Plasma amyloid-ß and risk of Alzheimer's disease in the Framingham Heart Study.

BACKGROUND: Plasma amyloid-ß (Aß) peptide levels have been examined as a low-cost accessible marker for risk of incident Alzheimer's disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community-based studies to date. METHODS: A total of 2189 dementia-free, Framingham Study participants aged >60 years (mean age, 72 ± 8 years; 56% women) had plasma Aß1-42 and Aß1-40 measured and were followed prospectively (mean, 7.6 ± 3.0 years) for dementia/AD. RESULTS: Increased plasma Aß1-42 levels were associated with lower risk of dementia (Aß1-42: hazard ratio [HR] = 0.80 [0.71‒0.90], P < .001; Aß1-42-to-Aß1-40 ratio: HR = 0.86 [0.76‒0.98], P = .027) and AD (Aß1-42: HR = 0.79 [0.69‒0.90], P < .001; Aß1-42-to-Aß1-40 ratio: HR = 0.83 [0.72‒0.96], P = .012). CONCLUSION: Our results suggest that lower plasma Aß levels are associated with risk of incident AD and dementia. They encourage further evaluation of plasma Aß levels as a biomarker for risk of developing clinical AD and dementia.

Application of a repeat-measure biomarker measurement error model to 2 validation studies: examination of the effect of within-person variation in biomarker measurements.

Repeat-biomarker measurement error models accounting for systematic correlated within-person error can be used to estimate the correlation coefficient (ρ) and deattenuation factor (λ), used in measurement error correction. These models account for correlated errors in the food frequency questionnaire (FFQ) and the 24-hour diet recall and random within-person variation in the biomarkers. Failure to account for within-person variation in biomarkers can exaggerate correlated errors between FFQs and 24-hour diet recalls. For 2 validation studies, ρ and λ were calculated for total energy and protein density. In the Automated Multiple-Pass Method Validation Study (n=471), doubly labeled water (DLW) and urinary nitrogen (UN) were measured twice in 52 adults approximately 16 months apart (2002-2003), yielding intraclass correlation coefficients of 0.43 for energy (DLW) and 0.54 for protein density (UN/DLW). The deattenuated correlation coefficient for protein density was 0.51 for correlation between the FFQ and the 24-hour diet recall and 0.49 for correlation between the FFQ and the biomarker. Use of repeat-biomarker measurement error models resulted in a ρ of 0.42. These models were similarly applied to the Observing Protein and Energy Nutrition Study (1999-2000). In conclusion, within-person variation in biomarkers can be substantial, and to adequately assess the impact of correlated subject-specific error, this variation should be assessed in validation studies of FFQs.

Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study.

BACKGROUND: Individuals with diabetes mellitus are at 2- to 3-fold increased risk for cardiovascular disease (CVD) relative to those without diabetes. Our objective was to examine CVD risk factor level changes among individuals with and without type 2 diabetes mellitus from 1970 to 2005 in the Framingham Heart Study. METHODS AND RESULTS: We included 4195 participants (3990 with no diabetes and 205 with diabetes) 50 years of age and 3495 participants (3178 with no diabetes and 317 with diabetes) 60 years of age. Contemporaneous CVD risk factor levels were measured; linear regression models were used to assess the interaction between diabetes status and calendar year on CVD risk factor levels. Among 50-year-olds without diabetes mellitus, there was an increase in body mass index of 0.39 kg/m(2) per 10 years, whereas for those with diabetes, there was an increase of 2.52 kg/m(2) (P value for the diabetes-by-calendar year interaction [P for interaction] <0.001). For low-density lipoprotein cholesterol, the mean decrease was -7.43 mg/dL per decade (nondiabetes) and -15.5 mg/dL for diabetes (P for interaction=0.002). For systolic blood pressure, the mean decrease was -3.35 mm Hg per decade (nondiabetes) and -3.50 mm Hg for diabetes (P for interaction=0.97). The direction of the trends for those with diabetes relative to those without diabetes was similar for 60-year-olds. CONCLUSIONS: Compared with individuals without diabetes mellitus, individuals with diabetes experienced a greater increase in body mass index, a greater decrease in low-density lipoprotein cholesterol, and a similar magnitude of decline in systolic blood pressure. Individuals with diabetes mellitus have not experienced the necessary declines in CVD risk factors to overcome their increased risk of CVD. Further efforts are needed to aggressively control CVD risk factors among individuals with diabetes mellitus.

Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005.

BACKGROUND: Despite population declines in all-cause mortality, women with diabetes mellitus may have experienced an increase in mortality rates compared with men. METHODS AND RESULTS: We examined change in all-cause, cardiovascular, and non-cardiovascular disease mortality rates among Framingham Heart Study participants who attended examinations during an "earlier" (1950 to 1975; n=930 deaths) and a "later" (1976 to 2001; n=773 deaths) time period. Diabetes mellitus was defined as casual glucose > or =200 mg/dL, fasting plasma glucose > or =126 mg/dL, or treatment. Among women, the hazard ratios (HRs) for all-cause mortality in the later versus the earlier time period were 0.59 (95% confidence interval, 0.50 to 0.70; P<0.0001) for those without diabetes mellitus and 0.48 (95% confidence interval, 0.32 to 0.71; P=0.002) for those with diabetes mellitus. Similar results were observed in men. Among women and men, the HR of cardiovascular disease mortality declined among those with and without diabetes mellitus. Non-cardiovascular disease mortality declined among women without diabetes mellitus (HR, 0.76; P=0.01), whereas no change was observed among women with diabetes mellitus or among men with or without diabetes mellitus. Individuals with versus those without diabetes mellitus were at increased risk of all-cause mortality in the earlier (HR, 2.44; P<0.0001) and later (HR, 1.95; P<0.0001) time periods. CONCLUSIONS: Reductions in all-cause mortality among women and men with diabetes mellitus have occurred over time. However, mortality rates among individuals with diabetes mellitus remain approximately 2-fold higher compared with individuals without diabetes mellitus.

Early-adulthood cardiovascular disease risk factor profiles among individuals with and without diabetes in the Framingham Heart Study.

OBJECTIVE: Many studies of diabetes have examined risk factors at the time of diabetes diagnosis instead of considering the lifetime burden of adverse risk factor levels. We examined the 30-year cardiovascular disease (CVD) risk factor burden that participants have up to the time of diabetes diagnosis. RESEARCH DESIGN AND METHODS: Among participants free of CVD, incident diabetes cases (fasting plasma glucose ≥ 126 mg/dL or treatment) occurring at examinations 2 through 8 (1979-2008) of the Framingham Heart Study Offspring cohort were age- and sex-matched 1:2 to controls. CVD risk factors (hypertension, high LDL cholesterol, low HDL cholesterol, high triglycerides, obesity) were measured at the time of diabetes diagnosis and at time points 10, 20, and 30 years prior. Conditional logistic regression was used to compare risk factor levels at each time point between diabetes cases and controls. RESULTS: We identified 525 participants with new-onset diabetes who were matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who eventually developed diabetes had higher levels of hypertension (odds ratio [OR], 2.2; P = 0.003), high LDL (OR, 1.5; P = 0.04), low HDL (OR, 2.1; P = 0.0001), high triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P < 0.0001) at time points 30 years before diabetes diagnosis. After further adjustment for BMI, the ORs for hypertension (OR, 1.9; P = 0.02) and low HDL (OR, 1.7; P = 0.01) remained statistically significant. CONCLUSIONS: CVD risk factors are increased up to 30 years before diagnosis of diabetes. These findings highlight the importance of a life course approach to CVD risk factor identification among individuals at risk for diabetes.

Relations of long-term and contemporary lipid levels and lipid genetic risk scores with coronary artery calcium in the framingham heart study.

OBJECTIVES: This study evaluated the association of timing of lipid levels and lipid genetic risk score (GRS) with subclinical atherosclerosis. BACKGROUND: Atherosclerosis is a slowly progressive disorder influenced by suboptimal lipid levels. Long-term versus contemporary lipid levels may more strongly impact the development of coronary artery calcium (CAC). METHODS: Framingham Heart Study (FHS) Offspring Cohort participants (n = 1,156, 44% male, 63 ± 9 years) underwent serial fasting lipids (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein, and triglycerides), Exam 1 (1971 to 1975) to Exam 7 (1998 to 2001). FHS Third Generation Cohort participants (n = 1,954, 55% male, 45 ± 6 years) had fasting lipid profiles assessed, 2002 to 2005. Computed tomography (2002 to 2005) measured CAC. Lipid GRSs were computed from significantly associated single-nucleotide polymorphisms. The association between early, long-term average, and contemporary lipids, and lipid GRS with elevated CAC was assessed using logistic regression. RESULTS: In FHS Offspring, Exam 1 and long-term average as compared with Exam 7 lipid measurements, including untreated lipid levels, were strongly associated with elevated CAC. In the FHS Third Generation, contemporary lipids were associated with CAC. The LDL-C GRS was associated with CAC (age-/sex-adjusted odds ratio: 1.14, 95% confidence interval: 1.00 to 1.29, p = 0.04). However, addition of the GRS to the lipid models did not result in a significant increase in the odds ratio or C-statistic for any lipid measure. CONCLUSIONS: Early and long-term average lipid levels, as compared with contemporary measures, are more strongly associated with elevated CAC. Lipid GRS was associated with lipid levels but did not predict elevated CAC. Adult early and long-term average lipid levels provide important information when assessing subclinical atherosclerosis and cardiovascular risk.

Lack of association between dietary protein intake and risk of stroke among middle-aged men.

BACKGROUND: Prospective cohort studies in Japanese populations have shown an inverse association between dietary protein and stroke risk. However, this association has not been examined among any study populations of US men. OBJECTIVE: Our objective was to examine the relation between dietary protein and risk of stroke in men who participated in the Health Professionals Follow-Up Study. DESIGN: A total of 43,960 men who were free of cardiovascular disease and cancer at baseline were included in the analysis. Dietary protein (total, animal, and vegetable) was assessed with the use of a food-frequency questionnaire at 5 time points during the follow-up period of 1986-2004. Cox proportional hazards models were used to calculate multivariate relative risks and 95% CIs, which represented the effect of the substitution of protein for an equal percentage of energy from carbohydrate. RESULTS: During 18 y of follow-up there were 1057 incident stroke events (638 ischemic, 171 hemorrhagic, and 248 of unknown type). For total stroke, the relative risk for the top quintile of percentage energy from protein compared with the bottom was 1.14 (95% CI: 0.90, 1.43; P for linear trend: 0.43) for total protein, 1.11 (95% CI: 0.87, 1.41; P for linear trend: 0.52) for animal protein, and 0.82 (95% CI: 0.60, 1.12; P for linear trend: 0.17) for vegetable protein. The results were similar when ischemic and hemorrhagic stroke subtypes were considered separately. CONCLUSION: In contrast to studies in Japanese populations, this study did not show a statistically significant association between total, animal, or vegetable protein and risk of stroke in this population of US men.

Dietary protein and risk of ischemic heart disease in middle-aged men.

BACKGROUND: Prospective studies in US women have suggested an inverse relation between dietary protein and risk of ischemic heart disease (IHD). However, no large-scale prospective studies have been conducted in US men. OBJECTIVE: The objective was to examine the association between dietary protein and risk of IHD in a prospective study of US men. DESIGN: Intakes of protein and other nutrients were assessed by using a validated food-frequency questionnaire at 4 time points during follow-up of 43,960 men participating in the Health Professionals Follow-Up Study. Cox proportional hazards models were used to calculate multivariable-adjusted relative risks (RRs) and 95% CIs. RESULTS: During 18 y of follow-up, we documented 2959 incident cases of IHD. The RR of IHD was 1.08 (95% CI: 0.95, 1.23; P for trend = 0.30) comparing the top with the bottom quintile of percentage of energy from total protein. RRs for animal and vegetable protein were 1.11 (95% CI: 0.97, 1.28; P for trend = 0.18) and 0.93 (95% CI: 0.78, 1.12; P for trend = 0.49), respectively. When the population was restricted to "healthy" men (those free of hypertension, hypercholesterolemia, and diabetes at baseline), the RR of IHD was 1.21 (95% CI: 1.01, 1.44; P for trend = 0.02) for total protein, 1.25 (95% CI: 1.04, 1.51; P for trend = 0.02) for animal protein, and 0.93 (95% CI: 0.72, 1.19; P for trend = 0.65) for vegetable protein. CONCLUSIONS: We observed no association between dietary protein and risk of total IHD in this group of men aged 40-75 y. However, higher intake of animal protein may be associated with an increased risk of IHD in "healthy" men.

Health insurance and cardiovascular disease risk factors.

BACKGROUND: Compared with those with health insurance, the uninsured receive less care for chronic conditions, such as hypertension and diabetes, and experience higher mortality. METHODS: We investigated the relations of health insurance status to the prevalence, treatment, and control of major cardiovascular disease risk factors-hypertension and elevated low-density lipoprotein (LDL) cholesterol-among Framingham Heart Study (FHS) participants in gender-specific, age-adjusted analyses. Participants who attended the seventh Offspring cohort examination cycle (1998-2001) or the first Third Generation cohort examination cycle (2002-2005) were studied. RESULTS: Among 6098 participants, 3.8% were uninsured at the time of the FHS clinic examination and ages ranged from 19 to 64 years. The prevalence of hypertension and elevated LDL cholesterol was similar for the insured and uninsured; however, the proportion of those who obtained treatment and achieved control of these risk factors was lower among the uninsured. Uninsured men and women were less likely to be treated for hypertension with odds ratios for treatment of 0.19 (95% confidence interval [CI], 0.07-0.56) for men and 0.31 (95% CI, 0.12-0.79) for women. Among men, the uninsured were less likely to receive treatment or achieve control of elevated LDL cholesterol than the insured, with odds ratios of 0.12 (95% CI, 0.04-0.38) for treatment and 0.17 (95% CI, 0.05-0.56) for control. CONCLUSION: The treatment and control of hypertension and hypercholesterolemia are lower among uninsured adults. Increasing the proportion of insured individuals may be a means to improve the treatment and control of cardiovascular disease risk factors and to reduce health disparities.

Neck circumference as a novel measure of cardiometabolic risk: the Framingham Heart study.

BACKGROUND: Neck circumference, a proxy for upper-body sc fat, may be a unique fat depot that confers additional cardiovascular risk above and beyond central body fat. METHODS AND RESULTS: Participants with neck circumference measures who underwent multidetector computed tomography to assess visceral adipose tissue (VAT) were included [n=3307, 48% women; mean age=51 yr; mean body mass index (BMI)=27.8 kg/m2; mean neck circumference=40.5 cm (men) and 34.2 cm (women)]. Sex-specific linear regression models were used to assess the association between sd increase in neck circumference and cardiovascular disease (CVD) risk factors (systolic and diastolic blood pressure; total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglycerides; and fasting plasma glucose, insulin, proinsulin, and homeostasis model assessment of insulin resistance). Neck circumference was correlated with VAT [r=0.63 (men); r=0.74 (women); P<0.001] and BMI [r=0.79 (men); r=0.80 (women); P<0.001]. After further adjustment for VAT, neck circumference was positively associated with systolic blood pressure, diastolic blood pressure in men only, triglycerides, fasting plasma glucose in women only, insulin, proinsulin, and homeostasis model assessment of insulin resistance and was inversely associated with high-density lipoprotein (all P values<0.01). Similar results were observed in models that adjusted for both VAT and BMI. In a secondary analysis of incident CVD as an outcome, there was no statistically significant association observed for neck circumference in multivariable-adjusted models. CONCLUSIONS: Neck circumference is associated with CVD risk factors even after adjustment for VAT and BMI. These findings suggest that upper-body sc fat may be a unique, pathogenic fat depot.

Eligibility of individuals with subclinical coronary artery calcium and intermediate coronary heart disease risk for reclassification (from the Framingham Heart Study).

Coronary artery calcium (CAC) predicts risk for coronary heart disease (CHD) events and perhaps CAC testing may further stratify risk in individuals at intermediate CHD risk. We sought to determine the percentage of participants at intermediate CHD risk who could potentially be reclassified as having a high CHD risk based on the presence of a high CAC score and the prevalence, treatment, and control of CHD risk factors in this group. Framingham Heart Study Offspring and Third Generation cohort participants underwent multidetector computed tomography (n = 3,529, mean age 51 years, 48% women). High CAC was defined as >or=90th age- and gender-specific percentiles based on a healthy reference group or by an absolute modified Agatston score of 100 HU. Prevalence of CHD risk factors (hypertension, hypercholesterolemia, high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, smoking, and obesity), their treatment, and control was compared between nondiabetic participants with and without high CAC. Of the 595 participants at intermediate CHD risk, 22% had CAC >or=90th percentile and 39% had CAC >or=100 and could be eligible for reclassification as having a high CHD risk based on the presence of a high CAC score. There were no statistically significant differences in prevalence, treatment, and control of risk factors between those with and without high CAC. In conclusion, prevalence of CHD risk factors did not differ between intermediate-risk participants with and without high CAC. Approximately 25% of intermediate-risk individuals have high CAC scores and may be eligible for reclassification into a higher-risk category.