Andrea L.C. Schneider

Prometheus® – a new extracorporeal system for the treatment of liver failure☆

BACKGROUND/AIMS Extracorporeal detoxification systems for supportive therapy of liver failure have recently gained much interest. We herein report results from the first clinical application of Prometheus, a new liver support system in which albumin-bound substances are directly removed from blood by special adsorber. In a simultaneous step, high-flux hemodialysis is performed. We assessed safety, adsorber efficiency and clinical efficacy of the Prometheus system. METHODS Eleven patients with acute-on-chronic liver failure and accompanying renal failure were treated with Prometheus on 2 consecutive days for >4 h. RESULTS Prometheus treatment significantly improved serum levels of conjugated bilirubin, bile acids, ammonia, cholinesterase, creatinine, urea and blood pH. There were no significant changes in hemoglobin and platelet levels, whereas leucocytes increased without signs of systemic infection. No treatment-related complications except a blood pressure drop in two patients with systemic infection were noted. In one patient (Child-Pugh score: 15) Prometheus treatment could not be completed due to onset of uncontrolled bleeding 16 h after dialysis. CONCLUSIONS Prometheus is a safe supportive therapy for patients with liver failure. A significant improvement of the biochemical milieu was observed already after two treatments. Prospective controlled studies with the Prometheus system are necessary to evaluate hard clinical end-points.

Stroke incidence and mortality trends in US communities, 1987 to 2011.

IMPORTANCE Prior studies have shown decreases in stroke mortality over time, but data on validated stroke incidence and long-term trends by race are limited. OBJECTIVE To study trends in stroke incidence and subsequent mortality among black and white adults in the Atherosclerosis Risk in Communities (ARIC) cohort from 1987 to 2011. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 14,357 participants (282,097 person-years) free of stroke at baseline was facilitated in 4 different US communities. Participants were recruited for the purpose of studying all stroke hospitalizations and deaths and for collection of baseline information on cardiovascular risk factors (via interviews and physical examinations) in 1987-1989. Participants were followed up (via examinations, annual phone interviews, active surveillance of discharges from local hospitals, and linkage with the National Death Index) through December 31, 2011. The study physician reviewers adjudicated all possible strokes and classified them as definite or probable ischemic or hemorrhagic events. MAIN OUTCOMES AND MEASURES Trends in rates of first-ever stroke per 10 years of calendar time were estimated using Poisson regression incidence rate ratios (IRRs), with subsequent mortality analyzed using Cox proportional hazards regression models and hazard ratios (HRs) overall and by race, sex, and age divided at 65 years. RESULTS Among 1051 (7%) participants with incident stroke, there were 929 with incident ischemic stroke and 140 with incident hemorrhagic stroke (18 participants had both during the study period). Crude incidence rates were 3.73 (95% CI, 3.51-3.96) per 1000 person-years for total stroke, 3.29 (95% CI, 3.08-3.50) per 1000 person-years for ischemic stroke, and 0.49 (95% CI, 0.41-0.57) per 1000 person-years for hemorrhagic stroke. Stroke incidence decreased over time in white and black participants (age-adjusted IRRs per 10-year period, 0.76 [95% CI, 0.66-0.87]; absolute decrease of 0.93 per 1000 person-years overall). The decrease in age-adjusted incidence was evident in participants age 65 years and older (age-adjusted IRR per 10-year period, 0.69 [95% CI, 0.59-0.81]; absolute decrease of 1.35 per 1000 person-years) but not evident in participants younger than 65 years (age-adjusted IRR per 10-year period, 0.97 [95% CI, 0.76-1.25]; absolute decrease of 0.09 per 1000 person-years) (P = .02 for interaction). The decrease in incidence was similar by sex. Of participants with incident stroke, 614 (58%) died through 2011. The mortality rate was higher for hemorrhagic stroke (68%) than for ischemic stroke (57%). Overall, mortality after stroke decreased over time (hazard ratio [HR], 0.80 [95% CI, 0.66-0.98]; absolute decrease of 8.09 per 100 strokes after 10 years [per 10-year period]). The decrease in mortality was mostly accounted for by the decrease at younger than age 65 years (HR, 0.65 [95% CI, 0.46-0.93]; absolute decrease of 14.19 per 100 strokes after 10 years [per 10-year period]), but was similar across race and sex. CONCLUSIONS AND RELEVANCE In a multicenter cohort of black and white adults in US communities, stroke incidence and mortality rates decreased from 1987 to 2011. The decreases varied across age groups, but were similar across sex and race, showing that improvements in stroke incidence and outcome continued to 2011.

Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002.

Objectives—We performed a prospective case–cohort study in initially healthy, middle-aged men and women from the MONICA/KORA Augsburg studies conducted between 1984 and 2002 to assess the role of IL-18 in comparison with IL-6 and CRP in the prediction of incident coronary heart disease (CHD). Methods and Results—Concentrations of IL-18 were measured in 382 case subjects with incident CHD and 1980 noncases. Mean follow-up was 11 years. Baseline concentrations of IL-18 were slightly higher in cases than in noncases (172.4 [1.0] versus 161.3 [1.0] pg/mL, respectively; P=0.114), but were clearly elevated for C-reactive protein (CRP) and IL-6 in cases compared with noncases. In multivariable analyses, accounting for classical cardiovascular risk factors and inflammatory markers, no statistically significant association was seen between increased concentrations of IL-18 and incident CHD both in men (hazard ratio [HR] and 95% confidence intervals [CIs] comparing extreme tertiles, 1.20; 95% CI, 0.85 to 1.69), and in women (HR, 1.25; 95% CI, 0.67 to 2.34). However, in this population increased concentrations of CRP and IL-6 were found to be independent predictors of future CHD events, even after multivariable adjustment. Conclusions—Elevated concentrations of CRP and IL-6, but not IL-18, were independently associated with risk of CHD in subjects from an area with moderate absolute risk.

Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study.

IMPORTANCE Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age. OBJECTIVE To evaluate the association between midlife (48-67 years of age) hypertension and the 20-year change in cognitive performance. DESIGN, SETTING, AND PARTICIPANTS The Atherosclerosis Risk in Communities cohort (1990-1992 through 2011-2013) underwent evaluation at field centers in Washington County, Maryland, Forsyth County, North Carolina, Jackson, Mississippi, and the Minneapolis, Minnesota, suburbs. Of 13 476 African American and white participants with baseline cognitive data, 58.0% of living participants completed the 20-year cognitive follow-up. EXPOSURES Hypertension, prehypertension, or normal blood pressure (BP) at visit 2 (1990-1992) constituted the primary exposure. Systolic BP at visit 2 or 5 (2011-2013) and indication for treatment at visit 2 based on the Eighth Joint National Committee (JNC-8) hypertension guidelines constituted the secondary exposures. MAIN OUTCOMES AND MEASURES Prespecified outcomes included the 20-year change in scores on the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test and in global cognition. RESULTS During 20 years, baseline hypertension was associated with an additional decline of 0.056 global z score points (95% CI, -0.100 to -0.012) and prehypertension was associated nonsignificantly with 0.040 more global z score points of decline (95% CI, -0.085 to 0.005) compared with normal BP. Individuals with hypertension who used antihypertensives had less decline during the 20 years than untreated individuals with hypertension (-0.050 [95% CI, -0.003 to -0.097] vs -0.079 [95% CI, -0.156 to -0.002] global z score points). Having a JNC-8-specified indication for initiating antihypertensive treatment at baseline was associated with a greater 20-year decline (-0.044 [95% CI, -0.085 to -0.003] global z score points) than not having an indication. We observed effect modification by race for the continuous systolic BP analyses (P = .01), with each 20-mm Hg increment at baseline associated with an additional decline of 0.048 (95% CI, -0.074 to -0.022) points in global cognitive z score in whites but not in African Americans (decline, -0.020 [95% CI, -0.026 to 0.066] points). Systolic BP at the end of follow-up was not associated with the preceding 20 years of cognitive change in either group. Methods to account for bias owing to attrition strengthened the magnitude of some associations. CONCLUSIONS AND RELEVANCE Midlife hypertension and elevated midlife but not late-life systolic BP was associated with more cognitive decline during the 20 years of the study. Greater decline is found with higher midlife BP in whites than in African Americans.

Diabetes in Midlife and Cognitive Change Over 20 Years: A Cohort Study

Context Data are limited on the relationship of midlife glycemic control and long-term cognitive impairment. Contribution This prospective longitudinal study involved 13351 adults living in 4 U.S. communities. Diabetes status was defined at baseline, and cognitive function was assessed at baseline and periodically during the 20-year follow-up. Caution The relationship between improvement in glucose control over time and cognitive decline could not be examined. Implication Diabetes and prediabetes in midlife were associated with a greater risk for cognitive decline over 20 years. Longer-duration diabetes had a stronger association with cognitive decline. The Editors The prevalence of diabetes has increased substantially over the past several decades to approximately 10%, and 21 million adults are affected in the United States (1). Type 2 diabetes is an established risk factor for heart disease, stroke, hypertension, blindness, and kidney disease (24). The association of diabetes with dementia risk is well-established (57), but the association of diabetes with cognitive decline is less well-characterized. Because cognitive decline is a precursor to dementia, strong risk factors for decline can help identify persons who may benefit from early intervention. The effects of diabetes and early hyperglycemic states assessed in midlife on long-term cognitive decline are relatively uncharacterized (6). Previous studies have been limited by short follow-up and a lack of rigorous adjustment for potential confounding variables, and most were limited to white persons and were done in elderly populations, where associations tend to be weaker (8, 9). Hemoglobin A1c (HbA1c) level is a measure of the average circulating glucose level in the blood over the preceding 2 to 3 months. It is the standard measure used in the clinical management of diabetes, and its use is now recommended for diagnosis of diabetes and identification of persons at risk for the condition (10). Studies have shown cross-sectional associations between HbA1c level and cognitive scores in persons with diabetes (11, 12). However, there is little evidence prospectively linking better glycemic control to slower cognitive decline, and few studies have examined whether chronic hyperglycemia below the threshold for a diagnosis of diabetes (prediabetes) is associated with long-term cognitive impairment (1315). Our objective was to examine the association of diabetes assessed in middle age with subsequent 20-year cognitive decline in a community-based population of black and white adults. We also examined the associations of prediabetes and glycemic control in the setting of diabetes with 20-year cognitive decline. An inherent challenge to accurately quantifying the long-term risk factor associations in observational studies is that participants who are ill are less likely to return for study visits. In this study, we used methods to account for this attrition, which is important in quantifying the long-term associations of diabetes with cognitive decline. Methods Study Population The ARIC (Atherosclerosis Risk in Communities) study is a community-based, prospective cohort study of 15792 middle-aged adults from 4 U.S. communities: Washington County, Maryland; Forsyth County, North Carolina; and suburbs of Minneapolis, Minnesota, and Jackson, Mississippi. The field centers in all 4 communities selected participants by probability sampling; the Mississippi field center recruited only black persons, the Forsyth County site recruited black and white persons, and the racial distribution in the other locations resulted in a small percentage of nonwhite participants. Participants were seen at 4 visits approximately 3 years apart beginning in 1987 to 1989, and a fifth visit took place in 2011 to 2013. Cognitive function was evaluated at visit 2 (1990 to 1992), at visit 4 (1996 to 1998), and as part of the ARIC-NCS (ARIC Neurocognitive Study) at visit 5 (2011 to 2013). Detailed information about the ARIC study can be found elsewhere (16). Baseline for the present analysis was visit 2, the first visit at which cognitive data were collected. Of the 14348 participants who attended visit 2, we excluded participants who were neither white nor black and the small number of black persons in the Minnesota and Washington County cohorts (n= 91), those missing results from 1 or more cognitive function tests at baseline (n= 217), and those missing variables of interest (n= 689), resulting in a final sample size of 13351 participants at baseline (93% of the visit 2 sample). A flow diagram of the study population and the pattern of visit attendance is provided in Figure 1 . Figure 1. Study flow diagram. Assessment of Cognitive Function We used 3 neuropsychological tests to assess cognitive function: the delayed word recall test (DWRT) (17), the digit symbol substitution test (DSST) of the Wechsler Adult Intelligence Scale-Revised (18), and the word fluency test (WFT) (19). Protocols for the tests were standardized, and trained examiners administered the tests in a fixed order during 1 session in a quiet room. The DWRT is a test of verbal learning and recent memory. Participants were asked to learn 10 common nouns by using each in a sentence. Two exposures to each word were given. After a 5-minute filled delay, participants had 60 seconds to recall the words. The score was equal to the number of words recalled. The DSST is a test of executive function and processing speed. In this 90-second test, participants were asked to use a key to translate numbers to symbols. The score was equal to the count of numbers correctly translated to symbols, with possible scores ranging from 0 to 93. The WFT is a test of executive function and language. Participants were given 60 seconds for each of the letters F, A, and S and were asked to generate as many words as possible beginning with each letter, excluding proper nouns. The score was equal to the total number of words generated for each letter. To facilitate comparison across cognitive tests, Zscores standardized to visit 2 were calculated for each test by subtracting the participants test score at each visit from the mean score at visit 2 and dividing by the SD of the visit 2 scores. A composite global cognitive Zscore was calculated by averaging the Zscores of the 3 tests and was then standardized to visit 2 by using the mean and SD of the global Zscores at visit 2. Thus, a Zscore of 1 would describe cognitive performance that is 1 SD below the mean score at visit 2. Composite global scores derived in this manner have been used in analyses of cognitive change in the ARIC study (20, 21) and elsewhere (2224). Assessment of Diabetes We defined diabetes as self-reported physician diagnosis or diabetes medication use or HbA1c level of 6.5% or greater. HbA1c Measurement We measured HbA1c level in stored whole-blood samples by using high-performance liquid chromatography methods standardized to the Diabetes Control and Complications Trial assay (Tosoh A1c 2.2 Plus and G7 analyzers) (25). For analyses of the association between HbA1c level and cognitive decline, HbA1c level was categorized by using standard clinical cut points (<5.7%, 5.7% to 6.4%, and 6.5% in persons without a history of diabetes and <7.0% and 7.0% in those with a history of diabetes) (10). Covariates All covariates used in the regression models were assessed at visit 2 except education, race, and sex, which were assessed at visit 1. We evaluated the following covariates as confounders: age; age squared; sex; racefield center (white persons from Minnesota, white persons from Washington County, white persons from Forsyth County, black persons from Forsyth County, and black persons from Mississippi); education (less than high school; high school, high school equivalent, or vocational school; or college, graduate, or professional school); cigarette smoking status (current, former, or never); alcohol consumption (current, former, or never); body mass index (kg/m2); hypertension, defined as use of blood pressurelowering medication, systolic blood pressure greater than 140 mm Hg, or diastolic blood pressure greater than 90 mm Hg (yes or no); history of coronary heart disease (yes or no, with persons who were unsure of their history classified as no); history of stroke (yes or no); and apolipoprotein E 4 genotype (0, 1, or 2 alleles). We also included interaction terms between each of these variables and time to allow for different rates of decline by these covariates. In sensitivity analyses, we treated cigarette smoking status, alcohol consumption, body mass index, hypertension, history of coronary heart disease, and history of stroke as time-varying and updated values at each study visit. We also adjusted for total cholesterol level and lipid-lowering medication use. Statistical Analysis We used linear models to estimate associations between diabetes and cognitive decline and fit them with generalized estimating equations to account for the within-person correlations of test scores arising from the repeated measures across time. We used unstructured correlation matrices and robust variance estimates. Time since baseline was modeled by using a linear spline with a knot at 6 years (the mean duration between visits 2 and 4). The spline term allowed for a nonlinear association between time and cognitive decline, more appropriately fit the study design than a quadratic term, and was supported by diagnostic Lowess smoothers. The primary coefficients of interest were the interactions between diabetes and the time spline terms, which address the hypothesis of greater decline among participants with diabetes after adjustment for age and the other covariates. To examine the role of stroke in mediating the association between diabetes and cognitive decline, we censored participant values at the time of stroke, thus excluding any poststroke cognitive information from our analyses. To test the robustness

Validity and Reliability of Self-reported Diabetes in the Atherosclerosis Risk in Communities Study

The objective of this study was to assess the validity of prevalent and incident self-reported diabetes compared with multiple reference definitions and to assess the reliability (repeatability) of a self-reported diagnosis of diabetes. Data from 10,321 participants in the Atherosclerosis Risk in Communities (ARIC) Study who attended visit 4 (1996-1998) were analyzed. Prevalent self-reported diabetes was compared with reference definitions defined by fasting glucose and medication use obtained at visit 4. Incident self-reported diabetes was assessed during annual follow-up telephone calls and was compared with reference definitions defined by fasting glucose, hemoglobin A1c, and medication use obtained during an in-person visit attended by a subsample of participants (n = 1,738) in 2004-2005. The sensitivity of prevalent self-reported diabetes ranged from 58.5% to 70.8%, and specificity ranged from 95.6% to 96.8%, depending on the reference definition. Similarly, the sensitivity of incident self-reported diabetes ranged from 55.9% to 80.4%, and specificity ranged from 84.5% to 90.6%. Percent positive agreement of self-reported diabetes during 9 years of repeat assessments ranged from 92.7% to 95.4%. Both prevalent self-reported diabetes and incident self-reported diabetes were 84%-97% specific and 55%-80% sensitive as compared with reference definitions using glucose and medication criteria. Self-reported diabetes was >92% reliable over time.

Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains and the most frequently reported neuropsychological tests within domains.

The objectives were to conduct a meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards to determine effect sizes (Cohens d) for cognitive dysfunction in adults with type 2 diabetes, relative to nondiabetic controls, and to obtain effect sizes for the most commonly reported neuropsychological tests within domains. Twenty-four studies, totaling 26,137 patients (n = 3351 with diabetes), met study inclusion criteria. Small to moderate effect sizes were obtained for five of six domains: motor function (3 studies, n = 2374; d = -0.36), executive function (12 studies, n = 1784; d = -0.33), processing speed (16 studies, n = 3076; d = -0.33), verbal memory (15 studies, n = 4,608; d = -0.28), and visual memory (6 studies, n = 1754; d = -0.26). Effect size was smallest for attention/concentration (14 studies, n = 23,143; d = -0.19). The following tests demonstrated the most notable performance decrements in diabetes samples: Grooved Pegboard (dominant hand) (d = -0.60), Rey Auditory Verbal Learning Test (immediate) (d = -0.40), Trails B (d = -0.39), Rey-Osterreith Complex Figure (delayed) (d = -0.38), Trails A (d = -0.34), and Stroop Part I (d = -0.28). This study provides effect sizes to power future epidemiological and clinical diabetes research studies examining cognitive function and to help inform the selection of neuropsychological tests.

Association between different domains of physical activity and markers of inflammation.

PURPOSE Physical activity has recently been established as a potential modifier of the inflammatory process, suggesting that it mitigates inflammation and consequently reduces the incidence of several chronic diseases such as cardiovascular events. METHODS This study examined the association between different domains ofself-reported physical activity (work, transportation, household, and leisure time) and three inflammatory markers (fibrinogen, C-reactive protein (CRP), and interleukin 6 (IL-6)). Study subjects included 796 men and women aged 35-74 yr with complete data for the main study variables who participated in the 1989/1990 MONItoring trends and determinants in CArdiovascular disease (MONICA) Augsburg Survey. Data were collected using the MONICA Optional Study on Physical Activity (MOSPA) questionnaire, and activity levels were classified into low, moderate, and vigorous physical activities. RESULTS Fibrinogen showed an inverse relationship with higher levels of work (Ptrend = 0.038), transportation (Ptrend = 0.025), leisure time (Ptrend = 0.013), and summary physical activity (Ptrend< 0.001). This relationship was still observed after adjusting for age and sex and further correction for body mass index, waist-to-hip ratio, smoking status, hypertension, diabetes, total-to-HDL cholesterol ratio, education, and self-reported limited physical activity due to health problems. IL-6 showed significant results for transportation (Ptrend = 0.031), leisure time (Ptrend = 0.016), and summary physical activity (Ptrend < 0.001), whereas CRP was inversely related with the summary activity (Ptrend = 0.003) in the fully adjusted model. No statistically significant inverse association between household physical activity and any of the investigated markers was found. We observed interactions between summary physical activity and smoking (fibrinogen: P = 0.003) as well as ex-smoking (CRP: P < 0.001; IL-6: P = 0.049). CONCLUSION These data indicate that beyond leisure time, work and transportation physical activity may reduce inflammation.

Endoscopic vacuum-assisted closure of upper intestinal anastomotic leaks.

BACKGROUND Management of intrathoracic anastomotic leaks remains an interdisciplinary challenge. Established treatment options include percutaneous drainage, endoscopic closure, or even surgical revision. All these procedures are associated with high morbidity and mortality rates. OBJECTIVE We report a new, effective endoscopic treatment option for intrathoracic esophageal anastomotic leaks by using an endoscopic vacuum-assisted closure system. PATIENTS Two patients with intrathoracic anastomotic leaks after esophagectomy and gastrectomy were included. METHODS Surgical reinterventions failed to seal the leaks in 1 patient, whereas in the other patient the anastomotic leakage persisted after endoscopic placement of 2 covered self-expanding metal stents. We endoscopically placed transnasal draining tubes that were armed with a size-adjusted sponge at their distal tip in the necrotic anastomotic cavities. Continuous suction was applied. Sponge and drain were changed twice a week. RESULTS No complications were noted during the course of treatment. After a median of 15 days, closure of the wound cavities was achieved in all cases. A median of 5 endoscopic interventions was necessary. Both patients returned gradually to a solid diet without recurrence of the leaks. CONCLUSION Endoscopic vacuum-assisted closure might be an effective alternative in the treatment of upper intestinal anastomotic leaks.

Association between midlife vascular risk factors and estimated brain amyloid deposition

Importance Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood. Objective To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET). Design, Setting, and Participants The Atherosclerosis Risk in Communities (ARIC)–PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015. Exposures Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level. Main Outcomes and Measures Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable. Results Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4% [n = 62], and 61.2% [n = 82], respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69). Conclusions and Relevance An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.