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Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

Objective Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most PRSs are constructed in European-ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late-onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH). Methods We employed a CH discovery (N=4,312) and independent validation sample (N=1,850) to construct an ancestry-specific PRS ("CH-PRS") and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH-PRS predicted conversion to LOAD in a subsample with longitudinal data (N=1,239). We also tested the CH-PRS in an independent replication CH cohort (N=200) and brain autopsy cohort (N=33). Finally, we tested the effect of ancestry on PRS by employing European and African American discovery cohorts to construct alternative PRSs ("EUR-PRS", "AA-PRS"). Results The full model (LOAD ~ CH-PRS + sex + age + APOE-i4), achieved an AUC=74% (ORCH-PRS =1.51 95%CI=1.36-1.68), raising to >75% in APOE-i4 non-carriers. CH-PRS alone achieved an AUC=72% in the autopsy cohort, raising to AUC=83% in full model. Higher CH-PRS was significantly associated with clinical LOAD in the replication CH cohort (OR=1.61, 95%CI=1.19-2.17) and significantly predicted conversion to LOAD (HR=1.93, CI=1.70-2.20) in the longitudinal subsample. EUR-PRS and AA-PRS reached lower prediction accuracy (AUC=58% and 53%, respectively). Interpretation Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. This article is protected by copyright. All rights reserved.

Introduction A growing number of dominantly inherited Alzheimer's disease (DIAD) cases have become known in Latin American (LatAm) in recent years. However, questions regarding mutation distribution and frequency by country remain open. Methods A literature review was completed aimed to provide estimates for DIAD pathogenic variants in the LatAm population. The search strategies were established using a combination of standardized terms for DIAD and LatAm. Results Twenty-four DIAD pathogenic variants have been reported in LatAm countries. Our combined dataset included 3583 individuals at risk; countries with highest DIAD frequencies were Colombia (n = 1905), Puerto Rico (n = 672), and Mexico (n = 463), usually attributable to founder effects. We found relatively few reports with extensive documentation on biomarker profiles and disease progression. Discussion Future DIAD studies will be required in LatAm, albeit with a more systematic approach to include fluid biomarker and imaging studies. Regional efforts are under way to extend the DIAD observational studies and clinical trials to Latin America.

