Health ABC Research Articles

Circulating Autoantibodies in Age-Related Macular Degeneration Recognize Human Macular Tissue Antigens Implicated in Autophagy, Immunomodulation, and Protection from Oxidative Stress and Apoptosis.

BackgroundWe investigated sera from elderly subjects with and without age-related macular degeneration (AMD) for presence of autoantibodies (AAbs) against human macular antigens and characterized their identity.MethodsSera were collected from participants in the Age-Related Maculopathy Ancillary (ARMA) Study, a cross-sectional investigation ancillary to the Health ABC Study, enriched with participants from the general population. The resulting sample (mean age: 79.2±3.9 years old) included subjects with early to advanced AMD (n = 131) and controls (n = 231). Sera were tested by Western blots for immunoreactive bands against human donor macular tissue homogenates. Immunoreactive bands were identified and graded, and odds ratios (OR) calculated. Based on these findings, sera were immunoprecipitated, and subjected to 2D gel electrophoresis (GE). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify the targets recognized by circulating AAbs seen on 2D-GE, followed by ELISAs with recombinant proteins to confirm LC-MS/MS results, and quantify autoreactivities.ResultsIn AMD, 11 immunoreactive bands were significantly more frequent and 13 were significantly stronger than in controls. Nine of the more frequent bands also showed stronger reactivity. OR estimates ranged between 4.06 and 1.93, and all clearly excluded the null value. Following immunoprecipitation, 2D-GE and LC-MS/MS, five of the possible autoreactivity targets were conclusively identified: two members of the heat shock protein 70 (HSP70) family, HSPA8 and HSPA9; another member of the HSP family, HSPB4, also known as alpha-crystallin A chain (CRYAA); Annexin A5 (ANXA5); and Protein S100-A9, also known as calgranulin B that, when complexed with S100A8, forms calprotectin. ELISA testing with recombinant proteins confirmed, on average, significantly higher reactivities against all targets in AMD samples compared to controls.ConclusionsConsistent with other evidence supporting the role of inflammation and the immune system in AMD pathogenesis, AAbs were identified in AMD sera, including early-stage disease. Identified targets may be mechanistically linked to AMD pathogenesis because the identified proteins are implicated in autophagy, immunomodulation, and protection from oxidative stress and apoptosis. In particular, a role in autophagy activation is shared by all five autoantigens, raising the possibility that the detected AAbs may play a role in AMD via autophagy compromise and downstream activation of the inflammasome. Thus, we propose that the detected AAbs provide further insight into AMD pathogenesis and have the potential to contribute to disease biogenesis and progression.

Abstract 19547: FOXO3 Genotype Strongly Impacts Coronary Heart Disease Mortality in Three Populations

The G allele of the FOXO3 SNP rs2802292 has a strong, consistently replicated protective association with longevity. We investigated the effect of FOXO3 genotype on coronary heart disease (CHD) mortality - a major cause of mortality worldwide. We genotyped DNA collected in 1991-93, at Exam 4 of the Honolulu Heart Program (HHP), from 3,584 American males of Japanese ancestry aged 71-93 years. Study participants were followed for up to 9 years for CHD mortality and for up to 11 years in a replication cohort - the Health Aging and Body Composition (Health ABC) study. Health ABC is a prospective observational study of 3,075 well functioning, community-dwelling, male and female, white and black Americans, aged 70-79 years at baseline. Cox proportional hazards models demonstrated that Americans of Japanese, white and black ethnicity who were G allele carriers had a combined risk reduction of 31% for CHD mortality (HR = 0.69; 95% CI, 0.58-0.82; P =0.00002). Reduction in risk of death from CHD was 38% in Japanese, 24% in whites and 29% in blacks. This finding remained virtually unchanged when included in a multivariable model of common CHD risk factors. We subsequently assessed the contribution of FOXO3 genotype, relative to other common risk factors, to CHD mortality in these populations by estimating population attributable risk (PAR). In the Americans of Japanese ancestry, PAR for the TT (non-protective) genotype was high, at 24%, equivalent to hypertension (24%), and greater than diabetes (21%), hypercholesterolemia (12%) and ever smoking (6%). PAR for FOXO3 genotype was lower at 9% and 3% in white and black Americans, respectively, principally due to lower prevalence of the TT (risk) genotype. We subsequently measured C-reactive protein (CRP) in a population subsample, and found lower blood CRP levels in G allele carriers ( P <0.05), suggesting a potential link to inflammation. In conclusion, the G allele of the FOXO3 SNP rs2802292 has a major protective effect on CHD mortality, possibly related to lower blood levels of inflammation. The findings support further research on potential mechanisms and point to FoxO3 as a potential target therapeutic target.

Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.

Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases.

Chronic inflammation and risk of colorectal and other obesity-related cancers: The health, aging and body composition study.

Evidence of the association between chronic inflammation and the risk of colorectal cancer (CRC) and other obesity-related cancers (OBRC) remains inconsistent, possibly due to a paucity of studies examining repeated measures of inflammation. In the Health ABC prospective study of 2,490 adults aged 70-79 years at baseline, we assessed whether circulating levels of three markers of systemic inflammation, IL-6, CRP and TNF-α, were associated with the risk of CRC and OBRC, a cluster including cancers of pancreas, prostate, breast and endometrium. Inflammatory markers were measured in stored fasting blood samples. While only baseline measures of TNF-α were available, IL-6 and CRP were additionally measured at Years 2, 4, 6 and 8. Multivariable Cox models were fit to determine whether tertiles and log-transformed baseline, updated and averaged measures of CRP and IL-6 and baseline measures of TNF-α were associated with the risk of incident cancer(s). During a median follow-up of 11.9 years, we observed 55 and 172 cases of CRC and OBRC, respectively. The hazard of CRC in the highest tertile of updated CRP was more than double that in the lowest tertile (HR = 2.29; 95% CI: 1.08-4.86). No significant associations were seen between colorectal cancer and IL-6 or TNF-α. Additionally, no significant associations were found between obesity-related cancers and the three inflammatory markers overall, but we observed a suggestion of effect modification by BMI and NSAID use. In summary, in this population, higher CRP levels were associated with increased risk of CRC, but not of OBRC. The findings provide new evidence that chronically elevated levels of CRP, as reflected by repeated measures of this marker, may play a role in colorectal carcinogenesis in older adults.

Polymorphisms in the ANKS1B gene are associated with cancer, obesity and type 2 diabetes

AbstractObesity and type 2 diabetes (T2D) are comorbidities with cancer which may be partially due to shared genetic variants. Genetic variants in the ankyrin repeat and sterile alpha motif domain containing (ANKS1B) gene may play a role in cancer, adiposity, body mass index (BMI), and body weight. However, few studies focused on the associations of ANKS1B with obesity and T2D. We examined genetic associations of 272 single nucleotide polymorphisms (SNPs) within the ANKS1B with the cancer (any diagnosed cancer omitting minor skin cancer), obesity and T2D using the Marshfield sample (716 individuals with cancers, 1442 individuals with obesity, and 878 individuals with T2D). The Health Aging and Body Composition (Health ABC) sample (305 obese and 1336 controls) was used for replication. Multiple logistic regression analysis was performed using the PLINK software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We identified 25 SNPs within the ANKS1B gene associated with cancer, 34 SNPs associated with obesity, and 12 SNPs associated with T2D (p &lt; 0.05). The most significant SNPs associated with cancer, T2D, and obesity were rs2373013 (p = 2.21 × 10−4), rs10860548 (p = 1.92 × 10−3), and rs7139028 (p = 1.94 × 10−6), respectively. Interestingly, rs3759214 was identified for both cancer and T2D (p = 0.0161 and 0.044, respectively). Furthermore, seven SNPs were associated with both cancer and obesity (top SNP rs2372719 with p = 0.0161 and 0.0206, respectively); six SNPs were associated with both T2D and obesity (top SNP rs7139028 with p = 0.0231 and 1.94 × 10−6, respectively). In the Health ABC sample, 18 SNPs were associated with obesity, 5 of which were associated with cancer in the Marshfield sample. In addition, three SNPs (rs616804, rs7295102, and rs201421) were associated with obesity in meta-analysis using both samples. These findings provide evidence of common genetic variants in the ANKS1B gene influencing the risk of cancer, obesity, and T2D and will serve as a resource for replication in other populations.

