialist investigation and support for younger people affected by dementia and consideration of culture when assessing whether someone had dementia and providing person-centred care. Guidelines recommended considering religion when providing person-centred and end-of-life care. For disability, it was recommended that healthcare workers consider intellectual disability and sensory impairment when assessing for dementia. Most recommendations related to sex recommended not using sex hormones to treat cognitive impairment in men and women. One guideline made one recommendation related to sexual orientation. The main limitation of this study is that we only included national guidelines applicable to a whole country meaning guidelines from countries with differing healthcare systems within the country may have been excluded. CONCLUSIONS: National guidelines for dementia vary in their consideration of protected characteristics. We found that around a fifth of the world's countries have guidelines for dementia. We have identified areas of good practice that can be considered for future guidelines and suggest that all guidelines provide specific evidence-based recommendations for minority groups with examples of how to implement them. This will promote equity in the care of people affected by dementia and help to ensure that people with protected characteristics also have high-quality clinical services.

A cross-sectional study of potentially modifiable risk factors for dementia and cognitive function in India: A secondary analysis of 10/66, LASI, and SAGE data.

OBJECTIVES: Dementia is rising globally, particularly in low-and-middle-income countries. India has almost four million people living with dementia, set to double by 2050. Targeting nine potentially modifiable risk factors (less education, hearing impairment, depression, physical inactivity, hypertension, obesity, smoking, diabetes, and social isolation) could possibly prevent or delay many dementias. We aimed for the first time to examine risk factors for dementia in India and their link with cognitive status and dementia, to inform prioritisation of public health interventions that could prevent or delay dementia. METHODS: We conducted a cross-sectional analysis using three studies: 10/66 Dementia Study (n = 2004), Longitudinal Aging Study of India (n = 386), and Study of Global Ageing (n = 2441). Our exposures were the nine risk factors above. We calculated a cognitive z-score within each study and used dementia diagnosis in 10/66. We adjusted for socioeconomic factors, age, and sex using multivariable linear for cognition and logistic regression for dementia. RESULTS: Less education, hearing impairment, depression, and physical inactivity were associated with lower z-scores and increased odds of dementia. Obesity was associated with higher z-score and lower odds of dementia. Social isolation was associated with lower z-scores and decreased odds of dementia. Results for smoking, diabetes, and hypertension were inconsistent. CONCLUSION: Our risk estimates were larger for less education, hearing impairment and physical inactivity compared to global estimates and should be intervention priorities. This study highlights the need for longitudinal studies to clarify the relationship between these potentially modifiable risk factors and dementia in India.

Differences in the potential for dementia prevention between major ethnic groups within one country: A cross sectional analysis of population attributable fraction of potentially modifiable risk factors in New Zealand.

BACKGROUND: Twelve potentially modifiable risk factors (less education, hypertension, obesity, alcohol, traumatic brain injury (TBI), hearing loss, smoking, depression, physical inactivity, social isolation, diabetes, air pollution) account for an estimated 40% of worldwide dementia cases. We aimed to calculate population attributable fractions (PAFs) for dementia for the four largest New Zealand ethnic groups (European, Maori, Asian, and Pacific peoples) to identify whether optimal dementia prevention targets differed by ethnicity. METHODS: We calculated risk factor prevalence for 10 risk factors using the New Zealand Health Survey 2018/19 and published reports for hearing loss and TBI prevalences. We calculated the PAF for each risk factor using calculated prevalence and relative risk estimates from previous meta-analyses. To account for risk factor overlap, we calculated communality of risk factors and a weighted PAF. FINDINGS: The weighted PAF for dementia was 47.7% overall in New Zealand, 47.6% for Europeans, 51.4% for Maori, 50.8% for Pacific peoples, and 40.8% for Asians. Highest PAFs for Europeans were hearing loss (8%) and social isolation (5.7%), and for Asians hearing loss (7.3%) and physical inactivity (5.5%). For Maori and Pacific peoples, highest PAFs were for obesity (7.3% and 8.9% respectively) and hearing loss (6.5% and 6.6%). INTERPRETATION: New Zealand has higher dementia prevention potential than worldwide estimates with high prevalences of untreated hearing loss and obesity. The relative contribution of individual risk factors PAFs varies by ethnic group. Public health strategies for dementia prevention need to be tailored to these differences. FUNDING: Health Research Council of New Zealand (HRC:20/021).

Effective interventions for potentially modifiable risk factors for late-onset dementia: a costs and cost-effectiveness modelling study.