Background The World Health Organization (WHO) has reframed health and healthcare for older people around achieving the goal of healthy ageing. The recent WHO Integrated Care for Older People (ICOPE) guidelines focus on maintaining intrinsic capacity, i.e., addressing declines in neuromusculoskeletal, vitality, sensory, cognitive, psychological, and continence domains, aiming to prevent or delay the onset of dependence. The target group with 1 or more declines in intrinsic capacity (DICs) is broad, and implementation may be challenging in less-resourced settings. We aimed to inform planning by assessing intrinsic capacity prevalence, by characterising the target group, and by validating the general approach—testing hypotheses that DIC was consistently associated with higher risks of incident dependence and death. Methods and findings We conducted population-based cohort studies (baseline, 2003–2007) in urban sites in Cuba, Dominican Republic, Puerto Rico, and Venezuela, and rural and urban sites in Peru, Mexico, India, and China. Door-knocking identified eligible participants, aged 65 years and over and normally resident in each geographically defined catchment area. Sociodemographic, behaviour and lifestyle, health, and healthcare utilisation and cost questionnaires, and physical assessments were administered to all participants, with incident dependence and mortality ascertained 3 to 5 years later (2008–2010). In 12 sites in 8 countries, 17,031 participants were surveyed at baseline. Overall mean age was 74.2 years, range of means by site 71.3–76.3 years; 62.4% were female, range 53.4%–67.3%. At baseline, only 30% retained full capacity across all domains. The proportion retaining capacity fell sharply with increasing age, and declines affecting multiple domains were more common. Poverty, morbidity (particularly dementia, depression, and stroke), and disability were concentrated among those with DIC, although only 10% were frail, and a further 9% had needs for care. Hypertension and lifestyle risk factors for chronic disease, and healthcare utilisation and costs, were more evenly distributed in the population. In total, 15,901 participants were included in the mortality cohort (2,602 deaths/53,911 person-years of follow-up), and 12,939 participants in the dependence cohort (1,896 incident cases/38,320 person-years). One or more DICs strongly and independently predicted incident dependence (pooled adjusted subhazard ratio 1.91, 95% CI 1.69–2.17) and death (pooled adjusted hazard ratio 1.66, 95% CI 1.49–1.85). Relative risks were higher for those who were frail, but were also substantially elevated for the much larger sub-groups yet to become frail. Mortality was mainly concentrated in the frail and dependent sub-groups. The main limitations were potential for DIC exposure misclassification and attrition bias. Conclusions In this study we observed a high prevalence of DICs, particularly in older age groups. Those affected had substantially increased risks of dependence and death. Most needs for care arose in those with DIC yet to become frail. Our findings provide some support for the strategy of optimising intrinsic capacity in pursuit of healthy ageing. Implementation at scale requires community-based screening and assessment, and a stepped-care intervention approach, with redefined roles for community healthcare workers and efforts to engage, train, and support them in these tasks. ICOPE might be usefully integrated into community programmes for detecting and case managing chronic diseases including hypertension and diabetes., In a population-based cohort study, Martin J. Prince and colleagues evaluate intrinsic capacity and its associations with incident dependence and mortality in Latin America, India and China., Author summary Why was this study done? As we grow older, we are affected to different degrees by declines in the working of our organs and body systems, limiting our ability to get around, be well nourished, see, hear, and think clearly, stay continent, and maintain mood and well-being. The World Health Organization has proposed a programme—Integrated Care for Older People (ICOPE)—supported by evidence that simple interventions may slow or reverse these processes, with potential to improve health and functioning and delay needs for care developing among older people. ICOPE targets low- and middle-income countries, but we do not yet know how many older people in these settings are significantly affected by early age-related decline, or whether these changes predict who will go on to deteriorate further, leading to needs for care and earlier death. What did the researchers do and find? We had already completed (between 2003 and 2007) baseline community surveys of 17,031 people aged 65 years and over living in 12 urban and rural sites in 6 Latin American countries, India, and China; we then tried to interview them again 3 to 5 years later (between 2008 and 2010) to identify who had died (in 11 sites, among 15,901 older people) and who had developed needs for care (in 10 sites, among 12,939 older people). Analysing baseline data from these studies, we found that between two-thirds and three-quarters of older people were affected by significant decline in at least 1 of the areas targeted by the ICOPE programme; this proportion was highest among the older old, who were also more likely to have problems in multiple areas. Most (nearly three-quarters) of those with significant decline at baseline had not yet gone on to become physically frail or develop needs for care; they were nevertheless 1.7 to 1.9 times more likely than those without any significant decline to develop needs for care over the follow-up period, and 1.3 to 1.4 times more likely to have died. What do these findings mean? Delivering comprehensive assessment, care planning, and community interventions to up to three-quarters of the older population would be a major challenge for poorly resourced health systems in low- and middle-income countries. Nevertheless, findings from our analyses support the World Health Organization’s strategy to promote health and well-being by targeting a broad group with early decline who do seem to be at increased risk of adverse outcomes. Future research should focus upon feasible, acceptable, and efficient methods of delivering the ICOPE programme (implementation science) and its effectiveness and cost-effectiveness in improving health and social outcomes (controlled trials). The main limitations were that health declines were measured in different ways, some of which may have been imprecise, and those who could not be followed up may have had different characteristics to those who were included in the analysis.