Antihypertensive Use and Recurrent Falls in Community-Dwelling Older Adults: Findings From the Health ABC Study.

Despite wide-spread use of antihypertensives in older adults, the literature is unclear about their association with incident recurrent falls over time. Health, Aging and Body Composition study participants (n = 2,948) who were well functioning at baseline (1997) were followed to Year 7 (2004). The main outcome was recurrent falls (≥2) in the ensuing 12 months. Antihypertensive use was examined as: (a) any versus none, (b) long- versus short-term (≥2 vs <2 years), and by (c) summated standardized daily dose (SDD; 1 = maximum recommended daily dose for one antihypertensive), and (d) subclass. Controlling for potential demographic, health status/behavior and access to care confounders, we found no increase in risk of recurrent falls in antihypertensive users compared to nonusers (adjusted odds ratio [AOR] = 1.13; 95% CI = 0.88-1.46), or those taking higher SDDs or for longer durations. Only those using a loop diuretic were found to have a modest increased risk of recurrent falls (AOR = 1.50; 95% CI = 1.11-2.03). Antihypertensive use overall was not statistically significantly associated with recurrent falls after adjusting for important confounders. Loop diuretic use may be associated with recurrent falls and needs further study.

Alzheimer’s Research on Black Americans Comes Up Short

Alzheimer’s Research on Black Americans Comes Up Short

Inflammation as a Mediator of the Association Between Race and Atrial Fibrillation: Results From the Health ABC Study (Health, Aging, and Body Composition)

ObjectivesThis study sought to determine the degree to which racial differences in atrial fibrillation (AF) risk are explained by differences in inflammation and adiposity. BackgroundDespite having a lower prevalence of established AF risk factors, whites exhibit substantially higher rates of this arrhythmia than blacks. The mechanism underlying this observation is not known. Both inflammation and obesity are risk factors for AF, and adipose tissue is a known contributor to systemic inflammation. MethodsBaseline serum inflammatory biomarker concentrations and abdominal adiposity (assessed by computed tomography) were quantified in a subset of black and white participants without prevalent AF in the Health ABC (Health, Aging, and Body Composition) study. Participants were prospectively followed for the diagnosis of AF, using study electrocardiography and Medicare claims data. Cox proportional hazards models were used to determine the adjusted relative hazard of incident AF between races before and after biomarker adjustment. ResultsAmong 2,768 participants (43% black), 721 participants developed incident AF over a median follow-up of 10.9 years. White race was associated with a heightened adjusted risk of incident AF (HR: 1.55; 95% confidence interval [CI]: 1.30 to 1.84, p < 0.001). Abdominal adiposity was not associated with AF when added to the adjusted model. Among the biomarkers studied, adiponectin, tumor necrosis factor (TNF)-α, TNF-α soluble receptor (SR) I, and TNF-α SR II concentrations were each higher among whites and independently associated with a greater risk of incident AF. Together, these inflammatory cytokines mediated 42% (95% CI: 15% to 119%, p = 0.004) of the adjusted association between race and AF. ConclusionsSystemic inflammatory pathways significantly mediate the heightened risk of AF among whites. The higher level of systemic inflammation and concomitant increased AF risk in whites is not explained by racial differences in abdominal adiposity or the presence of other proinflammatory cardiovascular comorbidities.

Physical Activity and Change in Long Distance Corridor Walk Performance in the Health, Aging, and Body Composition Study.