BACKGROUND: The potential economic value of interventions to prevent late-onset dementia is unknown. We modelled this for potentially modifiable risk factors for dementia. METHODS: For this modelling study, we searched PubMed and Web of Science from inception to March 12, 2020, and included interventions that: successfully targeted any of nine prespecified potentially modifiable risk factors (hypertension, diabetes, hearing loss, obesity, physical inactivity, social isolation, depression, cigarette smoking, and less childhood education); had robust evidence that the intervention improved risk or risk behaviour; and are feasible to enact in an adult population. We established when in the life course each intervention would be delivered. We calculated dementia incidence reduction from annual incidence of dementia in people with each risk factor, and population attributable fraction for each risk, corrected for risk factor clustering, and how effectively the intervention controls the risk factor. We calculated the discounted value of lifetime health gain and effect on cost (including NHS, social care and carer costs) per person eligible for treatment. We estimated annual total expenditure on the fully operational intervention programme in England. FINDINGS: We found effective interventions for hypertension, smoking cessation, diabetes prevention, and hearing loss. Treatments for stopping smoking and provision of hearing aids reduced cost. Treatment of hypertension was cost-effective by reference to standard UK thresholds. The three interventions when fully implemented would save £1·863 billion annually in England, reduce dementia prevalence by 8·5%, and produce quality-adjusted life-year gains. The intervention for diabetes was unlikely to be cost-effective in terms of effect on dementia alone. INTERPRETATION: There is a strong case for implementing the three effective interventions on grounds of cost-effectiveness and quality-of-life gains, as well as for improvements in general health. The interventions have the potential to remain cost-saving or cost-effective even with variations in dementia incidence and costs and effectiveness of interventions. FUNDING: Economic and Social Research Council.

Population attributable fractions for risk factors for dementia in low-income and middle-income countries: an analysis using cross-sectional survey data.

BACKGROUND: Nine potentially modifiable risk factors (less childhood education, midlife hearing loss, hypertension, and obesity, and later-life smoking, depression, physical inactivity, social isolation, and diabetes) account for 35% of worldwide dementia, but most data to calculate these risk factors come from high-income countries only. We aimed to calculate population attributable fractions (PAFs) for dementia in selected low-income and middle-income countries (LMICs) to identify potential dementia prevention targets in these countries. METHODS: The study was an analysis of cross-sectional data obtained from the 10/66 Dementia Research surveys of representative populations in India, China, and six Latin America countries (Cuba, Dominican Republic, Mexico, Peru, Puerto Rico, and Venezuela), which used identical risk factor ascertainment methods in each country. Between 2004 and 2006 (and between 2007 and 2010 for Puerto Rico), all residents aged 65 years and older in predefined catchment areas were invited to participate in the survey. We used risk factor prevalence estimates from this 10/66 survey data, and relative risk estimates from previous meta-analyses, to calculate PAFs for each risk factor. To account for individuals having overlapping risk factors, we adjusted PAF for communality between risk factors, and used these values to calculate overall weighted PAFs for India, China, and the Latin American sample. FINDINGS: The overall weighted PAF for potentially modifiable risk factors for dementia was 39·5% (95% CI 37·5-41·6) in China (n=2162 participants), 41·2% (39·1-43·4) in India (n=2004), and 55·8% (54·9-56·7) in our Latin American sample (n=12 865). Five dementia risk factors were more prevalent in these LMICs than worldwide estimates, leading to higher PAFs for dementia: less childhood education (weighted PAF of 10·8% in China, 13·6% in India, and 10·9% in Latin America vs 7·5% worldwide), smoking (14·7%, 6·4%, and 5·7%, respectively, vs 5·5% worldwide), hypertension (6·4%, 4·0%, and 9·3%, vs 2·0%), obesity (5·6%, 2·9%, and 7·9%, vs 0·8%), and diabetes (1·6%, 1·7%, and 3·2%, vs 1·2%). INTERPRETATION: The dementia prevention potential in India, China, and this sample of Latin American countries is large, and greater than in high-income countries. Less education in early life, hypertension, hearing loss, obesity, and physical inactivity have particularly high PAFs and could be initial targets for dementia prevention strategies. FUNDING: No funding.

A systematic review of interventions to detect dementia or cognitive impairment.

BACKGROUND: Memory services have been implemented nationally to increase early dementia diagnosis, and further evaluation of their impact and other strategies to increase timely dementia diagnosis are needed. AIMS: To systematically review the literature for interventions intended to increase the detection of dementia or suspected dementia or people presenting with memory complaints. METHOD: We searched electronic databases, hand searched references and contacted authors of included papers, contacted field experts and UK charities and councils for data about their dementia awareness programmes. RESULTS: We included 13 studies, of which four were randomised controlled trials (RCT). Two RCTs found that general practitioner (GP) education increased suspected dementia cases. One RCT found up to six home visits from a specialist geriatric nurse over 30 months increased the rate of accurately diagnosed dementia. There was preliminary evidence from non-randomised studies that memory clinics increase timely diagnosis, but no evidence they increase the overall diagnosis rate. CONCLUSIONS: There is good quality evidence that GP education increases the number of suspected dementia cases but not accurate or earlier dementia diagnoses. One RCT reported that multiple visits from a trained nurse increase the diagnosis rate. There is no cost effectiveness evidence. Our findings suggest good quality RCTs are needed to test the effectiveness and cost-effectiveness of interventions to increase dementia detection.