Objectives Depression and anxiety are common mental disorders in later life. Few population-based studies have investigated their potential impacts on mortality in low- and middle-income countries (LMICs). The aim of this study is to examine the associations between depression, anxiety, their comorbidity, and mortality in later life using a population-based cohort study across eight LMICs. Methods This analysis was based on the 10/66 cohort study including 15 991 people aged 65 years or above in Cuba, Dominican Republic, Venezuela, Mexico, Peru, Puerto Rico, China, and India, with an average follow-up time of 3.9 years. Subthreshold and clinical levels of depression were determined using EURO-D and ICD-10 criteria, and anxiety was based on Geriatric Mental State (GMS)-Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT). Cox proportional hazard modelling was used to estimate how having depression, anxiety, or both was associated with mortality adjusting for sociodemographic and health factors. Results Participants with clinical depression (hazard ratio [HR]: 1.45; 95% CI, 1.24-1.70) and subthreshold anxiety (HR: 1.26; 95% CI, 1.15-1.38) had higher risk of mortality than those without the conditions after adjusting for sociodemographic factors and health conditions. Comorbidity of depression and anxiety was associated with a 30% increased risk of mortality but the effect sizes varied across countries (Higgins I2 = 58.8%), with the strongest association in India (HR: 1.99; 95% CI, 1.21-3.27). Conclusions Depression and anxiety appear to be associated with mortality in older people living in LMICs. Variation in effect sizes may indicate different barriers to health service access across countries. Future studies may investigate underlying mechanisms and identify potential interventions to reduce the impact of common mental disorders.

Introduction Despite high dementia prevalence in Hispanic populations globally, especially Caribbean Hispanics, no study has comparatively examined the association between education and dementia among Hispanics living in the Caribbean Islands and older adults in the United States. Methods We used data on 6107 respondents aged 65 and older in the baseline wave of the population‐based and harmonized 10/66 survey from Cuba, the Dominican Republic, and Puerto Rico, collected between 2003 and 2008, and 11,032 respondents aged 65 and older from the U.S.‐based Health and Retirement Study data in 2014, a total of 17,139 individuals. We estimated multivariable logistic regression models examining the association between education and dementia, adjusted for age, income, assets, and occupation. The models were estimated separately for the Caribbean population (pooled and by setting) and the U.S. population by race/ethnicity (Hispanic, Black, and White), followed by pooled models across all populations Results In the Caribbean population, the relative risk of dementia among low versus high educated adults was 1.45 for women (95% confidence interval [CI] 1.17, 1.74) and 1.92 (95% CI 1.35, 2.49) for men, smaller compared to those in the United States, especially among non‐Hispanic Whites (women: 2.78, 95% CI 1.94, 3.61; men: 5.98, 95% CI 4.02, 7.95). Discussion The differential associations between education and dementia across the Caribbean and US settings may be explained by greater disparities in social conditions in the United States compared to the Caribbean, such as access to health care, healthy behaviors, and social stressors, which serve as potentially important mediators.

BackgroundResearch carried out in high income countries suggests that loneliness may be a common experience among older adults living in these settings. Loneliness is correlated with poor socioeconomic status, living alone, being widowed and is associated with adverse health outcomes, including mortality. There is still a lack of evidence about the epidemiology of loneliness among older adults living in low- and middle-income countries. This study was designed to explore prevalence and correlates of self-reported loneliness and to investigate whether loneliness predicts mortality in Latin America, China and India. MethodsThe study investigated population-based cross-sectional (2003-2007) and longitudinal surveys (follow-up 2007-2010) from the 10/66 Dementia Research Group project carried out among 16685 older adults in urban and rural catchment areas in Cuba, Dominican Republic, Puerto Rico, Venezuela, Peru, Mexico, China and India. Poisson regression and Cox regression analyses were conducted to analyse correlates of loneliness and its association with mortality. ResultsThe standardised prevalence of loneliness varied between 25.3% and 32.4% in Latin America and was 18.3% in India. China showed a low prevalence of loneliness (3.8%). In pooled meta-analyses, there was robust evidence to support an association between loneliness and mortality across Latin America (HR=1.13, 95% CI 1.01-1.26, I2=10.1%) and China (HR=1.58, 95% CI 1.03-2.41), but there were no associations in India. ConclusionsOur findings suggest potential cultural variances may exist in the concept of loneliness in older age. The effect of loneliness upon mortality is consistent across different cultural settings excluding India. Loneliness should therefore be considered as a potential dimension of public health among older populations.

Introduction Less than 10% of early-onset Alzheimer's disease (EOAD) is explained by known mutations. Methods We conducted genetic linkage analysis of 68 well-phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in APP, PSEN1, and PSEN2 and with two or more individuals with EOAD. Results We identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late-onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ∼3 Mb upstream of the ceroid lipofuscinosis 3 (CLN3) gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein. Discussion This study supports the notion that the genetic architectures of unexplained EOAD and late-onset AD overlap partially, but not fully.

