M. Maria Glymour

Contribution of Vascular Risk Factors to the Progression in Alzheimer Disease

BACKGROUND Vascular factors including medical history (heart disease, stroke, diabetes, and hypertension), smoking, and prediagnosis blood lipid measurements (cholesterol: total, high-density lipoprotein, low-density lipoprotein [LDL-C], and triglyceride concentrations) may be predictors for progression of Alzheimer disease (AD). OBJECTIVE To determine whether prediagnosis vascular risk factors are associated with progression of AD. DESIGN Inception cohort followed up longitudinally for a mean of 3.5 (up to 10.2) years. SETTING Washington Heights/Inwood Columbia Aging Project, New York, New York. Patients One hundred fifty-six patients with incident AD (mean age at diagnosis, 83 years). Main Outcome Measure Change in a composite score of cognitive ability from diagnosis onward. RESULTS In generalized estimating equation models (adjusted for age, race/ethnicity, and years of education), higher cholesterol (total cholesterol and LDL-C) concentrations and history of diabetes were associated with faster cognitive decline. Each 10-U increase in cholesterol and LDL-C was associated with a 0.10-SD decrease in cognitive score per year of follow-up (P < .001 for total cholesterol; P = .001 for LDL-C). High-density lipoprotein cholesterol and triglyceride concentrations were not associated with rate of decline. A history of diabetes was associated with an additional 0.05-SD decrease in cognitive score per year (P = .05). History of heart disease and stroke were associated with cognitive decline only in carriers of the apolipoprotein E epsilon4 (APOE-epsilon4) gene. In a final generalized estimating equation model that included high-density lipoprotein cholesterol and LDL-C concentrations and history of diabetes, only higher LDL-C was independently associated with faster cognitive decline. CONCLUSION Higher prediagnosis total cholesterol and LDL-C concentrations and history of diabetes were associated with faster cognitive decline in patients with incident AD, which provides further evidence for the role of vascular risk factors in the course of AD.

Effects of Social Integration on Preserving Memory Function in a Nationally Representative US Elderly Population

OBJECTIVES We tested whether social integration protects against memory loss and other cognitive disorders in late life in a nationally representative US sample of elderly adults, whether effects were stronger among disadvantaged individuals, and whether earlier cognitive losses explained the association (reverse causation). METHODS Using data from the Health and Retirement Study (N = 16,638), we examined whether social integration predicted memory change over 6 years. Memory was measured by immediate and delayed recall of a 10-word list. Social integration was assessed by marital status, volunteer activity, and frequency of contact with children, parents, and neighbors. We examined growth-curve models for the whole sample and within subgroups. RESULTS The mean memory score declined from 11.0 in 1998 to 10.0 in 2004. Higher baseline social integration predicted slower memory decline in fully adjusted models (P<.01). Memory among the least integrated declined at twice the rate as among the most integrated. This association was largest for respondents with fewer than 12 years of education. There was no evidence of reverse causation. CONCLUSIONS Our study provides evidence that social integration delays memory loss among elderly Americans. Future research should focus on identifying the specific aspects of social integration most important for preserving memory.

Education Does Not Slow Cognitive Decline with Aging: 12-Year Evidence from the Victoria Longitudinal Study

Although the relationship between education and cognitive status is well-known, evidence regarding whether education moderates the trajectory of cognitive change in late life is conflicting. Early studies suggested that higher levels of education attenuate cognitive decline. More recent studies using improved longitudinal methods have not found that education moderates decline. Fewer studies have explored whether education exerts different effects on longitudinal changes within different cognitive domains. In the present study, we analyzed data from 1014 participants in the Victoria Longitudinal Study to examine the effects of education on composite scores reflecting verbal processing speed, working memory, verbal fluency, and verbal episodic memory. Using linear growth models adjusted for age at enrollment (range, 54-95 years) and gender, we found that years of education (range, 6-20 years) was strongly related to cognitive level in all domains, particularly verbal fluency. However, education was not related to rates of change over time for any cognitive domain. Results were similar in individuals older or younger than 70 at baseline, and when education was dichotomized to reflect high or low attainment. In this large longitudinal cohort, education was related to cognitive performance but unrelated to cognitive decline, supporting the hypothesis of passive cognitive reserve with aging.

Credible Mendelian Randomization Studies: Approaches for Evaluating the Instrumental Variable Assumptions

As with other instrumental variable (IV) analyses, Mendelian randomization (MR) studies rest on strong assumptions. These assumptions are not routinely systematically evaluated in MR applications, although such evaluation could add to the credibility of MR analyses. In this article, the authors present several methods that are useful for evaluating the validity of an MR study. They apply these methods to a recent MR study that used fat mass and obesity-associated (FTO) genotype as an IV to estimate the effect of obesity on mental disorder. These approaches to evaluating assumptions for valid IV analyses are not fail-safe, in that there are situations where the approaches might either fail to identify a biased IV or inappropriately suggest that a valid IV is biased. Therefore, the authors describe the assumptions upon which the IV assessments rely. The methods they describe are relevant to any IV analysis, regardless of whether it is based on a genetic IV or other possible sources of exogenous variation. Methods that assess the IV assumptions are generally not conclusive, but routinely applying such methods is nonetheless likely to improve the scientific contributions of MR studies.