To examine the prospective relationship between self-reported physical activity and aerobic fitness in the Health, Aging, and Body Composition Study (Health ABC) using the Long Distance Corridor Walk (LDCW). Cohort study with 7 years of follow-up. Two U.S. clinical sites. Community-dwelling older adults enrolled in Health ABC (N = 3,075, aged 70-79, 52% female, 42% black) with no self-reported difficulty walking one-quarter of a mile or climbing 10 steps. Participants were classified based on a physical activity questionnaire as being inactive (≤1,000 kcal/wk exercise activity, ≤2,719 kcal/wk total physical activity), lifestyle active (≤1,000 kcal/wk exercise activity, >2,719 kcal/wk total physical activity), or exercisers (≥1,000 kcal/wk exercise activity). The LDCW, an endurance walking test (400 m), was administered at Years 1 (baseline), 2, 4, 6, and 8 to assess aerobic fitness. At baseline, LDCW completion times (adjusted for age and sex) were 351.8 seconds (95% confidence interval (CI) = 346.9-356.8 seconds) for the inactive group, 335.9 seconds (95% CI = 332.7-339.1 seconds) for the lifestyle active group, and 307.7 seconds (95% CI = 303.2-312.3 seconds) for the exerciser group (P < .001). From baseline to Year 8, the inactive group slowed 36.1 seconds (95% CI = 28.4-43.8 seconds), the lifestyle active group slowed 38.1 seconds (95% CI = 33.6-42.4 seconds), and the exerciser group slowed 40.8 seconds (95% CI = 35.2-46.5 seconds), and did not differ significantly between groups. In linear mixed-effects models, the rate of change in LDCW time did not differ between the groups, although exercisers consistently had the fastest completion times (P < .001 for all pairwise comparisons). Decline in LDCW time occurred regardless of baseline activity, although exercisers maintained higher aerobic fitness, which may delay reaching a critically low threshold of aerobic fitness at which independence is impaired.

Nursing experiences of caring for burns patience with sepsis in critical care unit in South West Nigeria (case study NOHI LAGOS)

Unless effective preventive strategies are implemented, aging of the population will result in a significant worsening of the heart failure (HF) epidemic. Few data exist on whether baseline electrocardiographic (ECG) abnormalities can refine risk prediction for HF.We examined a prospective cohort of 2,915 participants aged 70 to 79 years without preexisting HF, enrolled between April 1997 and June 1998 in the Health, Aging, and Body Composition (Health ABC) study. Minnesota Code was used to define major and minor ECG abnormalities at baseline and at year 4 follow-up. Using Cox models, we assessed (1) the association between ECG abnormalities and incident HF and (2) the incremental value of adding ECG to the Health ABC HF Risk Score using the net reclassification index.At baseline, 380 participants (13.0%) had minor, and 620 (21.3%) had major ECG abnormalities. During a median follow-up of 11.4 years, 485 participants (16.6%) developed incident HF. After adjusting for the Health ABC HF Risk Score variables, the hazard ratio (HR) was 1.27 (95% CI 0.96-1.68) for minor and 1.99 (95% CI 1.61-2.44) for major ECG abnormalities. At year 4, 263 participants developed new and 549 had persistent abnormalities; both were associated with increased subsequent HF risk (HR 1.94, 95% CI 1.38-2.72 for new and HR 2.35, 95% CI 1.82-3.02 for persistent ECG abnormalities). Baseline ECG correctly reclassified 10.5% of patients with HF events, 0.8% of those without HF events, and 1.4% of the overall population. The net reclassification index across the Health ABC HF risk categories was 0.11 (95% CI 0.03-0.19).Among older adults, baseline and new ECG abnormalities are independently associated with increased risk of HF. The contribution of ECG screening for targeted prevention of HF should be evaluated in clinical trials.

Single Muscle Fiber Characteristics of The Oldest-Old

PURPOSE: To examine single muscle fiber function in the oldest-old. METHODS: Vastus lateralis muscle biopsies were obtained from five healthy independently living individuals (3F/2M, 89 ± 1 y) enrolled in the Health, Aging and Body Composition (Health ABC) Study. Isolated myosin heavy chain (MHC) I and IIa muscle fibers were examined for cross-sectional area (CSA) and contractile properties prior to MHC isoform identification via SDS-PAGE. RESULTS: MHC I muscle fibers were 21% larger (P < 0.05) than MHC IIa. A summary of muscle fiber characteristics is provided below (values are means ± SE). CONCLUSION: This investigation was the first to examine single muscle fiber contractile properties of independently living individuals > 85 y. In line with previous aging research, MHC IIa fibers were smaller than MHC I, indicative of MHC IIa-specific atrophy. Normalized power (an indicator of muscle fiber quality incorporating size, strength and speed) of MHC I fibers from these individuals, when compared to previous research from our lab using identical procedures, was 28% higher than healthy 25 y olds and similar to younger octogenarians (∼82 y). MHC IIa normalized power was 63% greater than 25 y olds and 39% greater than younger octogenarians. These data support the idea that power output per unit size (i.e. muscle quality) of surviving muscle fibers improves with advancing age, a phenomenon more pronounced in MHC IIa fibers. Thus, a likely key contributor to the loss of muscle function with age is a quantitative loss of whole muscle specific force rather than a reduction in muscle quality of remaining muscle fibers.Table: No title available.

The Longitudinal Relationship between Inflammatory Burden and Gait Speed is Influenced by White Matter Microstructural Characteristics: Secondary Analysis of the Health ABC Study. (I10-2A)

The Longitudinal Relationship between Inflammatory Burden and Gait Speed is Influenced by White Matter Microstructural Characteristics: Secondary Analysis of the Health ABC Study. (I10-2A)

The Longitudinal Relationship between Inflammatory Burden and Gait Speed is Influenced by White Matter Microstructural Characteristics: Secondary Analysis of the Health ABC Study. (P6.213)

The Longitudinal Relationship between Inflammatory Burden and Gait Speed is Influenced by White Matter Microstructural Characteristics: Secondary Analysis of the Health ABC Study. (P6.213)

Arterialized venous bicarbonate is associated with lower bone mineral density and an increased rate of bone loss in older men and women.

Higher dietary net acid loads have been associated with increased bone resorption, reduced bone mineral density (BMD), and increased fracture risk. The objective was to compare bicarbonate (HCO3) measured in arterialized venous blood samples to skeletal outcomes. Arterialized venous samples collected from participants in the Health, Aging and Body Composition (Health ABC) Study were compared to BMD and rate of bone loss. The setting was a community-based observational cohort. A total of 2287 men and women age 74 ± 3 years participated. Arterialized venous blood was obtained at the year 3 study visit and analyzed for pH and pCO2. HCO3 was determined using the Henderson-Hasselbalch equation. BMD was measured at the hip by dual-energy x-ray absorptiometry at the year 1 (baseline) and year 3 study visits. Plasma HCO3 was positively associated with BMD at both year 1 (P = .001) and year 3 (P = .001) in models adjusted for age, race, sex, clinic site, smoking, weight, and estimated glomerular filtration rate. Plasma HCO3 was inversely associated with rate of bone loss at the total hip over the 2.1 ± 0.3 (mean ± SD) years between the two bone density measurements (P < .001). Across quartiles of plasma HCO3, the rate of change in BMD over the 2.1 years ranged from a loss of 0.72%/y in the lowest quartile to a gain of 0.15%/y in the highest quartile of HCO3. Arterialized plasma HCO3 was associated positively with cross-sectional BMD and inversely with the rate of bone loss, implying that systemic acid-base status is an important determinant of skeletal health during aging. Ongoing bone loss was linearly related to arterialized HCO3, even after adjustment for age and renal function. Further research in this area may have major public health implications because reducing dietary net acid load is possible through dietary intervention or through supplementation with alkaline potassium compounds.

Genetic and Environmental Factors Are Associated with Serum 25-Hydroxyvitamin D Concentrations in Older African Americans1–3

Background: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations.Objective: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study.Methods: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.Results: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-μg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences.Conclusions: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans.

Cognitive resilience to apolipoprotein E ε4: contributing factors in black and white older adults.

Apolipoprotein E (APOE) ε4 is an established risk factor for cognitive decline and the development of dementia, but other factors may help to minimize its effects. Using APOE ε4 as an indicator of high risk, we investigated factors associated with cognitive resilience among black and white older adults who are APOE ε4 carriers. Participants included 2487 community-dwelling older (aged 69-80 years at baseline) black and white adults examined at 2 community clinics in the prospective cohort Health, Aging, and Body Composition (Health ABC) study. The baseline visits occurred from May 1997 through June 1998. Our primary analytic cohort consisted of 670 APOE ε4 carriers (329 black and 341 white participants) who were free of cognitive impairment at baseline and underwent repeated cognitive testing during an 11-year follow-up (through 2008) using the Modified Mini-Mental State Examination. We stratified all analyses by race. Using the Modified Mini-Mental State Examination scores, we assessed normative cognitive change in the entire cohort (n = 2487) and classified the APOE ε4 carriers as being cognitively resilient vs nonresilient by comparing their cognitive trajectories with those of the entire cohort. We then conducted bivariate analyses and multivariable random forest and logistic regression analyses to explore factors predictive of cognitive resilience in APOE ε4 carriers. Among white APOE ε4 carriers, the strongest predictors of cognitive resilience were, in relative order of importance, no recent negative life events, a higher literacy level, advanced age, a higher educational level, and more time spent reading. Among black APOE ε4 carriers, the strongest predictors of cognitive resilience were, in relative order of importance, a higher literacy level, a higher educational level, female sex, and the absence of diabetes mellitus. In follow-up logistic regression models, higher literacy level (adjusted odds ratio [OR], 9.50 [95% CI, 2.67-60.89]), a higher educational level (adjusted OR for college graduate vs less than high school, 3.81 [95% CI, 1.13-17.56]), and age (adjusted OR for 73-76 vs 69-72 years, 2.01 [95% CI, 1.13-3.63]) had significant independent effects in predicting cognitive resilience among white APOE ε4 carriers. Among black APOE ε4 carriers, a higher literacy level (adjusted OR, 2.27 [95% CI, 1.29-4.06]) and a higher educational level (adjusted OR for high school graduate/some college vs less than high school, 2.86 [95% CI, 1.54-5.49]; adjusted OR for college graduate vs less than high school, 2.52 [95% CI, 1.14-5.62]) had significant independent effects in predicting cognitive resilience. Although APOE ε4 carriers are at high risk for cognitive decline, our findings suggest possible intervention targets, including the enhancement of cognitive reserve and improvement of other psychosocial and health factors, to promote cognitive resilience among black and white APOE ε4 carriers.

Association between Sleep Duration and Mortality Is Mediated by Markers of Inflammation and Health in Older Adults: The Health, Aging and Body Composition Study

Inflammation may represent a common physiological pathway linking both short and long sleep duration to mortality. We evaluated inflammatory markers as mediators of the relationship between sleep duration and mortality in community-dwelling older adults. Prospective cohort with longitudinal follow-up for mortality outcomes. Pittsburgh, Pennsylvania, and Memphis, Tennessee. Participants in the Health, Aging and Body Composition (Health ABC) Study (mean age 73.6 ± 2.9 years at baseline) were sampled and recruited from Medicare listings. Baseline measures of subjective sleep duration, markers of inflammation (serum interleukin-6, tumor necrosis factor-α, and C-reactive protein) and health status were evaluated as predictors of all-cause mortality (average follow-up = 8.2 ± 2.3 years). Sleep duration was related to mortality, and age-, sex-, and race-adjusted hazard ratios (HR) were highest for those with the shortest (< 6 h HR: 1.30, CI: 1.05-1.61) and longest (> 8 h HR: 1.49, CI: 1.15-1.93) sleep durations. Adjustment for inflammatory markers and health status attenuated the HR for short (< 6 h) sleepers (HR = 1.06, 95% CI = 0.83-1.34). Age-, sex-, and race-adjusted HRs for the > 8-h sleeper group were less strongly attenuated by adjustment for inflammatory markers than by other health factors associated with poor sleep with adjusted HR = 1.23, 95% CI = 0.93-1.63. Inflammatory markers remained significantly associated with mortality. Inflammatory markers, lifestyle, and health status explained mortality risk associated with short sleep, while the mortality risk associated with long sleep was explained predominantly by lifestyle and health status.

Hip Fractures Risk in Older Men and Women Associated With DXA-Derived Measures of Thigh Subcutaneous Fat Thickness, Cross-Sectional Muscle Area, and Muscle Density.

Mid-thigh cross-sectional muscle area (CSA), muscle attenuation, and greater trochanter soft tissue thickness have been shown to be independent risk factors of hip fracture. Our aim was to determine whether muscle and adipose tissue measures derived from dual-energy X-ray absorptiometry (DXA) scans would have a similar risk association as those measured using other imaging methods. Using a case-cohort study design, we identified 169 incident hip fracture cases over an average of 13.5 years among participants from the Health ABC Study, a prospective study of 3075 individuals initially aged 70 to 79 years. We modeled the thigh 3D geometry and compared DXA and computed tomography (CT) measures. DXA-derived thigh CSA, muscle attenuation, and subcutaneous fat thickness were found to be highly correlated to their CT counterparts (Pearson's r = 0.82, 0.45, and 0.91, respectively; p < 0.05). The fracture risk of men and women were calculated separately. We found that decreased subcutaneous fat, CT thigh muscle attenuation, and appendicular lean mass by height squared (ALM/Ht(2)) were associated with fracture risk in men; hazard ratios (HR) = 1.44 (1.02, 2.02), 1.40 (1.05, 1.85), and 0.58 (0.36, 0.91), respectively, after adjusting for age, race, clinical site, body mass index (BMI), chronic disease, hip bone mineral density (BMD), self-reported health, alcohol use, smoking status, education, physical activity, and cognitive function. In a similar model for women, only decreases in subcutaneous fat and DXA CSA were associated with hip fracture risk; HR = 1.39 (1.07, 1.82) and 0.78 (0.62, 0.97), respectively. Men with a high ALM/Ht(2) and low subcutaneous fat thickness had greater than 8 times higher risk for hip fracture compared with those with low ALM/Ht(2) and high subcutaneous fat. In women, ALM/Ht(2) did not improve the model when subcutaneous fat was included. We conclude that the DXA-derived subcutaneous fat thickness is a strong marker for hip fracture risk in both men and women, especially in men with high ALM/Ht(2).

Disability Trajectories at the End of Life Among the Very Old (TH307-A)

Objectives Assess functional trajectories as they differ by cause of death. Separate disability due to underlying chronic conditions from disability associated with end of life. Original Research Background: Investigators have identified varying trajectories of disability before death, but little is known about how decedent trajectories compare with those of matched survivors. Research Objectives: We examined self-reported disability at 6-month intervals before death among the 1,859 participants in the Health, Aging and Body Composition Study (Health ABC) who died before 2014 and made multiple comparisons with surviving participants. Methods: The original 3,075 study participants were recruited in 1997 from Medicare beneficiaries in Pittsburgh, PA, and Memphis, TN, who were at least 70 years of age and well functioning. Follow-up has continued for 17 years. Results: Disability trajectories among the decedents varied as expected. For example, difficulty dressing was reported 12 months before death by 27.5% of decedents with CHF or COPD compared with 8.1% who died from cancer (p<.0001). Compared to age-matched survivors, decedents with a history of stroke, dementia, pneumonia, or falls were more likely to report difficulty transferring at 6 months (46%-50% vs 22%, p<.0001) and also at 18 months before death (39%-45% vs 20%, p<.0001). Cancer decedents significantly differed from survivors only at 6 months before death. As expected, the proportion of study participants

Statins and brain integrity in older adults: Secondary analysis of the Health ABC study

IntroductionWe examined whether statins are associated with better cerebral white (WM) and gray matter (GM) indices in community-dwelling elders. MethodsIn 295 older adults, we compared white matter hyperintensities (WMH) on brain magnetic resonance imaging and, total WM fractional anisotropy (FA) and GM mean diffusivity (MD) on diffusion tensor imaging, of Alzheimer’s disease (AD) relevant regions in statin-exposed and statin-unexposed participants stratified by Modified Mini-Mental Status Examination (3MS) score. ResultsThere was no overall effect of statin exposure on cerebral structural indices. The interaction between statin exposure and 3MS was significant for total-WMH and WM FA (both P < .05) but not GM MD. In the lowest 3MS tertile (mean: 86), statin-exposed individuals had lower total-WMH and higher WM FA (P = .005 and P = .044) and FA of tracts linked to clinical AD (P-value range= .005–.04) despite statistical adjustments. These differences were not significant in the two higher 3MS tertiles. DiscussionStatins may benefit WM in older adults vulnerable to dementia.