Cuba, the Dominican Republic, and Puerto Rico, otherwise known as the Spanish Insular Caribbean, comprise a subgroup of insular territories that have similar cultural, historical, and colonial backgrounds. The Spanish Insular Caribbean population faces a particularly high risk for dementia, and only steadily emerging, albeit unique behavioral and psychological approaches for treatment. Comprehensive efforts to provide adequate and culturally congruent treatment are complex and characterized by social, economic, political, and public health influences. This chapter begins contextualizing the treatment of dementia by describing the cultural and historical landscape of the Spanish-speaking islands in the Caribbean. Prevalence rates of dementia in these regions are also discussed along with the current strategic, national guidelines for comprehensive care and the systems of healthcare provision in each country. Furthermore, cultural considerations for dementia management are discussed, including a summary of the psychological strengths exemplified within the Cuban, Dominican, and Puerto Rican communities. The chapter concludes with a review of treatment practices and interventions for individuals with dementia and their caregivers.

BackgroundThe World Health Organization has reframed health and healthcare for older people around achieving the goal of healthy ageing. Recent evidence-based guidelines on Integrated Care for Older People focus on maintaining intrinsic capacity, addressing declines in mobility, nutrition, vision and hearing, cognition, mood and continence aiming to prevent or delay the onset of care dependence. The target group (with one or more declines in intrinsic capacity) is broad, and implementation at scale may be challenging in less-resourced settings.Planning can be informed by assessing the prevalence of intrinsic capacity, characterising the target group, and validating the general approach by evaluating risk prediction for incident dependence and mortality.MethodsPopulation-based cohort studies in urban sites in Cuba, Dominican Republic, Puerto Rico, Venezuela, and rural and urban sites in Peru, Mexico, India and China. Sociodemographic, behaviour and lifestyle, health, healthcare utilisation and cost questionnaires, and physical assessments were administered to all participants, with ascertainment of incident dependence, and mortality, three to five years later.ResultsIn the 12 sites in eight countries, 17,031 participants were surveyed at baseline. Intrinsic capacity was least likely to be retained for locomotion (71.2%), vision (71.3%), cognition (73.5%), and mood (74.1%). Only 30% retained full capacity across all domains, varying between one quarter and two-fifths in most sites. The proportion retaining capacity fell sharply with increasing age, and declines affecting multiple domains were more common. Poverty, morbidity (particularly dementia, depression and stroke), and disability were concentrated among those with DIC, although only 10% were frail, and a further 9% had needs for care. Hypertension and lifestyle risk factors for chronic disease, healthcare utilization and costs were more evenly distributed in the general older population. 15,901 participants were included in the mortality cohort (2,602 deaths/ 53,911 person years of follow-up), and 12,965 participants in the dependence cohort (1900 incident cases/ 38,377 person-years). DIC (any decline, and number of domains affected) strongly and independently predicted incident dependence and death. Relative risks were higher for those who were frail, but were also substantially elevated for the much larger sub-groups yet to become frail. Mortality was mainly concentrated in the frail and dependent sub-groups.ConclusionsOur findings support the strategy to optimize intrinsic capacity in pursuit of healthy ageing. Most needs for care arise in those with declines in intrinsic capacity who are yet to become frail. Implementation at scale requires community-based screening and assessment, and a stepped-care approach to intervention. Community healthcare workers’ roles would need redefinition to engage, train and support them in these tasks. ICOPE could be usefully integrated into community programmes orientated to the detection and case management of chronic diseases including hypertension and diabetes.

Objective: The objective of this study was to estimate healthy life expectancies in eight low- and middle-income countries (LMICs), using two indicators: disability-free life expectancy (DFLE) and dependence-free life expectancy (DepFLE). Method: Using the Sullivan method, healthy life expectancy was calculated based on the prevalence of dependence and disability from the 10/66 cohort study, which included 16,990 people aged 65 or above in China, Cuba, Dominican Republic, India, Mexico, Peru, Puerto Rico, and Venezuela, and country-specific life tables from the World Population Prospects 2017. Results: DFLE and DepFLE declined with older age across all sites and were higher in women than men. Mexico reported the highest DFLE at age 65 for men (15.4, SE = 0.5) and women (16.5, SE = 0.4), whereas India had the lowest with (11.5, SE = 0.3) in men and women (11.7, SE = 0.4). Discussion: Healthy life expectancy based on disability and dependency can be a critical indicator for aging research and policy planning in LMICs.

