Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-ß monoclonal antibodies in dominantly inherited Alzheimer's disease.

PURPOSE: Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-ß (Aß) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to evaluate the efficacy of anti-Aß monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aß radiotracers were used. To study the consequences of using different Aß radiotracers to measure Aß clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aß monoclonal antibodies. METHODS: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aß PET imaging. RESULTS: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aß radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aß radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aß radiotracers were used versus trials where only one Aß radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. CONCLUSION: Gantenerumab treatment induces longitudinal changes in Aß PET, and the absolute rates of these longitudinal changes differ significantly between Aß radiotracers. These differences were not seen in the placebo arm, suggesting that Aß-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aß radiotracers. Our results suggest converting Aß PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aß PET biomarker data and, if feasible, use a single radiotracer for the best results. TRIAL REGISTRATION: ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered.

Admixture Mapping of Alzheimer's disease in Caribbean Hispanics identifies a new locus on 22q13.1.

Late-onset Alzheimer's disease (LOAD) is significantly more frequent in Hispanics than in non-Hispanic Whites. Ancestry may explain these differences across ethnic groups. To this end, we studied a large cohort of Caribbean Hispanics (CH, N = 8813) and tested the association between Local Ancestry (LA) and LOAD ("admixture mapping") to identify LOAD-associated ancestral blocks, separately for ancestral components (European [EUR], African [AFR], Native American[NA]) and jointly (AFR + NA). Ancestral blocks significant after permutation were fine-mapped employing multi-ethnic whole-exome sequencing (WES) to identify rare variants associated with LOAD (SKAT-O) and replicated in the UK Biobank WES dataset. Candidate genes were validated studying (A) protein expression in human LOAD and control brains; (B) two animal AD models, Drosophila and Zebrafish. In the joint AFR + NA model, we identified four significant ancestral blocks located on chromosomes 1 (p value = 8.94E-05), 6 (p value = 8.63E-05), 21 (p value = 4.64E-05) and 22 (p value = 1.77E-05). Fine-mapping prioritized the GCAT gene on chromosome 22 (SKAT-O p value = 3.45E-05) and replicated in the UK Biobank (SKAT-O p value = 0.05). In LOAD brains, a decrease of 28% in GCAT protein expression was observed (p value = 0.038), and GCAT knockdown in Amyloid-ß42 Drosophila exacerbated rough eye phenotype (68% increase, p value = 4.84E-09). In zebrafish, gcat expression increased after acute amyloidosis (34%, p value = 0.0049), and decreased upon anti-inflammatory Interleukin-4 (39%, p value = 2.3E-05). Admixture mapping uncovered genomic regions harboring new LOAD-associated loci that might explain the observed different frequency of LOAD across ethnic groups. Our results suggest that the inflammation-related activity of GCAT is a response to amyloid toxicity, and reduced GCAT expression exacerbates AD pathology.

Apolipoprotein E (APOE) genotype, dementia, and memory performance among Caribbean Hispanic versus US populations.

INTRODUCTION: Apolipoprotein E (APOE) is considered the major susceptibility gene for developing Alzheimer's disease. However, the strength of this risk factor is not well established across diverse Hispanic populations. METHODS: We investigated the associations among APOE genotype, dementia prevalence, and memory performance (immediate and delayed recall scores) in Caribbean Hispanics (CH), African Americans (AA), Hispanic Americans (HA) and non-Hispanic White Americans (NHW). Multivariable logistic regressions and negative binomial regressions were used to examine these associations by subsample. RESULTS: Our final dataset included 13,516 participants (5198 men, 8318 women) across all subsamples, with a mean age of 74.8 years. Prevalence of APOE ε4 allele was similar in CHs, HAs, and NHWs (21.8%-25.4%), but was substantially higher in AAs (33.6%; P < 0.001). APOE ε4 carriers had higher dementia prevalence across all groups. DISCUSSION: APOE ε4 was similarly associated with increased relative risk of dementia and lower memory performance in all subsamples.

Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm-FINGERS): Study design and harmonization.

INTRODUCTION: Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm-FINGERS) is the first non-pharmacological multicenter randomized clinical trial (RCT) to prevent cognitive impairment in Latin America (LA). Our aim is to present the study design and discuss the strategies used for multicultural harmonization. METHODS: This 1-year RCT (working on a 1-year extension) investigates the feasibility of a multi-domain lifestyle intervention in LA and the efficacy of the intervention, primarily on cognitive function. An external harmonization process was carried out to follow the FINGER model, and an internal harmonization was performed to ensure this study was feasible and comparable across the 12 participating LA countries. RESULTS: Currently, 1549 participants have been screened, and 815 randomized. Participants are ethnically diverse (56% are Nestizo) and have high cardiovascular risk (39% have metabolic syndrome). DISCUSSION: LatAm-FINGERS overcame a significant challenge to combine the region's diversity into a multi-domain risk reduction intervention feasible across LA while preserving the original FINGER design.

Polygenic Risk Score for Alzheimer's Disease in Caribbean Hispanics.

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 used 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 using European and African American discovery cohorts to construct alternative PRSs ("EUR-PRS", "AA-PRS"). RESULTS: The full model (LOAD ~ CH-PRS + sex + age + APOE-ɛ4), achieved an AUC = 74% (ORCH-PRS  = 1.51 95%CI = 1.36-1.68), raising to >75% in APOE-ɛ4 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. ANN NEUROL 2021;90:366-376.

FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer's disease.

Alzheimer's disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10-7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood-brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

Progranulin mutations in clinical and neuropathological Alzheimer's disease.

INTRODUCTION: Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology. METHODS: We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, ß-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers. RESULTS: Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort. DISCUSSION: GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with ß-amyloid load or AD.

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the second Latinos & Alzheimer's Symposium.

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

Intrinsic capacity and its associations with incident dependence and mortality in 10/66 Dementia Research Group studies in Latin America, India, and China: A population-based cohort study.

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.

Sex disparities in the prevalence of physical function disabilities: a population-based study in a low-income community.

BACKGROUND: Functional disability continues to be a significant public health problem that increases older adults' vulnerability to experience a diminished quality of life, loss of independence, higher healthcare costs and health services utilization, and increased risks of mortality. Thus, we aimed to study the prevalence of functional disabilities by sex according to the types of daily living activities, controlling for specific sociodemographic variables among older Hispanics from low-income communities. METHODS: We used a cross-sectional epidemiological research design, considering a complex sampling design of households to interview adults ≥65 years living in low-income communities in Puerto Rico. Functional disability was measured by the PROMIS® Physical Function Short Form-20 T-score. The selected community was reported to have 5980 adult residents ≥65 years, according to the USA Census. The prevalence of functional disability was estimated using the logistic regression model, weighting by the effect of the sampling. Our estimated prevalence was compared between sexes using the prevalence ratio (PR), which was estimated with logistic regression models, controlling for age, income, number of chronic conditions, high and low impact of chronic conditions in functional disabilities, marital status, and sampling design. RESULTS: We recruited 211 older Hispanics from a randomly selected sample. Their mean age was 74.4 ± 7.1 years, with female predominance (57.3%). The overall estimated prevalence of physical function disability using T-score among females was 2.70 (95% CI: 1.4, 5.1) times the estimated prevalence of physical function disability among males. Women were more likely to report functional disabilities in instrumental activities of daily living, self-care activities, and functional mobility compared to males. However, sex differences were largely explained by the presence of musculoskeletal conditions of high impact in functional disability. CONCLUSIONS: The females in our study bear the greater burden of physical function disability in their adult age. Health policies, as well as future studies, should be targeted at reducing the burden of physical function disabilities in different types of daily activities through gender-sensitive disability self-management programs.

Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes.

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.

The association between, depression, anxiety, and mortality in older people across eight low- and middle-income countries: Results from the 10/66 cohort study.

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.

Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci.

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.

Inbreeding among Caribbean Hispanics from the Dominican Republic and its effects on risk of Alzheimer disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The prevalence, correlates and impact of anaemia among older people in Cuba, Dominican Republic, Mexico, Puerto Rico and Venezuela.

Anaemia among older people is increasingly recognized as a matter of public health concern. Data from low- and middle-income countries are sparse. We surveyed 10915 people aged 65 years and over (8423 with blood tests) in catchment areas in Cuba, Dominican Republic, Puerto Rico, Venezuela and Mexico, to assess prevalence and correlates of anaemia and impact on disability. Prevalence varied widely between sites, from 6·4% in rural Mexico to 9·2% in urban Mexico, 9·8% in Venezuela, 19·2% in Cuba, 32·1% in Puerto Rico and 37·3% in Dominican Republic. Prevalence was higher in men and increased with age, but sociodemographic composition did not account for prevalence differences between sites. Standardized morbidity ratios indicated a much higher prevalence in Cuba (173), Puerto Rico (280) and Dominican Republic (332) compared with USA National Health and National Examination Surveys. Anaemia was associated with undernutrition, physical impairments, and serum creatinine. There was an association with greater African admixture in Dominican Republic but not in Cuba. African admixture is therefore unlikely to fully explain the high prevalence in the Caribbean islands, which may also arise from environmental, possibly dietary factors. Given an important independent contribution of anaemia to disability, more research is needed to identify preventable and treatable causes.

The Effect of Visit-to-Visit Blood Pressure Variability on Renal Function in Geriatric Chronic Kidney Disease.

OBJECTIVE: The visit-to-visit variability (VVV) of blood pressure (BP) has been recognized as a risk factor for cardiovascular events and chronic kidney disease (CKD). The objective of this study is to valuate the association between the VVV of BP and changes in estimated glomerular filtration rate (eGFR) in elderly CKD patients at different stages of renal function. MATERIALS AND METHODS: For 60 months, we analyzed the medical records of 105 patients with and without diabetes and hypertension. Systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) were examined. A multivariable linear regression model was used to analyze the correlation between eGFR and the VVV of BP. RESULTS: No differences were demonstrated between the groups in the clinical characteristics. Mean SBP and DBP were not significant between the groups, and we observed no decrease in renal function. A significant negative correlation between PP and eGFR was observed in the total CKD population with a P of .010 (95% CI: -0.20, -0.03) and a correlation coefficient of -0.11. CONCLUSION: Our study shows no statistical significances in terms of the VVVs of BP in any of the geriatric groups, with no significant decreases in renal function. However, we observed a significant negative correlation between PP and eGFR. We demonstrated that if a VVV of BP does not occur, there is no decrease in eGFR.

Dementia Attributable Healthcare Utilizations in the Caribbean versus United States.

BACKGROUND: Despite the high burden of Alzheimer's disease and other dementias among the Hispanic population worldwide, little is known about how dementia affects healthcare utilizations among this population outside of the US, in particular among those in the Caribbean region. OBJECTIVE: This study examines healthcare utilization associated with Alzheimer's disease and other dementias among older adults in the Caribbean as compared to the US. METHODS: We conducted harmonized analyses of two population-based surveys, the 10/66 Dementia Group Research data collected in Dominican Republic, Cuba, and Puerto Rico, and the US-based Health and Retirement Study. We examined changes in hospital nights and physician visits in response to incident and ongoing dementias. RESULTS: Incident dementia significantly increased the risk of hospitalization and number of hospital nights in both populations. Ongoing dementia increased the risk of hospitalization and hospital nights in the US, with imprecise estimates for the Caribbean. The number of physician visits was elevated in the US but not in the Caribbean. CONCLUSIONS: The concentration of increased healthcare utilization on hospital care and among patients with incident dementia suggests an opportunity for improved outpatient management of new and existing dementia patients in the Caribbean.