Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Grip Strength, Gait Speed and Plasma Markers of Neurodegeneration in Asymptomatic Middle-aged and Older Adults.

BACKGROUND: Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimer's Disease and neurodegeneration have not been elucidated. OBJECTIVES: To examine association between physical function measures and plasma markers of Alzheimer's Disease (AD) and neurodegeneration. DESIGN: Cross-sectional and longitudinal analyses. SETTING: Community-based cohort in the city of Framingham, Massachusetts. PARTICIPANTS: 2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61. MEASUREMENTS: Plasma Aß40 and Aß42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aß isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results: Grip strength at Exam-7 was associated with plasma Aß40 (ß -0.006, p-value 0.032) at Exam-7 and plasma total-tau (ß -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS: ß -0.009, p 0.0005; FWS: ß -0.226, p-value <0.0001). Chair stand speed was not associated with plasma markers; Aß42 was not associated with function. CONCLUSION: Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

Elevated midlife blood pressure increases stroke risk in elderly persons: the Framingham Study.

BACKGROUND: Stroke risk predictions are traditionally based on current blood pressure (BP). The potential impact of a subject's past BP experience (antecedent BP) is unknown. We assessed the incremental impact of antecedent BP on the risk of ischemic stroke. METHODS: A total of 5197 stroke-free subjects (2330 men) in the community-based Framingham Study cohort were enrolled from September 29, 1948, to April 25, 1953, and followed up to December 31, 1998. We determined the 10-year risk of completed initial ischemic stroke for 60-, 70-, and 80-year-old subjects as a function of their current BP (at baseline), recent antecedent BP (average of readings at biennial examinations 1-9 years before baseline), and remote antecedent BP (average at biennial examinations 10-19 years earlier), with adjustment for smoking and diabetes mellitus. Models incorporating antecedent BP were also adjusted for baseline BP. The effect of each BP component (systolic BP, diastolic BP, and pulse pressure) was assessed separately. RESULTS: Four hundred ninety-one ischemic strokes (209 in men) were observed in eligible subjects. The antecedent BP influenced the 10-year stroke risk at the age of 60 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.68 [95% confidence interval, 1.25-2.25]; and men, 1.92 [95% confidence interval, 1.39-2.66]) and at the age of 70 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.66 [95% confidence interval, 1.28-2.14]; and men, 1.30 [95% confidence interval, 0.97-1.75]). This effect was evident for recent and remote antecedent BP, consistent in hypertensive and nonhypertensive subjects, and demonstrable for all BP components. CONCLUSIONS: Antecedent BP contributes to the future risk of ischemic stroke. Optimal prevention of late-life stroke will likely require control of midlife BP.

Job strain and cognitive decline: a prospective study of the framingham offspring cohort.

BACKGROUND: Workplace stress is known to be related with many behavioral and disease outcomes. However, little is known about its prospective relationship with measures of cognitive decline. OBJECTIVE: To investigate the association of job strain, psychological demands and job control on cognitive decline. METHODS: Participants from Framingham Offspring cohort (n=1429), were assessed on job strain, and received neuropsychological assessment approximately 15 years and 21 years afterwards. RESULTS: High job strain and low control were associated with decline in verbal learning and memory. Job strain was associated with decline in word recognition skills. Active job and passive job predicted decline in verbal learning and memory relative to low strain jobs in the younger subgroup. Active job and demands were positively associated with abstract reasoning skills. CONCLUSIONS: Job strain and job control may influence decline in cognitive performance.

The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort.

OBJECTIVES: To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD. DESIGN: From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD. SETTING: A community-based center for epidemiological research. PARTICIPANTS: Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing. MAIN OUTCOME MEASURE: Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing. RESULTS: Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years. CONCLUSIONS: The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long. Arch Neurol. 2000.

Lifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham Study.

We estimated the remaining lifetime risks of developing Alzheimer's disease (AD) and dementia from all causes, based on data from longitudinal population studies. The risk of developing AD during one's lifetime depends on both disease incidence and life expectancy. Conventional estimates of cumulative incidence overestimate the risk when there is a substantial probability of mortality due to competing causes. A total of 2,611 cognitively intact subjects (1,061 men, 1,550 women; mean age, 66 +/- 7 years) were prospectively evaluated for the development of AD or other dementia. A modified survival analysis was used to estimate both cumulative incidence and the sex-specific remaining lifetime risk estimates for quinquennial age groups above age 65 years. Over a 20-year follow-up period, 198 subjects developed dementia (120 with AD). The remaining lifetime risk of AD or other dementia depended on sex, being higher in women, but varied little with age between 65 and 80 years. In a 65-year-old man, the remaining lifetime risk of AD was 6.3% (95% CI, 3.9 to 8.7) and the remaining lifetime risk of developing any dementing illness was 10.9% (95% CI, 8.0 to 13.8); corresponding risks for a 65-year-old woman were 12% (95% CI, 9.2 to 14.8) and 19% (95% CI, 17.2 to 22.5). The cumulative incidence between age 65 and 100 years was much higher: for AD, 25.5% in men and 28.1% in women; for dementia, 32.8% in men and 45% in women. The actual remaining lifetime risk of AD or dementia varies with age, sex, and life expectancy and is lower than the hypothetical risk estimated by a cumulative incidence in the same population.

Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study.

Apolipoprotein E type 4 allele (apoE epsilon4) is associated with Alzheimer's disease (AD) in the late-onset familial form and in sporadic cases, but the age-associated risk in a randomly sampled elderly population is not established. We examined the association of apoE epsilon4 with AD and other dementias (mainly multi-infarct or dementia following stroke) in 1,030 persons aged 71 to 100 years in the population-based Framingham Study cohort. Kaplan-Meier survival analysis revealed that 55% of the apoE epsilon4/epsilon4 homozygotes developed AD by age 80, whereas 27% of apoE epsilon3/epsilon4 heterozygotes developed AD by age 85, and 9% of those without a 4 allele developed AD by age 85 years. In comparison with persons without a 4 allele, the risk ration for AD was 3.7 (95% CI = 1.9 to 7.5) for apoE epsilon3/epsilon4 heterozygotes and 30.1 (95% CI = 10.7 to 84.4) for apoE epsilon4 homozygotes. ApoE epsilon2 (2/2, 2/3, or 2/4 genotypes) was associated with an absence of AD. One-half (n=21) of the 43 AD patients were either homozygous or heterozygous for apoE epsilon4. We found evidence for an association of apoE epsilon4 with other dementia, primarily multi-infarct dementia and stroke. The risk ratio was 2.3 (95% CI = 0.9 to 6.1) for non-AD dementias among persons with apoE epsilon3/epsilon4. Although the apoE epsilon4 allele is a potent risk factor for AD and may be associated with other forms of dementia, most apoE epsilon4 carriers do not develop dementia, and about one-half of AD is not apoE epsilon4 associated. The low positive predictive value of this marker (0.10) suggest that use of apoE genotyping as a screening test for AD is not supported.

Influence of the history on physicians' interpretations of girls' genital findings.

OBJECTIVE: Because physicians customarily obtain histories before examining children in cases of possible sexual abuse, and because the resulting diagnostic opinions can influence important social and legal decisions, we investigated whether clinical histories influence physicians' interpretations of girls' genital findings. DESIGN: In mailed questionnaires, 1387 randomly selected Fellows of the American Academy of Pediatrics and all 802 members of four professional groups concerned with child abuse or pediatric gynecology were asked to interpret seven simulated cases. Respondents were asked to interpret seven additional cases in separate questionnaires mailed 4 months later. Both sets of cases involved the same seven photographs of girls' external genitalia. However, in six of the seven case pairs, the histories in the two questionnaires differed in the extent to which they suggested sexual abuse. In the remaining (control) pair, the same history was presented in both questionnaires. RESULTS: Of 2189 physicians, 1114 (50.9%) responded. Responses from 604 physicians (54.2%) were eligible for analysis. Overall, the genital findings were interpreted most consistently by the most experienced physicians and least consistently by the least experienced physicians. The proportion of physicians whose interpretations of a photograph reversed in the direction suggested by the change in the associated history from "no indication of abuse" to "probable abuse," or vice versa, ranged for experienced physicians from none to 5.6%; for moderately experienced physicians from 1.6% to 19.8%; and for inexperienced physicians from 3.6% to 27.2%. This difference between the experience groups was statistically significant in four case pairs. Mean interpretation scores for genital findings changed significantly when the histories changed in two case pairs for the experienced physicians, in five pairs for the moderately experienced physicians, and in all six pairs for the inexperienced physicians. CONCLUSIONS: In some cases and especially for less experienced physicians, diagnostic expectation appears likely to influence physicians' interpretations of girls' genital findings. Physicians should be alert to the possibility of diagnostic expectation bias and its potentially serious social and legal consequences.

Monocular acuity norms for the Teller Acuity Cards between ages one month and four years.

PURPOSE: To derive norms for monocular grating acuity and interocular acuity differences that are appropriate for clinical applications using the acuity card procedure (ACP) and Teller Acuity Cards (TAC). METHODS: Monocular acuities were measured in 460 children in 12 age groups between 1 month and 4 years. Inclusion criteria were term birth, good general health and normal development, normal eyes, and cycloplegic refraction within specific limits. Each child was tested by two ACP testers who were aware of TAC spatial frequency but not grating location during testing. RESULTS: Three monocular tests were completed in the first session in 99% of children. Median time to complete the tests of both eyes ranged from 3.2 to 8.4 minutes. Monocular acuity norms were calculated using 95% and 99% prediction limits. The new norms spanned higher spatial frequencies than the preliminary ACP norms between ages 1 month and 18 months but were similar between 24 and 36 months. The lower normal 2.5% limits were similar to lower limits of other normative studies. The interocular acuity difference was zero or 0.5 octave in 99% of subjects of all ages. Acuities obtained by the same tester on different days and by different testers on the same day were within 0.5 octave in at least 90% of subjects, comparable to previous studies. CONCLUSIONS: This study provides monocular acuity norms that are appropriate for clinical settings in which the ACP and TAC are used and should replace the preliminary ACP norms.

A predictive instrument for coronary artery aneurysms in Kawasaki disease. US Multicenter Kawasaki Disease Study Group.

To construct a predictive instrument for developing coronary artery abnormalities in patients with acute Kawasaki disease treated with aspirin and intravenous gamma globulin within the first 10 days of illness, data available from a multicenter database of patients with acute Kawasaki disease were analyzed. A development data set (n = 212) was used to construct a sequential risk classification instrument based on easily measured baseline laboratory test results and temperature. The instrument was then validated in 3 test data sets (n = 192, 264, and 92, respectively). Risk factors used in the sequential classification instrument included baseline neutrophil and band counts, hemoglobin concentration, platelet count, and temperature on the day after infusion of intravenous gamma globulin. In the development data set, the instrument classified 123 of 212 patients (58%) as low risk; none developed coronary artery abnormalities. Among 89 patients classified as high risk, 3 of 36 female (8.3%) and 9 of 53 male patients (17.0%) developed coronary artery abnormalities. The instrument performed similarly in the 3 test data sets; no patient in any data set classified as low risk developed coronary artery abnormalities. This simple instrument allows the clinician to identify within 1 day of treatment low-risk children in whom extensive and frequent cardiac testing may be unnecessary, as well as high-risk children who require closer monitoring and may be candidates for additional therapies.

Poverty, race, and medication use are correlates of asthma hospitalization rates. A small area analysis in Boston.

Hospitalization rates for asthma in New York City are highest in poor urban neighborhoods, although the reasons for this are unknown. We performed a small area analysis of asthma hospitalization rates in Boston, to determine whether this pattern of asthma hospitalization also obtained in a medium-sized city and to identify characteristics of neighborhoods with high hospitalization rates, including the relative use of inhaled anti-inflammatory medication. Zip codes were used to define 22 small areas within Boston. The number of asthma hospitalizations for residents of each area in 1992 was obtained from the Codman Research Group. Population and demographic characteristics of each area were obtained from the 1990 US Census. Estimates of inhaled asthma medications (beta-agonists, steroids, and cromolyn) dispensed in each area in 1992 were obtained from IMS America. Asthma hospitalization rates for each of the six areas with the highest rates (5.3 to 9.8 per 1,000 persons) were significantly greater than the city-wide average of 4.2 hospitalizations per thousand persons (p < 0.001 for each comparison). Asthma hospitalization rate was positively correlated with poverty rate and with the proportion of nonwhite residents and inversely correlated with income and educational attainment. Asthma hospitalization rate was inversely correlated with the ratio of inhaled anti-inflammatory to beta-agonist medication use (r = -0.55, p = 0.008). We conclude that asthma hospitalization rates in Boston are highest in poor inner city neighborhoods, and that these high rates affect both genders and all age groups. Underuse of inhaled anti-inflammatory medication may be one of the many factors that contributes to this excess hospitalization.

Assessments of girl's genital findings and the likelihood of sexual abuse: agreement among physicians self-rated as skilled.

OBJECTIVES: To measure agreement about genital examination findings among physicians who rate themselves as skilled in evaluating children for suspected sexual abuse, to compare these physicians' descriptions and interpretations with consensus standards developed by an expert panel, and to investigate the effects of physician and case characteristics on agreement. STUDY DESIGN: Questionnaires including 7 simulated cases, each consisting of a brief history and 1 photograph of a girl's genitalia, were mailed to random samples of 2 groups: the members of 4 physician organizations concerned with child abuse or pediatric gynecology, and pediatricians at large. Among the surveyed physicians who rated their own skill in evaluating cases of suspected sexual abuse as higher than average, we measured agreement, both overall and between those with the most and with less clinical experience, and assessed their conformity with consensus standard descriptions and interpretations. RESULTS: We received responses from 548 (50.9%) of 1076 physicians; 414 responses (75.5%) were analyzable. Two hundred six physicians (50%) rated themselves as skilled in assessing children for sexual abuse. On average, 45% of these physicians' descriptions and 72.6% of their interpretations conformed with the consensus standards. In 4 cases, between 5% and 20.7% of these physicians described genital findings that the expert panel had considered absent from the photographs. Conformity with standard interpretations tended to be higher in cases with photographs concordant with the accompanying, unambiguous histories (P=.06). The most experienced physicians resembled the expert panel more closely than did the less experienced self-rated skilled physicians in interpreting 3 simulated cases (P< or =.001). CONCLUSIONS: Assessments of girls' genital findings by physicians who rate themselves as skilled in examining children for suspected sexual abuse often differ. In some cases, among physicians who all rate themselves as skilled, assessments made by very experienced physicians may conform more closely to consensus standards than do assessments made by less experienced physicians.

Adjusting Medicare capitation payments using prior hospitalization data.

The diagnostic cost group approach to a reimbursement model for health maintenance organizations is presented. Diagnostic information about previous hospitalizations is used to create empirically determined risk groups, using only diagnoses involving little or no discretion in the decision to hospitalize. Diagnostic cost group and other models (including Medicare's current formula and other prior-use models) are tested for their ability to predict future costs, using R2 values and new measures of predictive performance. The diagnostic cost group models perform relatively well with respect to a range of criteria, including administrative feasibility, resistance to provider manipulation, and statistical accuracy.

A longitudinal study of the impact of behavioural change intervention on cleanliness, diarrhoeal morbidity and growth of children in rural Bangladesh.

A community-based intervention was developed through direct participation of the target population in assessment and iterative trials to improve hygiene practices and to reduce childhood diarrhoea in lowland rural Bangladesh. A total of 185 (98%) households with children ages 0-18 months in five contiguous villages were targeted for the interventions. A comparison site was selected for a detailed observational study and for use as a control for the intervention. About 97% of all households with children ages 0-18 months were enrolled for study at the control site. Children in this age group were targeted because at this developmental stage they were most vulnerable to diarrhoeal morbidity and malnutrition (related to unhygienic practices). The intervention was implemented with the assistance of village leaders through a "Clean Life" campaign by local project workers and volunteer mothers who were chosen from the target households. The intervention activities started in January 1986 and lasted for 7 months. Higher adoption rates of the intervention were associated with better cleanliness status, which was related to lower diarrhoea and malnutrition rates in the intervention site. The results of between-site longitudinal analyses showed that after the intervention, the intervention site had substantially higher cleanliness scores, lower diarrhoeal morbidity, and better growth status compared to those of the control site, with differences increasing over time. The findings suggest that this type of community-based intervention can be very beneficial in modifying hygiene behaviours and lowering childhood diarrhoea and malnutrition.

Maternal education and child feeding practices in rural Bangladesh.

This study in rural lowland Bangladesh used spot and event observations from 185 children aged 4-27 months in order to examine whether child feeding practices differed with mother's education and with household education. Each child and his/her caretakers were observed for a mean of 20 hr over 6 months from February to July 1986. Only 25% of mothers and 51% of fathers had had any formal education. Exploratory partial correlations and stepwise multiple regression analyses revealed significant behavioral differences with both maternal and household measures of education while controlling for wealth. Caretakers in families with education were found to feed the children more frequently, with fresher food, and in cleaner, more protected places. They did not allow their children to eat food intended for someone else as often, and were more observant when their children's food dropped during the feeding. These caretakers also used more cups and bottles for feedings, breastfed their children less frequently, and their mothers terminated the breastfeedings more often. These behaviors suggested a shift from less attentive feeding practices and less frequent feedings to more frequent feedings in which the caretaker took more control of the child's feeding sessions. They also suggest a commitment to more labor-intensive child care. These associations between education and child feeding practices are mechanisms through which maternal education may improve child health and growth. They suggest the need for promoting more formal and nonformal education.

Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging.

OBJECTIVE: Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort. METHODS: We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). RESULTS: Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: ß ± SE = -0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (ß ± SE = -0.47 ± 0.18; p = 0.008), executive function (ß ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (ß ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models. CONCLUSION: Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.

Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline.

OBJECTIVE: Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline. METHODS: A total of 1,352 participants without dementia from the prospective Framingham Offspring Cohort Study were examined. Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume (WMHV), total brain volume (TBV), temporal horn volume, logical memory delayed recall, visual reproductions delayed-recall (VR-d), and Trail-Making Test B-A (TrB-A) performance a decade later. RESULTS: Hypertension in midlife was associated with accelerated WMHV progression (p < 0.001) and worsening executive function (TrB-A score; p = 0.012). Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume, a surrogate marker of accelerated hippocampal atrophy (p = 0.017 and p = 0.008, respectively). Midlife smoking also predicted a more marked decrease in total brain volume (p = 0.025) and increased risk of extensive change in WMHV (odds ratio = 1.58 [95%confidence interval 1.07-2.33], p = 0.021). Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function (1.39 [1.02-1.88], p = 0.035) and increasing waist-to-hip ratio was associated with marked decline in TBV (10.81 [1.44-81.01], p = 0.021). Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function. CONCLUSIONS: Midlife hypertension, diabetes, smoking, and obesity were associated with an increased rate of progression of vascular brain injury, global and hippocampal atrophy, and decline in executive function a decade later.

Depressive symptoms and risk of dementia: the Framingham Heart Study.

OBJECTIVES: Depression may be associated with an increased risk for dementia, although results from population-based samples have been inconsistent. We examined the association between depressive symptoms and incident dementia over a 17-year follow-up period. METHODS: In 949 Framingham original cohort participants (63.6% women, mean age = 79), depressive symptoms were assessed at baseline (1990-1994) using the 60-point Center for Epidemiologic Studies Depression Scale (CES-D). A cutpoint of > or = 16 was used to define depression, which was present in 13.2% of the sample. Cox proportional hazards models adjusting for age, sex, education, homocysteine, and APOE epsilon4 examined the association between baseline depressive symptoms and the risk of dementia and Alzheimer disease (AD). RESULTS: During the 17-year follow-up period, 164 participants developed dementia; 136 of these cases were AD. A total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. Depressed participants (CES-D >/=16) had more than a 50% increased risk for dementia (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.04-2.84, p = 0.035) and AD (HR 1.76, 95% CI 1.03-3.01, p = 0.039). Results were similar when we included subjects taking antidepressant medications as depressed. For each 10-point increase on the CES-D, there was significant increase in the risk of dementia (HR 1.46, 95% CI 1.18-1.79, p < 0.001) and AD (HR 1.39, 95% CI 1.11-1.75, p = 0.005). Results were similar when we excluded persons with possible mild cognitive impairment. CONCLUSIONS: Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.

Association of parental dementia with cognitive and brain MRI measures in middle-aged adults.

OBJECTIVES: Studies of autosomal dominant Alzheimer disease (AD) have shown structural and cognitive changes in mutation carriers decades prior to clinical disease. Whether such changes are detectable in offspring of persons with sporadic dementia remains unknown. We related prospectively verified parental dementia to brain MRI and cognitive testing in the offspring, within a 2-generational community-based cohort. METHODS: A total of 717 Framingham offspring (mean age: 59 +/- 8 years) were studied. In multivariate analyses, we compared offspring with and without verified parental dementia (and AD) for 1) performance on tests of memory, abstract reasoning, and cognitive flexibility, and 2) volumetric brain MRI measures of total cerebral brain volume (TCBV), hippocampal volume (HV), and white matter hyperintensity volume (WMHV), assessed cross-sectionally and longitudinally. RESULTS: When testing the association of parental dementia and AD with baseline cognitive performance, we observed an interaction of parental dementia and AD with APOE epsilon4 status (p < 0.002). In APOE epsilon4 carriers only (n = 165), parental dementia was associated with poorer scores on tests of verbal memory (beta = -1.81 +/- 0.53, p < 0.001) and visuospatial memory (beta = -1.73 +/- 0.47, p < 0.001). These associations were stronger for parental AD (beta = -1.97 +/- 0.52, p < 0.001, beta = -1.95 +/- 0.48, p < 0.001), equivalent to 14-16 years of brain aging. Among APOE epsilon4 carriers, offspring of participants with dementia were also more likely to show an annual decline in TCBV in the top quartile (odds ratio = 4.67 [1.26-17.30], p = 0.02). Regardless of APOE epsilon4 status, participants with parental dementia were more likely to be in the highest quartile of decline in executive function test scores (odds ratio = 1.61 [1.02-2.53], p = 0.04). CONCLUSIONS: Among middle-aged carriers of the APOE epsilon4 allele, parental dementia and Alzheimer disease were associated with poorer verbal and visuospatial memory and a higher rate of global brain atrophy.