Inbreeding can be associated with a modification of disease risk due to excess homozygosity of recessive alleles affecting a wide range of phenotypes. We estimated the inbreeding coefficient in Caribbean Hispanics and examined its effects on risk of late-onset Alzheimer disease.The inbreeding coefficient was calculated in 3,392 subjects (1,451 late-onset Alzheimer disease patients and 1,941 age-matched healthy controls) of Caribbean Hispanic ancestry using 177,997 nearly independent single-nucleotide polymorphisms from genome-wide array. The inbreeding coefficient was estimated using the excess homozygosity method with and without adjusting for admixture.The average inbreeding coefficient in Caribbean Hispanics without accounting for admixture was F = 0.018 (±0.048), suggesting a mating equivalent to that of second cousins or second cousins once removed. Adjusting for admixture from three parent populations, the average inbreeding coefficient was found to be 0.0034 (±0.019) or close to third-cousin mating. Inbreeding coefficient was a significant predictor of Alzheimer disease when age, sex, and APOE genotype were used as adjusting covariates (P = 0.03).The average inbreeding coefficient of this population is significantly higher than that of the general Caucasian populations in North America. The high rate of inbreeding resulting in increased frequency of recessive variants is advantageous for the identification of rare variants associated with late-onset Alzheimer disease.Genet Med 17 8, 639-643.

Objective To detect rare coding variants underlying loci detected by genome-wide association studies (GWAS) of late onset Alzheimer disease (LOAD). Methods We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry-matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population-based allele frequencies. Results Overall we detected a statistically significant 3.1-fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop-gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered. Interpretation Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease-related mechanisms and potential therapies. Ann Neurol 2015;78:487–498

Objective In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD. Methods About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets. Results A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case–control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005

BackgroundAdult leg length is influenced by nutrition in the first few years of life. Adult head circumference is an indicator of brain growth. Cross-sectional studies indicate inverse associations with dementia risk, but there have been few prospective studies.MethodsPopulation-based cohort studies in urban sites in Cuba, Dominican Republic Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, and anthropometric measures taken, with ascertainment of incident 10/66 dementia, and mortality, three to five years later.ResultsOf the original at risk cohort of 13,587 persons aged 65 years and over, 2,443 (18.0%) were lost to follow-up; 10,540 persons with skull circumference assessments were followed up for 40,466 person years, and 10,400 with leg length assessments were followed up for 39,954 person years. There were 1,009 cases of incident dementia, and 1,605 dementia free deaths. The fixed effect pooled meta-analysed adjusted subhazard ratio (ASHR) for leg length (highest vs. lowest quarter) was 0.80 (95% CI, 0.66-0.97) and for skull circumference was 1.02 (95% CI, 0.84-1.25), with no heterogeneity of effect between sites (I2=0%). Leg length measurements tended to be shorter at follow-up, particularly for those with baseline cognitive impairment and dementia. However, leg length change was not associated with dementia incidence (ASHR, per cm 1.006, 95% CI 0.992-1.020), and the effect of leg length was little altered after adjusting for baseline frailty (ASHT 0.82, 95% CI 0.67-0.99). A priori hypotheses regarding effect modification by gender or educational level were not supported.ConclusionsConsistent findings across settings provide quite strong support for an association between adult leg length and dementia incidence in late-life. Leg length is a relatively stable marker of early life nutritional programming, which may confer brain reserve and protect against neurodegeneration in later life through mitigation of cardiometabolic risk. Further clarification of these associations could inform predictive models for future dementia incidence in the context of secular trends in adult height, and invigorate global efforts to improve childhood nutrition, growth and development.