APOE ε4 allele predicts faster cognitive decline in mild Alzheimer disease

Objective: To determine whether APOE ε4 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 ε4 status in each sample. Results: The presence of at least one ε4 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 ε4 may influence rate of cognitive decline most significantly in the earliest stages of Alzheimer disease.

Health Disadvantage in US Adults Aged 50 to 74 Years: A Comparison of the Health of Rich and Poor Americans With That of Europeans

OBJECTIVES We compared the health of older US, English, and other European adults, stratified by wealth. METHODS Representative samples of adults aged 50 to 74 years were interviewed in 2004 in 10 European countries (n = 17,481), England (n = 6527), and the United States (n = 9940). We calculated prevalence rates of 6 chronic diseases and functional limitations. RESULTS American adults reported worse health than did English or European adults. Eighteen percent of Americans reported heart disease, compared with 12% of English and 11% of Europeans. At all wealth levels, Americans were less healthy than were Europeans, but differences were more marked among the poor. Health disparities by wealth were significantly smaller in Europe than in the United States and England. Odds ratios of heart disease in a comparison of the top and bottom wealth tertiles were 1.94 (95% confidence interval [CI] = 1.69, 2.24) in the United States, 2.13 (95% CI = 1.73, 2.62) in England, and 1.38 (95% CI = 1.23, 1.56) in Europe. Smoking, obesity, physical activity levels, and alcohol consumption explained a fraction of health variations. CONCLUSIONS American adults are less healthy than Europeans at all wealth levels. The poorest Americans experience the greatest disadvantage relative to Europeans.

Conceptual and measurement challenges in research on cognitive reserve.

Cognitive reserve, broadly conceived, encompasses aspects of brain structure and function that optimize individual performance in the presence of injury or pathology. Reserve is defined as a feature of brain structure and/or function that modifies the relationship between injury or pathology and performance on neuropsychological tasks or clinical outcomes. Reserve is challenging to study for two reasons. The first is: reserve is a hypothetical construct, and direct measures of reserve are not available. Proxy variables and latent variable models are used to attempt to operationalize reserve. The second is: in vivo measures of neuronal pathology are not widely available. It is challenging to develop and test models involving a risk factor (injury or pathology), a moderator (reserve) and an outcome (performance or clinical status) when neither the risk factor nor the moderator are measured directly. We discuss approaches for quantifying reserve with latent variable models, with emphasis on their application in the analysis of data from observational studies. Increasingly latent variable models are used to generate composites of cognitive reserve based on multiple proxies. We review the theoretical and ontological status of latent variable modeling approaches to cognitive reserve, and suggest research strategies for advancing the field.

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.

Association among socioeconomic status, health behaviors, and all-cause mortality in the United States.

Background: Health behaviors may contribute to socioeconomic inequalities in mortality, although the extent of such contribution remains unclear. We assessed the extent to which smoking, alcohol consumption, and physical inactivity have mediated the association between socioeconomic status (SES) and all-cause mortality in a representative sample of US adults. Methods: Initiated in 1992, the Health and Retirement Study is a longitudinal, biennial survey of a national sample of US adults born between 1931 and 1941. Our analyses are based on a sample of 8037 participants enrolled in 1992 and followed for all-cause mortality from 1998 through 2008. We used exploratory and confirmatory factor analysis to derive a measure of adult SES based on respondents’ education, occupation, labor force status, household income, and household wealth. Potential mediators (smoking, alcohol consumption, and physical inactivity) were assessed biennially. We used inverse probability–weighted mediation models to account for time-varying covariates. Results: During the 10-year mortality follow-up, 859 (10%) participants died. After accounting for age, sex, and baseline confounders, being in the most-disadvantaged quartile of SES compared with the least disadvantaged was associated with a mortality risk ratio of 2.84 (95% confidence interval = 2.25–3.60). Together, smoking, alcohol consumption, and physical inactivity explained 68% (35–104%) of this association, leaving a risk ratio of 1.59 (1.03–2.45) for low SES. Conclusions: The distribution of health-damaging behaviors may explain a substantial proportion of excess mortality associated with low SES in the United States, suggesting the importance of social inequalities in unhealthy behaviors.

Lifecourse Social Conditions and Racial and Ethnic Patterns of Cognitive Aging

A lifecourse perspective is key for understanding and interpreting racial and ethnic patterns in neuropsychological test performance. In this article, we discuss contextual factors that shape the environmental conditions encountered by racial and ethnic minorities in the United States, in particular African-Americans. These conditions include geographic segregation at the level of regions, metropolitan areas, and neighborhoods; intra- and inter-national migration patterns; socioeconomic position, including financial resources, and occupational and educational opportunities; discrimination; and group resources. Each of these exposures sets in course a cascade of individual mediators that ultimately manifest in neuropsychological outcomes. The physiological and behavioral consequences of these pathways likely accumulate across the lifecourse. We focus on cognitive aging, although the processes discussed here begin in infancy and likely influence cognitive outcomes throughout life from childhood into old age. A lifecourse framework can help inform clinical encounters, neuropsychological research, and surveillance regarding the population prevalence of cognitive impairments.