Contribution of Global Amyloid-PET Imaging for Predicting Future Cognition in the MEMENTO Cohort.

BACKGROUND AND OBJECTIVES: Global amyloid-PET is associated with cognition and cognitive decline, but most research on this association does not account for past cognitive information. We assessed the prognostic benefit of amyloid-PET measures for future cognition when prior cognitive assessments are available, evaluating the added value of amyloid measures beyond information on multiple past cognitive assessments. METHODS: The French MEMENTO cohort (a cohort of outpatients from French research memory centers to improve knowledge on Alzheimer disease and related disorders) includes older outpatients with incipient cognitive changes, but no dementia diagnosis at inclusion. Global amyloid burden was assessed using positron emission tomography (amyloid-PET) for a subset of participants; semiannual cognitive testing was subsequently performed. We predicted mini-mental state examination (MMSE) scores using demographic characteristics (age, sex, marital status, and education) alone or in combination with information on prior cognitive measures. The added value of amyloid burden as a predictor in these models was evaluated with percent reduction of the mean squared error (MSE). All models were conducted separately for evaluating the added value of dichotomous amyloid positivity status compared with a continuous amyloid-standardized uptake-value ratio. RESULTS: Our analytic sample comprised 510 individuals who underwent amyloid-PET scans with at least 4 MMSE assessments. The mean age at the PET scan was 71.6 (standard deviation 7.4) years; 60.7% were female. The median follow-up was 4.6 years (interquartile range: 0.9 years). Adding amyloid burden when adjusting for only demographic characteristics reduced the MSE of predictions by 5.08% (95% CI 0.97%-10.86%) and 12.64% (95% CI 3.35%-25.28%) for binary and continuous amyloid, respectively. If the model included 1 past MMSE measure, the MSE improvement was 3.51% (95% CI 1.01%-7.28%) when adding binary amyloid and 8.83% (95% CI 2.63%-16.37%) when adding continuous amyloid. Improvements in model fit were smaller with the addition of amyloid burden when more than 1 past cognitive assessment was included. For all models incorporating past cognitive assessments, differences in predictions amounted to a fraction of 1 MMSE point on average. DISCUSSION: In a clinical setting, global amyloid burden did not appreciably improve cognitive predictions when past cognitive assessments were available. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02164643.

Validity of Online Versus In-Clinic Self-Reported Everyday Cognition Scale.

BACKGROUND: Online cognitive assessments are alternatives to in-clinic assessments. OBJECTIVES: We evaluated the relationship between online and in-clinic self-reported Everyday Cognition Scale (ECog). METHODS: In 94 Alzheimer's Disease Neuroimaging Initiative and Brain Health Registry (ADNI-BHR) participants, we estimated associations between online and in-clinic Everyday Cognition using Bland-Altman plots and regression. In 472 ADNI participants, we estimated reliability of in-clinic Everyday Cognition completed six months apart using Bland-Altman plots and regression. RESULTS: Online Everyday Cognition associations: Mean difference was 0.11 (95% limits of agreement: -0.41 to 0.64). In-clinic Everyday Cognition score increased by 0.81 for each online Everyday Cognition score unit increase (R2=0.60). In-clinic Everyday Cognition reliability: Mean difference was 0.01 (95% limits of agreement: -0.61 to 0.62). In-clinic Everyday Cognition score at enrollment increased by 0.79 for each in-clinic Everyday Cognition score unit increase at six months (R2=0.61). CONCLUSION: Online Everyday Cognition closely corresponded with in-clinic Everyday Cognition, supporting validity of using online cognitive assessments to more efficiently facilitate Alzheimer's disease research.

Racial/Ethnic Disparities in Young Adulthood and Midlife Cardiovascular Risk Factors and Late-life Cognitive Domains: The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study.

BACKGROUND: Midlife cardiovascular risk factors (CVRF) increase dementia risk. Less is known about whether CVRF identified before midlife impact late-life cognition in diverse populations. METHODS: Linear regression models examined hypertension, hyperlipidemia, and overweight/obesity at ages 30 to 59 with late-life executive function, semantic memory, verbal episodic memory, and global cognition in a cohort of Asians, blacks, Latinos, and whites (n=1127; mean age=75.8, range=65 to 98). Models adjusted for age at CVRF, age at cognitive assessment, sex, race/ethnicity, participant education, and parental education. RESULTS: Overall, 34% had 1 CVRF at ages 30 to 59; 19% had 2+. Blacks (26%) and Latinos (23%) were more likely to have 2+ CVRF than Asians (14%) or whites (13%). Having 2+ CVRF was associated with lower global cognition [ß=-0.33; 95% confidence interval (CI)=-0.45, -0.21], executive function (ß=-0.26; 95% CI=-0.39, -0.13), verbal episodic memory (ß=-0.34; 95% CI=-0.48, -0.20), and semantic memory (ß=-0.20; 95% CI=-0.33, -0.07). Interaction by age (P=0.06) indicated overweight/obesity was negatively associated with executive function at ages 30 to 39 but not at ages 40 to 59. Race/ethnic-specific effects showed disparities in CVRF prevalence impact population disparities in late-life cognition. CONCLUSION: Being overweight/obese in early adulthood and having 2+ CVRF in early adulthood/midlife are modifiable targets to redress racial/ethnic disparities in cognitive impairment and dementia.

Childhood Psychological Distress and Healthy Cardiovascular Lifestyle 17-35 Years Later: The Potential Role of Mental Health in Primordial Prevention.

Background: Maintaining a healthy lifestyle in adulthood has been shown to significantly reduce cardiovascular disease risk. Increasing evidence suggests that behavioral risk factors for cardiovascular disease are established in childhood; however, limited research has evaluated whether childhood psychological factors play a role. Purpose: To evaluate the association between childhood psychological distress and young to mid adulthood healthy lifestyle. Methods: Using prospective data from the 1958 British Birth Cohort, we assessed whether psychological distress in childhood (captured by internalizing and externalizing symptoms at ages 7, 11, and 16 years) predicted healthy lifestyle at ages 33 (N = 10,748) and 42 (N = 9,581) years. Healthy lifestyle was measured using an index previously demonstrated to predict cardiovascular disease, consisting of five components: absence of smoking, moderate alcohol consumption, regular physical activity, healthy diet, and ideal body weight. Results: Few participants (3.8% at age 33 years and 2.8% at age 42 years) endorsed all five healthy lifestyle components. Linear regression models, adjusting for potential child- and family-level confounders, revealed that higher distress levels in childhood were negatively associated with healthy lifestyle at age 33 years (ß = -0.11, SE = 0.01, p < .001) and 42 years (ß = -0.13, SE = 0.01, p < .001). Higher distress was also associated with significantly lower odds of endorsing each lifestyle component, except physical activity, at both ages. Additional analyses indicated that childhood distress levels were highest among those whose lifestyle scores were low at age 33 and further declined between ages 33 and 42. Conclusions: Psychological distress in childhood may indicate children at risk of less healthy lifestyle practices later in life. Although our findings are preliminary, psychological distress may also provide an important target for public health interventions aimed at preventing cardiovascular disease.

Post-traumatic stress disorder symptom duration and remission in relation to cardiovascular disease risk among a large cohort of women.

BACKGROUND: Prior studies suggest that post-traumatic stress disorder (PTSD) is associated with elevated cardiovascular disease (CVD) risk, but effects of duration and remission of PTSD symptoms have rarely been evaluated. METHOD: We examined the association of time-updated PTSD symptom severity, remission and duration with incident CVD risk (552 confirmed myocardial infarctions or strokes) over 20 years in 49 859 women in the Nurses' Health Study II. Among women who reported trauma on the Brief Trauma Questionnaire, PTSD symptoms, assessed by a screener, were classified by symptom severity and chronicity: (a) no symptoms, (b) 1-3 ongoing, (c) 4-5 ongoing, (d) 6-7 ongoing, (e) 1-3 remitted, (f) 4-7 remitted symptoms. Inverse probability weighting was used to estimate marginal structural logistic regression models, adjusting for time-varying and time-invariant confounders. RESULTS: Compared with women with no trauma exposure, women with trauma/no PTSD [odds ratio (OR) 1.30, 95% confidence interval (CI) 1.03-1.65] and women with trauma/6-7 symptoms (OR 1.69, 95% CI 1.08-2.63) had elevated risk of CVD; women with remitted symptoms did not have elevated CVD risk. Among women exposed to trauma, every 5 additional years of PTSD symptomology was associated with 9% higher CVD incidence compared with women with trauma/no PTSD. CONCLUSIONS: The findings suggest that alleviating PTSD symptoms shortly after onset may attenuate CVD risk.

Compartmental Model Diagrams as Causal Representations in Relation to DAGs.

Compartmental model diagrams have been used for nearly a century to depict causal relationships in infectious disease epidemiology. Causal directed acyclic graphs (DAGs) have been used more broadly in epidemiology since the 1990s to guide analyses of a variety of public health problems. Using an example from chronic disease epidemiology, the effect of type 2 diabetes on dementia incidence, we illustrate how compartmental model diagrams can represent the same concepts as causal DAGs, including causation, mediation, confounding, and collider bias. We show how to use compartmental model diagrams to explicitly depict interaction and feedback cycles. While DAGs imply a set of conditional independencies, they do not define conditional distributions parametrically. Compartmental model diagrams parametrically (or semiparametrically) describe state changes based on known biological processes or mechanisms. Compartmental model diagrams are part of a long-term tradition of causal thinking in epidemiology and can parametrically express the same concepts as DAGs, as well as explicitly depict feedback cycles and interactions. As causal inference efforts in epidemiology increasingly draw on simulations and quantitative sensitivity analyses, compartmental model diagrams may be of use to a wider audience. Recognizing simple links between these two common approaches to representing causal processes may facilitate communication between researchers from different traditions.

Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice.

Post-traumatic stress disorder (PTSD) has been declared 'a life sentence' based on evidence that the disorder leads to a host of physical health problems. Some of the strongest empirical research - in terms of methodology and findings - has shown that PTSD predicts higher risk of cardiometabolic diseases, specifically cardiovascular disease (CVD) and type 2 diabetes (T2D). Despite mounting evidence, PTSD is not currently acknowledged as a risk factor by cardiovascular or endocrinological medicine. This view is unlikely to change absent compelling evidence that PTSD causally contributes to cardiometabolic disease. This review suggests that with developments in methods for epidemiological research and the rapidly expanding knowledge of the behavioral and biological effects of PTSD the field is poised to provide more definitive answers to questions of causality. First, we discuss methods to improve causal inference using the observational data most often used in studies of PTSD and health, with particular reference to issues of temporality and confounding. Second, we consider recent work linking PTSD with specific behaviors and biological processes, and evaluate whether these may plausibly serve as mechanisms by which PTSD leads to cardiometabolic disease. Third, we evaluate how looking more comprehensively into the PTSD phenotype provides insight into whether specific aspects of PTSD phenomenology are particularly relevant to cardiometabolic disease. Finally, we discuss new areas of research that are feasible and could enhance understanding of the PTSD-cardiometabolic relationship, such as testing whether treatment of PTSD can halt or even reverse the cardiometabolic risk factors causally related to CVD and T2D.

Association of Alzheimer's related genotypes with cognitive decline in multiple domains: results from the Three-City Dijon study.

Several genetic polymorphisms have been associated with Late Onset Alzheimer's Disease (LOAD), but there has been limited evidence on whether these polymorphisms predict intermediary stage outcomes such as cognitive changes in prospective community-based studies. Our aim was to evaluate whether polymorphisms previously established as predictors of LOAD also predict worse cognitive function and accelerated decline across multiple cognitive domains. We analyzed data from the 3C-Dijon study, in which 4931 respondents aged 65+ were examined up to 5 times over 10 years with a neuropsychological assessment. We evaluated the associations of polymorphisms in APOE, CR1, BIN1, CLU, PICALM, ABCA7, MS4A6A, CD33, MS4A4E and CD2AP with level and change in 5 neuropsychological tests, assuming a dominant effect model. To optimize measurement, we used a mixed regression model with a latent process for each cognitive domain: global cognition (Mini Mental State Examination); verbal fluency (Isaac's Set Test); visual memory (Benton Visual Retention Test); information processing (Trail Making Test B) and literacy (National Adult Reading Test). APOE was associated with accelerated decline in global cognition and verbal fluency. Only two non-APOE genetic polymorphisms were associated with cognitive decline: CR1 was associated with rate of change in verbal fluency and BIN1 was associated with rate of change in global cognition. In a large prospective population-based study of dementia-free individuals, only a few cognitive domains were associated with established LOAD risk alleles. The most consistent associations were for global cognition and verbal fluency.

Body mass index and cognitive function: the potential for reverse causation.

OBJECTIVE: Higher late life body mass index (BMI) is unrelated to or even predicts lower risk of dementia in late life, a phenomenon that may be explained by reverse causation due to weight loss during preclinical phases of dementia. We aim to investigate the association of baseline BMI and changes in BMI with dementia in a large prospective cohort, and to examine whether weight loss predicts cognitive function. METHODS: Using a national cohort of adults average age 58 years at baseline in 1994 (n=7029), we investigated the associations between baseline BMI in 1994 and memory scores from 2000 to 2010. We also examined the association of BMI change from 1994 to 1998 with memory scores from 2000 to 2010. Last, to investigate reverse causation, we examined whether memory scores in 1996 predicted BMI trajectories from 2000 to 2010. RESULTS: Baseline overweight predicted better memory scores 6 to 16 years later (ß=0.012, 95% confidence interval (CI)=0.001; 0.023). Decline in BMI predicted lower memory scores over the subsequent 12 years (ß=-0.026, 95% CI= -0.041; -0.011). Lower memory scores at mean age 60 years in 1996 predicted faster annual rate of BMI decline during follow-up (ß=-0.158 kg m(-2) per year, 95% CI= -0.223; -0.094). CONCLUSION: Consistent with reverse causation, greater decline in BMI over the first 4 years of the study was associated with lower memory scores over the next decade and lower memory scores was associated with a decline in BMI. These findings suggest that preclinical dementia predicts weight loss for people as early as their late 50s.

Do genetic risk scores for body mass index predict risk of phobic anxiety? Evidence for a shared genetic risk factor.

BACKGROUND: Obesity and anxiety are often linked but the direction of effects is not clear. METHOD: Using genetic instrumental variable (IV) analyses in 5911 female participants from the Nurses' Health Study (NHS, initiated 1976) and 3697 male participants from the Health Professional Follow-up Study (HPFS, initiated 1986), we aimed to determine whether obesity increases symptoms of phobic anxiety. As instrumental variables we used the fat mass and obesity-associated (FTO) gene, the melanocortin 4 receptor (MC4R) gene and a genetic risk score (GRS) based on 32 single nucleotide polymorphisms (SNPs) that significantly predict body mass index (BMI). 'Functional' GRSs corresponding with specific biological pathways that shape BMI (adipogenesis, appetite and cardiopulmonary) were considered. The main outcome was phobic anxiety measured by the Crown Crisp Index (CCI) in 2004 in the NHS and in 2000 in the HPFS. RESULTS: In observational analysis, a 1-unit higher BMI was associated with higher phobic anxiety symptoms [women: ß = 0.05, 95% confidence interval (CI) 0.030-0.068; men: ß = 0.04, 95% CI 0.016-0.071). IV analyses showed that BMI was associated with higher phobic anxiety symptoms in the FTO-instrumented analysis (p = 0.005) but not in the GRS-instrumented analysis (p = 0.256). Functional GRSs showed heterogeneous, non-significant effects of BMI on phobic anxiety symptoms. CONCLUSIONS: Our findings do not provide conclusive evidence in favor of the hypothesis that higher BMI leads to higher levels of phobic anxiety, but rather suggest that genes that influence obesity, in particular FTO, may have direct effects on phobic anxiety, and hence that obesity and phobic anxiety may share common genetic determinants.

Genetic vulnerability to diabetes and obesity: does education offset the risk?

The prevalence of type 2 diabetes (T2D) and obesity has recently increased dramatically. These common diseases are likely to arise from the interaction of multiple genetic, socio-demographic and environmental risk factors. While previous research has found genetic risk and education to be strong predictors of these diseases, few studies to date have examined their joint effects. This study investigates whether education modifies the association between genetic background and risk for type 2 diabetes (T2D) and obesity. Using data from non-Hispanic Whites in the Health and Retirement Study (HRS, n = 8398), we tested whether education modifies genetic risk for obesity and T2D, offsetting genetic effects; whether this effect is larger for individuals who have high risk for other (unobserved) reasons, i.e., at higher quantiles of HbA1c and BMI; and whether effects differ by gender. We measured T2D risk using Hemoglobin A1c (HbA1c) level, and obesity risk using body-mass index (BMI). We constructed separate genetic risk scores (GRS) for obesity and diabetes respectively based on the most current available information on the single nucleotide polymorphism (SNPs) confirmed as genome-wide significant predictors for BMI (29 SNPs) and diabetes risk (39 SNPs). Linear regression models with years of schooling indicate that the effect of genetic risk on HbA1c is smaller among people with more years of schooling and larger among those with less than a high school (HS) degree compared to HS degree-holders. Quantile regression models show that the GRS × education effect systematically increased along the HbA1c outcome distribution; for example the GRS × years of education interaction coefficient was -0.01 (95% CI = -0.03, 0.00) at the 10th percentile compared to -0.03 (95% CI = -0.07, 0.00) at the 90th percentile. These results suggest that education may be an important socioeconomic source of heterogeneity in responses to genetic vulnerability to T2D.

Genetic taste blindness to bitter and body composition in childhood: a Mendelian randomization design.

BACKGROUND: The ability to taste 6-n-propylthiouracil (PROP) may be associated with body composition, but previous findings from observational studies are conflicting and cannot be interpreted causally. The aim of this study was to estimate the causal association between PROP taster status and body composition in a population-based cohort study. METHODS: The study was embedded in a population-based prospective birth cohort study. The TAS2R38 genotype (rs713598) was used as an instrumental variable (IV) to obtain unbiased effect estimates of the relation between PROP taster status and body weight (n=3778). Adiposity measures included body mass index (BMI) and fat mass measured by dual- energy X-ray absorptiometry scan at the child's age of 6 years. Associations were investigated using both ordinary linear regression (OLS) and two-stage least squares regression (2SLS). RESULTS: Non-taster girls had higher BMI standard deviation scores (SDS) and higher body fat as compared with taster girls (results from linear regression BMI SDS: -0.09, P=0.023, body fat mass (%): -0.49, P=0.028). The TAS2R38 genotype predicted PROP phenotype (F=240), indicating a strong IV. The 2SLS effect estimates were imprecise but similar to the observational estimates (-0.08 for BMI SDS and -0.46 for body fat mass %) and were not significantly different from the OLS results (Hausman test: P>0.10). For boys there were no differences observed between tasters and non-tasters. CONCLUSIONS: Our findings suggest a causal relation between PROP taster status and body weight among 6-year-old girls; Mendelian randomization was consistent with conventional estimates. In contrast, body weight among boys appeared to be independent of the PROP taster status. Further research should focus on possible underlying pathways, such as dietary behavior.

Occupational solvent exposure and cognition: does the association vary by level of education?

OBJECTIVE: Chronic occupational solvent exposure is associated with long-term cognitive deficits. Cognitive reserve may protect solvent-exposed workers from cognitive impairment. We tested whether the association between chronic solvent exposure and cognition varied by educational attainment, a proxy for cognitive reserve. METHODS: Data were drawn from a prospective cohort of French national gas and electricity (GAZEL) employees (n = 4,134). Lifetime exposure to 4 solvent types (chlorinated solvents, petroleum solvents, benzene, and nonbenzene aromatic solvents) was assessed using a validated job-exposure matrix. Education was dichotomized at less than secondary school or below. Cognitive impairment was defined as scoring below the 25th percentile on the Digit Symbol Substitution Test at mean age 59 (SD 2.8; 88% of participants were retired at testing). Log-binomial regression was used to model risk ratios (RRs) for poor cognition as predicted by solvent exposure, stratified by education and adjusted for sociodemographic and behavioral factors. RESULTS: Solvent exposure rates were higher among less-educated patients. Within this group, there was a dose-response relationship between lifetime exposure to each solvent type and RR for poor cognition (e.g., for high exposure to benzene, RR = 1.24, 95% confidence interval 1.09-1.41), with significant linear trends (p < 0.05) in 3 out of 4 solvent types. Recency of solvent exposure also predicted worse cognition among less-educated patients. Among those with secondary education or higher, there was no significant or near-significant relationship between any quantification of solvent exposure and cognition. CONCLUSIONS: Solvent exposure is associated with poor cognition only among less-educated individuals. Higher cognitive reserve in the more-educated group may explain this finding.

Depressive symptoms predict incident stroke independently of memory impairments.

BACKGROUND: We evaluated whether depressive symptoms predict the onset of first stroke independently of memory impairment. We conceptualized memory impairment as a marker of preexisting cerebrovascular disease. We hypothesized that if depressive symptoms are causally related to stroke through mechanisms unrelated to cerebrovascular disease, depressive symptoms should predict stroke independently of memory impairment. METHODS: Incidence of first stroke was assessed with self or proxy reports from 19,087 participants in the Health and Retirement Study cohort (1,864 events). Elevated depressive symptoms (3+ on an 8-item Centers for the Epidemiologic Study of Depression scale) and memory impairment (score of ≤6 on a combined immediate and delayed recall of a 10-word list) were used as predictors of incident stroke in Cox survival models with adjustment for sociodemographic and cardiovascular risk factors. RESULTS: After adjustment for sociodemographic and cardiovascular risk factors, elevated depressive symptoms (hazard ratio = 1.25; 95% confidence interval 1.12-1.39) and memory impairment (hazard ratio = 1.26; 95% confidence interval 1.13-1.41) each predicted stroke incidence in separate models. Hazard ratios were nearly unchanged and remained significant (1.23 for elevated depressive symptoms and 1.25 for memory impairment) when models were simultaneously adjusted for both elevated depressive symptoms and memory impairment. Elevated depressive symptoms also predicted stroke when restricting analyses to individuals with median memory score or better. CONCLUSIONS: Memory impairments and depressive symptoms independently predict stroke incidence. Memory impairment may reflect undiagnosed cerebrovascular disease. These results suggest that depressive symptoms might be directly related to stroke rather than merely indicating preexisting cerebrovascular disease.

Does childhood schooling affect old age memory or mental status? Using state schooling laws as natural experiments.

BACKGROUND: The association between schooling and old age cognitive outcomes such as memory disorders is well documented but, because of the threat of reverse causation, controversy persists over whether education affects old age cognition. Changes in state compulsory schooling laws (CSL) are treated as natural experiments (instruments) for estimating the effect of education on memory and mental status among the elderly. Changes in CSL predict changes in average years of schooling completed by children who are affected by the new laws. These educational differences are presumably independent of innate individual characteristics such as IQ. METHODS: CSL-induced changes in education were used to obtain instrumental variable (IV) estimates of education's effect on memory (n = 10,694) and mental status (n = 9751) for white, non-Hispanic US-born Health and Retirement Survey participants born between 1900 and 1947 who did not attend college. RESULTS: After adjustment for sex, birth year, state of birth and state characteristics, IV estimates of education's effect on memory were large and statistically significant. IV estimates for mental status had very wide confidence intervals, so it was not possible to draw meaningful conclusions about the effect of education on this outcome. CONCLUSIONS: Increases in mandatory schooling lead to improvements in performance on memory tests many decades after school completion. These analyses condition on individual states, so differences in memory outcomes associated with CSL changes cannot be attributed to differences between states. Although unmeasured state characteristics that changed contemporaneously with CSL might account for these results, unobserved genetic variation is unlikely to do so.

APOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer disease.

OBJECTIVE: To determine whether APOE epsilon 4 predicts rate of cognitive change in incident and prevalent Alzheimer disease (AD). METHODS: Individuals were recruited from two longitudinal cohort studies-the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based)--and were followed for an average of 4 years. Three samples of participants diagnosed with AD, with diverse demographic characteristics and baseline cognitive functioning, were studied: 1) 199 (48%) of the incident WHICAP cases; 2) 215 (54%) of the prevalent WHICAP cases; and 3) 156 (71%) of the individuals diagnosed with AD in the Predictors Study. Generalized estimating equations were used to test whether rate of cognitive change, measured using a composite cognitive score in WHICAP and the Mini-Mental State Examination in Predictors, varied as a function of epsilon 4 status in each sample. RESULTS: The presence of at least one epsilon 4 allele was associated with faster cognitive decline in the incident population-based AD group (p = 0.01). Parallel results were produced for the two prevalent dementia samples only when adjusting for disease severity or excluding the most impaired participants from the analyses. CONCLUSION: APOE epsilon 4 may influence rate of cognitive decline most significantly in the earliest stages of Alzheimer disease.

Frailty modifies effectiveness of psychosocial intervention in recovery from stroke.

OBJECTIVE: To evaluate the impact of a psychosocial intervention on instrumental activities of daily living, physical performance, cognition and mortality after stroke. DESIGN: A randomized clinical trial. SETTING: Patients were recruited from hospitals and rehabilitation centres; the intervention took place in subjects' homes. SUBJECTS: Two-hundred and ninety-one stroke survivors over age 45. One-hundred and forty-six subjects were assigned to the intervention and 145 subjects were assigned to usual care. INTERVENTION: Up to 16 meetings conducted over six months in the patient's home (approximately weekly for 12 weeks, followed by tri-weekly sessions for another 12 weeks). Sessions lasted approximately 1 hour and included, when possible, the entire support system (stroke survivor, primary caregiver, additional family and friends, and professional caregivers). MAIN OUTCOME MEASURES: Instrumental activities of daily living, physical performance, and cognition were assessed six months post stroke; mortality was assessed at an average of 47 months post stroke. RESULTS: No significant differences in outcomes were observed between the intervention and usual care groups when analysing the total study population. Among non-frail participants (n = 156), subjects randomized to treatment had better scores on instrumental activities of daily living (mean score among treated = 12.4 (standard deviation (SD) = 2.1), mean score among usual care subjects = 11.3 (SD = 2.9), P-value for difference in means = 0.01) and reduced risk of mortality (P = 0.03) than subjects randomized to usual care. CONCLUSION: While there is evidence that the treatment benefited healthier subgroups, results also show evidence that the treatment was not effective, and possibly harmful, in frail subgroups.