The phosphoinositide phosphatase synaptojanin 1 (SYNJ1) is a key regulator of synaptic function. We first tested whether SYNJ1 contributes to phenotypic variations in familial Alzheimer's disease (FAD) and show that SYNJ1 polymorphisms are associated with age of onset in both early- and late-onset human FAD cohorts. We then interrogated whether SYNJ1 levels could directly affect memory. We show that increased SYNJ1 levels in autopsy brains from adults with Down syndrome (DS/AD) are inversely correlated with synaptophysin levels, a direct readout of synaptic integrity. We further report age-dependent cognitive decline in a mouse model overexpressing murine Synj1 to the levels observed in human sporadic AD, triggered through hippocampal hyperexcitability and defects in the spatial reproducibility of place fields. Taken together, our findings suggest that SYNJ1 contributes to memory deficits in the aging hippocampus in all forms of AD., Fundação para a Ciência e Tecnologia (PD/BD/105915/2014 to A.M.M.), the Philippe Chatrier Foundation (C.M.), the Lejeune Foundation (1149 to G.D.P.), the Alzheimer’s Association (2015-NIRG-341570 to S.A.H.), ANR Investissements d’Avenir (ANR-10-IAIHU-06 to M.-C.P.), and the NIH (R01AG050425 to S.A.H.; RO1HD064993 to E.H. and F.A.S.; and RO1HD065160, P50AG16573, and U01AG051412 to I.T.L.). Data collection on Caribbean Hispanic families with at least one G206A founder mutation in the PSEN1 gene was supported by the BrightFocus Foundation (A2015633S) and NIH/National Institute on Aging (NIA) (R56 AG051876-01A1) to J.H.L. Data collection for the EFIGA project was supported by the Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (EFIGA), funded by the NIH/NIA (5R37AG015473, RF1AG015473, and R56AG051876). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study, info:eu-repo/semantics/publishedVersion

BackgroundDiabetes prevalence is already high in middle income countries, particularly among older people. Current evidence on diabetes as a risk factor for dementia is limited to cohort studies in high income countries. Few studies carried out fasting glucose assessments to identify undiagnosed cases, and assess diabetes control. We aimed to determine the association between both diagnosed diabetes and total diabetes (including undiagnosed cases) and incident dementia, examining also the impact of glycaemic control on dementia risk.MethodsPopulation-based cohort studies of those aged 65 years and over in sites in Cuba, Dominican Republic, Puerto Rico, Peru, Venezuela, and Mexico. Diagnosed diabetes was assessed through self-reported diagnosis, and undiagnosed diabetes through fasting blood samples (glucose >= 7mmol/L). Blood pressure, smoking, underactivity and waist circumference were assessed from questionnaires and physical examination. Incident 10/66 dementia (and subtypes), and mortality, were ascertained three to five years later.Results12,297 interviews were completed at baseline, with 80-95% responding by site. The ‘at risk’ cohort comprised 10,945 dementia-free individuals, of whom 8,171 (75%) provided blood samples. Mean age varied from 72.0 to 75.1 years by site. Total diabetes prevalence was 43.5% in Puerto Rico, ranging from 11.5% to 27.0% in other sites. Most diabetes cases (50.2% to 68.4%) were not controlled (fasting glucose >7.0 mmol/L). 7,000 participants were followed up for 26,423 person-years with 659 incident dementia cases, and 905 dementia free deaths. Total diabetes was associated with incident 10/66 dementia (pooled meta-analysed adjusted sub-hazard ratio [pASHR] 1.25, 95% CI, 1.05-1.49, I2=48.6%), with a stronger association for uncontrolled (pASHR 1.47, 95% CI 1.19-1.81, I2=49.6%) than controlled cases (pASHR 1.29, 95% CI 0.95-1.74, I2=13.3%). Total diabetes was strongly associated with the incidence of vascular dementia (pASHR 2.25, 95% CI 1.24-4.08, I2=23.7%), but not Alzheimer’s Disease (pASHR 0.99, 95% CI 0.70-1.42, I2=49.0%).ConclusionsDiabetes, particularly when poorly controlled, may increase dementia risk. There is considerable scope for improved detection and control of diabetes among older people in these settings, and hence an opportunity to carry out proof of concept prevention trials. Overlapping epidemics of these age dependent disorders will challenge poorly-resourced health systems in the future.

BackgroundExposure to endogenous estrogen may protect against dementia, but evidence remains equivocal. Such effects may be assessed more precisely in settings where exogenous estrogen administration is rare. We aimed to determine whether reproductive period (menarche to menopause), and other indicators of endogenous estrogen exposure are inversely associated with dementia incidenceMethodsPopulation-based cohort studies, of women aged 65 years and over in urban sites in Cuba, Dominican Republic Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, including ages at menarche, birth of first child, and menopause, and parity, with ascertainment of incident 10/66 dementia, and mortality, three to five years later.Results9,428 women participated in the baseline phase, with response rates of 72–98% by site. The ‘at risk’ cohort comprised 8,466 dementia-free women. Mean age at baseline varied from 72.0 to 75.4 years, lower in rural than urban sites and in China than in Latin America. Mean parity was 4.1, generally higher in rural than urban sites and ranging from 2.4-7.2 by site. 6,854 women with baseline reproductive period data were followed up for 26,463 person years. There were 692 cases of incident dementia, and 895 dementia free deaths. Pooled meta-analysed fixed effects, per year, for reproductive period (Adjusted Sub-Hazard Ratio [ASHR] 1.001, 95% CI 0.988-1.015) did not support any association with dementia incidence, with no evidence also for any interaction between APOE genotype and reproductive period (ASHR 0.993, 95% CI 0.947-1.041, I2=39.3%). Similarly no association was observed between incident dementia and; ages at menarche, birth of first child, and menopause: nulliparity; or index of cumulative endogenous estrogen exposure. Greater parity was positively associated with incident dementia (ASHR 1.030, 95% CI 1.002-1.059, I2=0.0%).ConclusionsWe found no evidence to support the theory that natural variation in cumulative exposure to endogenous oestrogens across the reproductive period influences the incidence of dementia in late life.

Pathogenic mutations in the three known genes – the amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) – are known to cause familial Alzheimer's disease (AD) and tend to be associated with early-onset AD. However, the frequency and risk associated with these mutations vary widely. In addition, mutations in the frontotemporal lobar degeneration (FTLD) genes – the microtubule-associated protein tau (MAPT), granulin (GRN) – have also been found to be associated with clinical AD. Here, we conducted targeted resequencing of the exons in genes encoding APP, PSEN1, PSEN2, GRN, and MAPT in 183 individuals from families with four or more affected relatives, presumed to be AD, and living in the Dominican Republic and Puerto Rico. We then performed linkage and family-based association analyses in carrier families, and genotyped 498 similarly aged unrelated controls from the same ethnic background. Twelve potentially pathogenic mutations were found to be associated with disease in 53 individuals in the five genes. The most frequently observed mutation was the p.Gly206Ala variant in PSEN1 present in 30 (57%) of those sequenced. In the combined linkage and association analyses several rare variants were associated with dementia. In Caribbean Hispanics with familial AD, potentially pathogenic variants were present in 29.2%, four were novel mutations, while eight had been previously observed. In addition, some family members carried variants in the GRN and MAPT genes which are associated with FTLD.

OBJECTIVES: To estimate the prevalence, social patterning, treatment and control of hypertension among older people in the 10/66 Dementia Research Group developing country sites. METHODS: Cross-sectional surveys of SBP, hypertension, and hypertension awareness, treatment and control among 17?014 people aged 65 years and over in eight urban and four rural sites in Latin America, India and China. RESULTS: Hypertension prevalence was higher in urban (range 52.6-79.8%) than rural sites (range 42.6-56.9%), and lower in men than women [pooled prevalence ratio 0.89, 95% confidence interval (CI) 0.85-0.93]. Educational attainment was positively associated with hypertension in rural and least-developed sites. Age-standardized morbidity ratios, compared to USA (100), were higher in urban sites in Cuba (105), Dominican Republic (109), and Venezuela (107), similar in Puerto Rico (105), urban Mexico (99) and urban India (101), and lower in urban (75) and rural (61) Peru, rural Mexico (81), urban (91) and rural (84) China and rural India (65). In most Latin American centres, and urban China just over one-third of those with hypertension were controlled (BP?140/90). Control was poor in rural China (2%), urban India (12%) and rural India (9%). The proportion controlled, not compositional factors (age, sex, education and obesity), explained most of the between-site variation in SBP. CONCLUSION: Uncontrolled hypertension is common among older people in developing countries, and may rise further during the demographic and health transitions. It is a major determinant of population SBP level. Strengthening primary care to improve hypertension management is necessary for primary prevention.

Amyloid β (Aβ), the putative culprit in Alzheimer’s disease (AD) is produced by successive β-secretase (BACE) cleavage of the amyloid precursor protein (APP) at the N-terminus of the Aβ peptide followed by γ-secretase cleavage of the membrane-bound C-terminal APP fragment.1 This mechanism explains Aβ accumulation in early-onset familial AD due to mutations in the APP2 presenilin 1 (PSEN1),3 and presenilin 2 (PSEN2)4 genes. The explanation for the accumulation of Aβ40 and Aβ42 in the common late-onset form of the disease remains largely unknown. APP and the secretases are integral transmembrane proteins. They are dynamically sorted into the plasma membrane and the membranes of intracellular organelles.5,6 As a consequence, sorting mechanisms that cause APP and the secretases to colocalize in the same cellular compartment are expected to play important roles in the regulation of Aβ production. During the last 2 decades, the trans-Golgi network and the endosome were identified as the key organelles managing the complex movement of the transmembrane proteins via secretory and endocytic pathways.7,8 We and others have previously reported9–16 that variants in the Sortilin-related receptor (SORL1), which maps to chromosome 11q23.3, are associated with AD, that SORL1 is involved in trafficking of APP from the cell surface to the Golgi-endoplasmic reticulum complex, and that under expression of SORL1 leads to overexpression of Aβ and an increased risk of AD.9 SORL1 belongs to the mammalian Vps10p-domain sorting receptor family, which is a group of 5 type-I membrane homologs (SORL1, Sortilin, SorCS1, SorCS2, and SorCS3).17–20 All 5 proteins are characterized by a luminal, extracellular VPS10 domain. In sortilin, the VPS10 domain is the only luminal, extracellular module. In SORL1 the VPS10 domain is followed by low-density lipoprotein (LDL) receptor-like regions and fibronectin type-III domains. In the homologous SorCS1, SorCS2, and SorCS3 the transmembrane domain is preceded by a leucine-rich module.21 Following the extracellular and transmembrane segment, each receptor carries a short (40–80 amino acids) cytoplasmic domain comprising typical motifs for interaction with cytosolic adaptor molecules. All of these receptors are prominently expressed in the nervous system and particularly high in the brain, and may be important for neuronal activity,22,23 although their precise function remains elusive. We hypothesized that genetic variants in SORL1 homologues, in particular SORCS1, might also affect the risk of AD. This was supported by the facts that: (1) we previously observed an association of single nucleotide polymorphism (SNP) rs7082289 in SORCS1 (p = 0.013) in late-onset AD families9; and that (2) Li et al.24 examined a Canadian dataset of 753 AD cases and 736 controls, and SNP rs601883 in SORCS1 was associated with AD risk (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.87–6.23), and SNP rs7907690 was also significant in logistic regression analyses (p = 0.05). In a chromosome 10–specific association study with 1,412 SNPs in 4 independent Caucasian datasets,25 SNP rs600879 in SORCS1 was significantly associated with AD in an exploratory sample set and an independent replication sample set, although the authors used replication rather than correction for multiple testing for evidence of association (uncorrected p-value across datasets: 0.0043). In a case-control dataset of 506 cases and 558 controls, rs17277986 in SORCS1 was significant in the overall datasets (p = 0.0025) and most significant in the female subset (allelic association p = 0.00002) in single-marker and haplotype analyses.26 The goal of this study was to analyze the genetic associations between AD and SORCS1 in 6 independent data sets that had sufficient power to detect modest gene effects. We focused on the SNPs that had been reported by the previous studies as described above, adding SNP rs7082289 at 108,357,010bp that was associated with AD in a previous report by us.9 We also compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in expanded microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation.