The Influence of Education and Apolipoprotein ε4 on Mortality in Community-Dwelling Elderly Men and Women

Duke Appiah; Richard N. Baumgartner

doi:10.1155/2018/6037058

The Influence of Education and Apolipoprotein ε4 on Mortality in Community-Dwelling Elderly Men and Women

Appiah, Duke;Baumgartner, Richard N. 2018-03-25 00:00:00 Hindawi Journal of Aging Research Volume 2018, Article ID 6037058, 7 pages https://doi.org/10.1155/2018/6037058 Research Article The Influence of Education and Apolipoprotein ε4 on Mortality in Community-Dwelling Elderly Men and Women 1 2 Duke Appiah and Richard N. Baumgartner Department of Public Health, Texas Tech University Health Sciences Center, 3601 4th Street, STOP 9403, Lubbock, TX 79430, USA Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray St., Louisville, KY 40202, USA Correspondence should be addressed to Duke Appiah; duke.appiah@ttuhsc.edu Received 16 September 2017; Accepted 7 February 2018; Published 25 March 2018 Academic Editor: Kathryn Peri Copyright © 2018 Duke Appiah and Richard N. Baumgartner. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We investigated the risk of death in relation to the apolipoprotein ε4 allele and evaluated how it interacts with education in 504 elderly adults (mean age 73 years, 65.3% women) who were enrolled in 1993 into the New Mexico Aging Process Study. During 9 years of follow-up, apolipoprotein ε2 appeared to be associated with a lower risk for all-cause mortality (hazard ratio (HR) � 0.73, 95% conﬁdence interval (CI): 0.30–1.71) compared to apolipoprotein ε3 carriers in models adjusted for age, sociodemographic variables, medical conditions, adiposity, and lifestyle factors. +e apolipoprotein ε4 allele conferred almost a threefold elevated risk of mortality (HR � 2.76, CI: 1.42–5.37). An interaction between education and apolipoprotein e4 (p � 0.027) was observed with the HR of mortality among e4 carriers compared to noncarriers being 1.59 (0.64–3.96) for those with≥college education; 6.66 (1.90–23.4) for those with some college or trade; and 14.1 (3.03–65.6) for participants with≤high school education. No signiﬁcant interaction was identiﬁed between apolipoprotein E genotype and cognitive function for mortality risk. +ese ﬁndings suggest that genetic (apolipoprotein ε4) and environmental (education) factors act interactively to inﬂuences survival in the elderly with higher education attenuating the adverse eﬀect of apolipoprotein ε4 on mortality. Alzheimer’s and cardiovascular disease, two conditions that 1. Introduction in themselves are among the most prevalent causes of Apolipoprotein E(APOE),with regardtolongevity, can besaid mortality in the elderly, resulting in survival bias with re- to be the most extensively studied gene [1]. APOE, a 299 amino duced frequency of the e4 allele in persons aged 65 and older acid plasma protein with its gene found on chromosome 19, [8]. Additionally, secular trends and geographic variation in plays a central role in lipid transport and metabolism and also the rates of the aforementioned chronic diseases suggest that possesses several immunomodulatory properties such as the risk of death conferred by APOE genotype may depend suppressing lymphocytic Tcell proliferation [2–4]. It has three on complex interactions with various environmental or polymorphisms: ε2, ε3, and ε4 with the later being associated behavioral risk factors over the lifespan of an individual. In with increased susceptibility for several chronic diseases as well this regard, numerous reviews have raised the issue that as mortality [5–7], while ε2 has been suggested to have most studies assessing the eﬀect of APOE across populations a protective eﬀect, compared to ε3 [8]. and time ignore the eﬀects of behavioral factors that pre- Reports on the association of APOE allelic variation with disposes people to disease [1]. mortality has been equivocal with diﬀerences in estimates A large body of research has demonstrated a positive observed among diﬀerent ethnic/racial populations [9–13]. association of educational attainment with better health Some of the possible explanations for the inconsistent results outcomes [14, 15] as well as reduced mortality [16]. Ac- across studies is that APOE ε4 allele is associated with cordingly, over the last decades, reports from numerous 2 Journal of Aging Research school, college degree, some grad school, masters degree, and studies allude to a gene-environment interaction between APOE genotype and education on health outcomes, namely, doctorate. Other covariates of interest were sex, marital status, body mass index (BMI), bone mineral density, smoking status, dementia [17], brain structure and development [18, 19], and cognitive function [20–22]. However, observations con- diastolic blood pressure, and levels of total cholesterol and cerning the possible modifying eﬀect of educational status triglyceride. BMI was calculated by dividing weight in kilo- on mortality in the elderly, independent of chronic grams by the square of height in meters. Bone mineral density comorbidities, are limited. +erefore, we aimed to evaluate was measured by Lunar DPX DXA (GE/Lunar Radiation whether educational status would oﬀset the adverse inﬂu- Corp., Madison, WI). Chronic conditions including cancer, ence of the APOE ε4 allele on mortality among community- nonvertebral or vertebral fracture, diabetes, ischemic heart dwelling elderly adults. disease, and cerebrovascular disease were all self-reported at each annual visit, veriﬁed against medical records, and coded according to the International Classiﬁcation of Diseases, Ninth 2. Materials and Methods Revision (ICD-9) codes. ICD-9 codes used were 140–208 for cancer; 250 for diabetes (or fasting blood glucose lev- +e New Mexico Aging Process Study (NMAPS) was a longitudinal study conducted between 1979 and 2001 in el≥ 7 mmol/L); 290, 294, and 331 for dementia; 430–438 for Albuquerque, NM, to describe the nutritional status and cerebrovascular disease; 410–414 and 428–429 for ischemic factors associated with healthy aging in community-dwelling heart disease; and 800–829 nonvertebral or vertebral fracture. elderly persons. +e study design, subject recruitment, and Deaths were ascertained using the National Death Index and inclusion and exclusion criteria have been described in detail veriﬁed whenever possible against state death certiﬁcates and previously [23]. Brieﬂy, to be enrolled in the study, a person local obituary reports. had to be 60 years and older and have no preexisting medical conditions such as cancer (with the exception of non- 2.1. Statistical Analysis. Diﬀerences in baseline characteris- melanoma skin cancer), recent myocardial infarction, type 2 diabetes mellitus, chronic obstructive pulmonary disease, or tics by APOE genotype were assessed using chi-square for categorical variables and ANOVA for continuous variables uncontrolled hypertension. About 90% of participants were non-Hispanic whites, 8% of Hispanic origin, and close to 2% that were normally distributed or the Kruskal–Wallis test for being nonwhite. An annual visit was required for all par- nonnormally distributed variables. In time-to-event analysis, ticipants in whom blood samples were obtained, and body the Kaplan–Meier method was used to evaluate the incidence composition, physical, functional, cognitive, and nutritional of all-cause mortality in relation to APOE genotype groups status were assessed. +e yearly dropout rate for the study with the censoring date being December 31, 2002. Attained was approximately 3.6% with major chronic conditions and age was used as the time scale for all analyses as this procedure migration out of Albuquerque being the main reasons. +e oﬀers the opportunity to account for the eﬀect of survival bias study was approved by the Human Subjects Research Review (thus individual with the highest risk of mortality are not observed) [28]. Furthermore, the use of attained age as the Committee of the University of the New Mexico School of Medicine with all participants providing informed consent time scale provides a more straight-forward interpretation of mortality since it is free of the confounding eﬀect of age which in accordance with the Declaration of Helsinki, and all methods were carried out in accordance with the relevant is intrinsically taken into account as a measure of survival guidelines and regulations. Participants who were alive at time [29]. Survival curves were then produced to graphically 1993, were followed up for 9 years (median, 7 years), and had depict incident events with diﬀerences among groups genotype data together with measures of cognitive function assessed by means of the log-rank test. Adjusted hazard ratios were included in the current analysis. (HRs) and 95% conﬁdence intervals (CIs) for mortality were APOE genotypes were assessed by restriction fragment calculated using Cox proportional hazards regression. Four models with progressive adjustments were used. Model 1 was length polymorphism analysis of polymerase chain reaction products, as previously developed [24, 25]. +e assays were adjusted for demographic variables such as age, sex, educa- tion, and marital status. Model 2 comprised model 1 with conducted in the Aging and Genetic Epidemiology (AGE) laboratory [23]. Of the 577 individuals who participated at further adjustment for levels of triglyceride, BMI, bone mineral density, and diastolic blood pressure. Model 3 further baseline, 519 had APOE genotyped successfully. To distin- guish unambiguously the eﬀect of the APOE allele and adjusted for psychological factors such as scores on both the genotype, we further excluded participants with APOE 2/4 Geriatric Depression Scale and the Modiﬁed Mini-Mental (n � 15), resulting in an analytic sample of 504 participants. State Examination. Finally, model 4 also adjusted for incident Cognitive function was evaluated by using the modiﬁed medical conditions, including all cancers, nonvertebral or version of the Mini-Mental State Examination (3MS) [26]. vertebral fractures, diabetes, ischemic heart disease, and Depression was measured using the short form of the Ge- cerebrovascular disease. APOE status was identiﬁed with dummy coded indicator variables with the 3/3 genotype used riatric Depression Scale [27], with a score of 5 or higher suggestive of depressive symptomatology. as the referent. Interactions of APOE ε4 allele and educational as well as other statistically signiﬁcant covariates on the risk of Educational status was assessed using a questionnaire with possible responses being less than 12 years of education mortality were explored using the likelihood ratio test to compare models with and without the interaction terms. +e (high school), high school graduate or passed the tests of general educational development, some college or technical assumptionof proportionalhazards wasassessed bygraphical Journal of Aging Research 3 Table 1: Baseline characteristics of participants in the New Mexico Aging Process Study. Apolipoprotein E genotype group Characteristics p value APOE 2 carriers (N � 71) APOE 3/3 (N � 336) APOE 4 carriers (N � 97) Age, years 73.8 (6.4) 73.5 (6.5) 72.4 (5.8) 0.261 Sex, % 0.110 Male 45.1 32.1 36.1 Female 54.9 67.9 63.9 Education, % 0.642 High school or less 16.9 17.2 15.5 Some college or trade 36.6 28.3 27.8 College degree or higher 46.9 54.5 56.7 Marital status, % 0.160 Single 30.4 42.9 40.4 Married 69.6 57.1 59.6 Current smoker, % 7.3 3.9 3.2 0.361 Depressive symptoms, % 4.2 4.5 4.1 0.988 Diastolic blood pressure (mmHg) 80.4 (10.2) 79.5 (11.3) 79.5 (10.8) 0.805 Total cholesterol (mmol/l) 5.10 (0.75) 5.47 (0.93) 5.49 (1.04) 0.008 Triglycerides (mmol/l) 1.61 (0.82) 1.62 (0.99) 1.55 (0.86) 0.820 Body mass index (kg/m ) 25.4 (3.49) 25.5 (4.01) 24.7 (3.91) 0.252 Waist to hip ratio 0.92 (0.11) 0.88 (0.1) 0.89 (0.11) 0.062 Bone mineral density 1.10 (0.13) 1.07 (0.12) 1.09 (0.11) 0.145 Mini-Mental State Exam scores 94.6 (4.91) 95.2 (4.28) 94.1 (5.73) 0.107 Medical conditions at follow-up Diabetes 4.2 3.3 4.1 0.817 Fractures 12.7 13.4 11.3 0.867 Cancers 5.6 12.5 15.5 0.144 Ischemic heart disease 7.0 7.4 10.3 0.626 Cerebrovascular disease 5.6 4.5 9.3 0.190 Deceased at the end of study 9.9 11.0 17.5 0.183 Values are mean (standard deviation) for continuous variables and percentages for categorical variables; p values based on the chi-square test for categorical variables and ANOVA for normally distributed continuous variables or the Kruskal–Wallis test for nonnormally distributed continuous variables. methods using Schoenfeld residuals. To assess the robustness common genotype was APOE 3/3 found in 66.7% of par- of the estimates, we performed a sensitivity analysis which ticipants with 13.9% and 18.1% having ε2/3 and ε3/4 geno- included information for the 15 participants with APOE ε2/4. types, respectively. Additionally, only 19.2% of participants had at least one ε4 allele. +ese percentages are consistent A two-tailed probability value less than 0.05 was considered statistically signiﬁcant, and all analyses were performed using with other prospective population studies among the el- SAS software, version 9.4 (SAS Institute, Inc., Cary, NC) derly, especially those 60 years and older. As expected, total cholesterol levels varied across APOE genotype groups (p � 0.01) with APOE ε2 carriers having the lowest for trend 3. Results levels of total cholesterol. +e mean age of participants at baseline was 73.4 (range During follow-up, 61 (12%) deaths were recorded with 61–91) with 65.3% being women. Approximately half of the fatal events occurring twice as often in men than women. participants reported having a college degree or higher and Figure 1 shows unadjusted Kaplan–Meier cumulative in- only 11.3% had a BMI of 30 or higher. Nearly 5% of the cohort cidence estimates for all-cause mortality according to APOE was identiﬁed as having depressive symptomatology in- genotype and allele. +e log-rank statistic suggests that APOE dicative of depression, and less than 2% of participants were genotype and allele inﬂuenced mortality, with APOE ε4 classiﬁed as having dementia. Several diﬀerences in baseline carriers having a signiﬁcantly higher number of deaths. In multivariable models (Table 2), participants with the APOE characteristics were observed between men and women. Men were more likely than women to be older and have higher ε4/ε4 genotype had a greater risk of mortality (HR � 2.56, 95% CI: 1.33–4.94) compared to persons homozygous for ε3 allele bone mineral density and higher body weight, with a signif- icantly greater proportion reporting having graduated from (model 3). APOE ε4 carriers had a twofold elevated risk of college (66.3% versus 47.1%), currently married (86.2% mortality compared to non-APOE ε4 carriers (HR � 2.21, versus 44.9%), diagnosed with ischemic heart disease (14.3% 95% CI: 1.20–4.09). +ese estimates increased in magni- versus 4.6%), and cancer (16% versus 10%). Women were tude after further adjustment for chronic medical condi- more likely to have higher levels of total cholesterol and tions yielding hazard ratios of 2.61(CI: 1.33–5.14) and 2.76 triglyceride with a signiﬁcantly greater proportion reporting (CI: 1.42–5.37) for APOE ε4/ε4 genotype and e4 allele fractures (15.5% versus 8%). A description of the cohort carriers compared to persons homozygous for ε3 allele and according to APOE genotype is shown in Table 1. +e most non-APOE ε4 carriers, respectively. 4 Journal of Aging Research 100 100 80 80 60 60 p = 0.011 40 40 p = 0.005 20 20 0 0 65 70 75 80 85 90 95 100 65 70 75 80 85 90 95 100 Attained age (years) Attained age (years) APOE genotype APOE e4 allele APOE 3/3 Noncarrier APOE 2/2, 2/3 Carrier APOE 3/4, 4/4 (a) (b) Figure 1: Kaplan–Meier cumulative incidence estimates for all-cause mortality by (a) APOE genotype and (b) APOE ε4 allele. Table 2: APOE genotype and allele as predictors of all-cause mortality. Unadjusted Model 1 Model 2 Model 3 Model 4 Apolipoprotein E genotype APOE ε3/3 1 1 1 1 1 APOE ε2/2, 2/3 0.80 (0.34–1.80) 0.73 (0.32–1.65) 0.73 (0.32–1.68) 0.75 (0.32–1.74) 0.73 (0.31–1.71) APOE ε3/4, 4/4 2.38 (1.33–4.26) 2.34 (1.30–4.36) 2.53 (1.35–4.73) 2.56 (1.33–4.94) 2.61 (1.33–5.14) Apolipoprotein E allele APOE ε4 noncarrier 1 1 1 1 1 APOE ε4 carrier 1.99 (1.17–3.38) 2.20 (1.25–3.86) 2.26 (1.24–4.13) 2.21 (1.20–4.09) 2.76 (1.42–5.37) Model 1: adjusted for age, sex, education, and marital status; model 2: model 1 plus levels of triglyceride, body mass index, bone mineral density, and diastolic blood pressure; model 3: model 2 plus Geriatric Depression Scale and the Modi ed Mini-Mental State Examination scores; model 4: model 3 plus incident medical conditions occurring during follow-up (cancers, nonvertebral or vertebral fractures, diabetes, ischemic heart disease, and cerebrovascular disease). Educational status appeared to be negatively associated important confounders. However, this elevated mortality risk with mortality with persons who had college education or was oŽset by higher educational status. To our knowledge, this more having lower risk of mortality compared to participants is the rst study to report that APOE (genetic factor) and with high school education or less (HR 0.79, 0.35–1.76). education (environmental factor) act interactively to in- Howbeit, this did not approach statistical signi cance. Finally, ’uences survival in the elderly. we observed a signi cant interaction between educational While the underlying mechanism by which education status and APOE ε4 allele on the risk of mortality (p 0.027). ameliorates the in’uence of APOE genotype on mortality †e HR of mortality among ε4 carriers compared to non- among elderly adults is a topic of major interest, it is not fully carriers was 1.59 (0.64–3.96) for those with ≥college educa- understood. It is possible that education may exert some tion; 6.66 (1.90–23.4) for those with some college or trade; and bene cial eŽects on survival through two main avenues. †at 14.1 (3.03–65.6) for participants with ≤high school education. is, either through increased socioeconomic resources over the No signi cant interaction was identi ed between APOE life course that could aid in the prevention of chronic diseases genotype and cognitive function for mortality risk. †ese or through neuroprotective mechanism involved in reducing results remained unchanged when information from the 15 age-related or pathological changes in the structure and participants with APOE ε2/4 was included in the analysis, and function of the brain which in the long term might in’uence APOE ε2/4 was not signi cantly associated with mortality longevity [30, 31]. On the one hand, higher education, more which could possibly be attributed to the small sample size often than not, provides numerous resources such as higher (data not shown). income, stable employment, better social networks, health- related self-e˜cacy, and access to safe neighborhoods [32]. Accordingly, a large body of evidence has shown that higher 4. Discussion educational attainment, whether measured as years of edu- In this community-based sample of elderly adults, we ob- cation or degree completion, is associated with reduced in- served that the APOE ε3/4 and ε4/4 genotypes were associated cidence of chronic morbidities [33], delayed mortality [34], with higher incidence of all-cause mortality, independent of and improved overall health primarily due to better access Incidence (%) Incidence (%) Journal of Aging Research 5 persons who were predominantly Caucasians and gener- and utilization of health care and the adaption of health- promoting behaviors and lifestyles [14]. ally in good health. +us, the results may not be generalizable to other ethnic/racial groups or elderly community-dwelling On the other hand, education may moderate the ex- pression of the APOE ε4 allele on the risk of mortality in the persons. Second, not all participants enrolled in the study elderly by inﬂuencing age-related or pathological changes in consented to give blood for genotyping. Although such brain-matter and cognitive reserve. Some [35], but not all participants were older, there was no diﬀerence with respect [36, 37], neuroimaging studies of cognitively healthy elders to mortality and chronic medical conditions between those have found higher education to be associated with low ac- who did and did not have genotype data. In any case, the eﬀect cumulation of amyloid-beta deposition [38]; physiologically of any diﬀerence on our results cannot be estimated. Because the distribution of APOE genotype was similar to that re- increasing regional cortical thickness [39]; increasing white and gray matter volume [35] in the superior temporal gyrus, ported in other prospective cohort studies of elderly persons, we believe that our results are not seriously biased. +ird, the insula, and anterior cingulate cortex [18]; decreasing mean diﬀusivity in the bilateral hippocampus [40]; and inﬂuencing sample size of the cohort was relatively smaller, and with the occurrence of fatal events not being common, the statistical a greater metabolism in the anterior cingulate cortex [18]. Furthermore, higher education is reported to be positively power to detect very weak associations is limited. None- related with anterior cingulate connectivity which in turn is theless, the associations detected were strong and statistically associated with improved cognitive performances [18]. +ese signiﬁcant. Finally, we did not observe any eﬀect modiﬁcation results and several others provide profound evidence that of chronic ailments such as cancer, impaired cognitive brain and cognitive reserve delays the clinical manifestations function, diabetes, ischemic heart disease, and cerebrovas- of dementia [18]. Compared to persons without the APOE ε4 cular disease with APOE genotype on longevity. +is may primarily be due to the low prevalence of these conditions in variant, those with two copies of the ε4 variant are known to have more than a sevenfold elevated risk of developing our cohort. Serious chronic medical conditions were the main reason for dropout from the NMAPS, followed by migration. Alzheimer’s disease [38], the 6th leading cause of mortality in the United States. Taken together, these results and that of the However, persons who dropped out still contributed in- formation to the analysis since they were censored at the last present study suggest that higher education may oﬀset the negative eﬀects of the APOE ε4 on mortality by increasing date known to be alive. Also, follow-up for mortality status in cerebral reserve capacity against Alzheimer’s disease and the cohort was nearly complete. Nonetheless, it remains other late-life cognitive-related diseases. Even among elderly possible that these medical conditions may play a moderating adults with Alzheimer’s disease, a history of higher education role in the relationship between APOE and mortality. has been reported to aid in coping better with the eﬀects of In summary, we observed that APOE ε4 allele is positively brain atrophy by increasing cognitive reserve [39]. related to mortality risk with this elevated mortality oﬀset by higher educational status; however, the mechanism un- +ere is a strong, positive, and well-documented relation between APOE genotype and morbidity and mortality, and derlying this association is not fully understood. Discovering candidate genes that inﬂuence longevity has great public our results are consistent with some [12, 41–46] but not other studies [2, 8–11, 13, 47, 48] conducted among the elderly. For health importance. With almost 15% of the general pop- instance, the Cache County study with 4701 participants aged ulation known to have the APOE ε4 variant and this pro- 65 and older found a greater mortality risk in persons carrying portion increasing to about 40% among persons with the ε3/4 and ε4/4 genotype which persisted even after ac- Alzheimer’s disease [38], the moderating eﬀects of education, counting for the eﬀect of Alzheimer’s and cardiovascular lifestyle, and behavioral factors on genes should be studied to disease [42]. One of the several reasons for the diverging achieve a better understanding of their inﬂuence on longevity. results for APOE and mortality may pertain to small samples. +is will go a long way to aid in targeting interventions to- +e improvement in statistical power oﬀered by studies with wards high-risk individuals which will in turn reduce mor- bidity and improve longevity as well as quality of life among longer follow-up, such as the NMAPS, is important because thereis agreaterchance of identifyingan eﬀectif ittruly exists. such persons. +e Rotterdam study which followed 6852 participants for a mean of 5.4 years [47] did not identify any association Conflicts of Interest between APOE genotype and longevity. However, after follow-up was extended to a mean of 11.1 years [4], with +e authors declare that there are no conﬂicts of interest improved risk factor adjustments, APOE ε2 carriers with regarding the publication of this article. normal weight were found to have a reduced risk of mortality. Other reasons for the divergent results could be due to the Acknowledgments heterogeneity in the relative frequency of the APOE ε4 allele among ethnic/racial groups, as well as methodological +e authors wish to acknowledge and thank Dr. Philip Garry issues including selection bias and inadequate adjustment who served as the Principal Investigator of the NMAPS and for confounders, which can all potentially inﬂuence study originally collected the data for APOE genotypes used in this results [49]. analysis. +is study was conducted within the New Mexico +is study has several potential limitations. 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Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2018 Duke Appiah and Richard N. Baumgartner. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 2090-2204
eISSN: 2090-2212
DOI: 10.1155/2018/6037058
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Abstract

Hindawi Journal of Aging Research Volume 2018, Article ID 6037058, 7 pages https://doi.org/10.1155/2018/6037058 Research Article The Influence of Education and Apolipoprotein ε4 on Mortality in Community-Dwelling Elderly Men and Women 1 2 Duke Appiah and Richard N. Baumgartner Department of Public Health, Texas Tech University Health Sciences Center, 3601 4th Street, STOP 9403, Lubbock, TX 79430, USA Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray St., Louisville, KY 40202, USA Correspondence should be addressed to Duke Appiah; duke.appiah@ttuhsc.edu Received 16 September 2017; Accepted 7 February 2018; Published 25 March 2018 Academic Editor: Kathryn Peri Copyright © 2018 Duke Appiah and Richard N. Baumgartner. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We investigated the risk of death in relation to the apolipoprotein ε4 allele and evaluated how it interacts with education in 504 elderly adults (mean age 73 years, 65.3% women) who were enrolled in 1993 into the New Mexico Aging Process Study. During 9 years of follow-up, apolipoprotein ε2 appeared to be associated with a lower risk for all-cause mortality (hazard ratio (HR) � 0.73, 95% conﬁdence interval (CI): 0.30–1.71) compared to apolipoprotein ε3 carriers in models adjusted for age, sociodemographic variables, medical conditions, adiposity, and lifestyle factors. +e apolipoprotein ε4 allele conferred almost a threefold elevated risk of mortality (HR � 2.76, CI: 1.42–5.37). An interaction between education and apolipoprotein e4 (p � 0.027) was observed with the HR of mortality among e4 carriers compared to noncarriers being 1.59 (0.64–3.96) for those with≥college education; 6.66 (1.90–23.4) for those with some college or trade; and 14.1 (3.03–65.6) for participants with≤high school education. No signiﬁcant interaction was identiﬁed between apolipoprotein E genotype and cognitive function for mortality risk. +ese ﬁndings suggest that genetic (apolipoprotein ε4) and environmental (education) factors act interactively to inﬂuences survival in the elderly with higher education attenuating the adverse eﬀect of apolipoprotein ε4 on mortality. Alzheimer’s and cardiovascular disease, two conditions that 1. Introduction in themselves are among the most prevalent causes of Apolipoprotein E(APOE),with regardtolongevity, can besaid mortality in the elderly, resulting in survival bias with re- to be the most extensively studied gene [1]. APOE, a 299 amino duced frequency of the e4 allele in persons aged 65 and older acid plasma protein with its gene found on chromosome 19, [8]. Additionally, secular trends and geographic variation in plays a central role in lipid transport and metabolism and also the rates of the aforementioned chronic diseases suggest that possesses several immunomodulatory properties such as the risk of death conferred by APOE genotype may depend suppressing lymphocytic Tcell proliferation [2–4]. It has three on complex interactions with various environmental or polymorphisms: ε2, ε3, and ε4 with the later being associated behavioral risk factors over the lifespan of an individual. In with increased susceptibility for several chronic diseases as well this regard, numerous reviews have raised the issue that as mortality [5–7], while ε2 has been suggested to have most studies assessing the eﬀect of APOE across populations a protective eﬀect, compared to ε3 [8]. and time ignore the eﬀects of behavioral factors that pre- Reports on the association of APOE allelic variation with disposes people to disease [1]. mortality has been equivocal with diﬀerences in estimates A large body of research has demonstrated a positive observed among diﬀerent ethnic/racial populations [9–13]. association of educational attainment with better health Some of the possible explanations for the inconsistent results outcomes [14, 15] as well as reduced mortality [16]. Ac- across studies is that APOE ε4 allele is associated with cordingly, over the last decades, reports from numerous 2 Journal of Aging Research school, college degree, some grad school, masters degree, and studies allude to a gene-environment interaction between APOE genotype and education on health outcomes, namely, doctorate. Other covariates of interest were sex, marital status, body mass index (BMI), bone mineral density, smoking status, dementia [17], brain structure and development [18, 19], and cognitive function [20–22]. However, observations con- diastolic blood pressure, and levels of total cholesterol and cerning the possible modifying eﬀect of educational status triglyceride. BMI was calculated by dividing weight in kilo- on mortality in the elderly, independent of chronic grams by the square of height in meters. Bone mineral density comorbidities, are limited. +erefore, we aimed to evaluate was measured by Lunar DPX DXA (GE/Lunar Radiation whether educational status would oﬀset the adverse inﬂu- Corp., Madison, WI). Chronic conditions including cancer, ence of the APOE ε4 allele on mortality among community- nonvertebral or vertebral fracture, diabetes, ischemic heart dwelling elderly adults. disease, and cerebrovascular disease were all self-reported at each annual visit, veriﬁed against medical records, and coded according to the International Classiﬁcation of Diseases, Ninth 2. Materials and Methods Revision (ICD-9) codes. ICD-9 codes used were 140–208 for cancer; 250 for diabetes (or fasting blood glucose lev- +e New Mexico Aging Process Study (NMAPS) was a longitudinal study conducted between 1979 and 2001 in el≥ 7 mmol/L); 290, 294, and 331 for dementia; 430–438 for Albuquerque, NM, to describe the nutritional status and cerebrovascular disease; 410–414 and 428–429 for ischemic factors associated with healthy aging in community-dwelling heart disease; and 800–829 nonvertebral or vertebral fracture. elderly persons. +e study design, subject recruitment, and Deaths were ascertained using the National Death Index and inclusion and exclusion criteria have been described in detail veriﬁed whenever possible against state death certiﬁcates and previously [23]. Brieﬂy, to be enrolled in the study, a person local obituary reports. had to be 60 years and older and have no preexisting medical conditions such as cancer (with the exception of non- 2.1. Statistical Analysis. Diﬀerences in baseline characteris- melanoma skin cancer), recent myocardial infarction, type 2 diabetes mellitus, chronic obstructive pulmonary disease, or tics by APOE genotype were assessed using chi-square for categorical variables and ANOVA for continuous variables uncontrolled hypertension. About 90% of participants were non-Hispanic whites, 8% of Hispanic origin, and close to 2% that were normally distributed or the Kruskal–Wallis test for being nonwhite. An annual visit was required for all par- nonnormally distributed variables. In time-to-event analysis, ticipants in whom blood samples were obtained, and body the Kaplan–Meier method was used to evaluate the incidence composition, physical, functional, cognitive, and nutritional of all-cause mortality in relation to APOE genotype groups status were assessed. +e yearly dropout rate for the study with the censoring date being December 31, 2002. Attained was approximately 3.6% with major chronic conditions and age was used as the time scale for all analyses as this procedure migration out of Albuquerque being the main reasons. +e oﬀers the opportunity to account for the eﬀect of survival bias study was approved by the Human Subjects Research Review (thus individual with the highest risk of mortality are not observed) [28]. Furthermore, the use of attained age as the Committee of the University of the New Mexico School of Medicine with all participants providing informed consent time scale provides a more straight-forward interpretation of mortality since it is free of the confounding eﬀect of age which in accordance with the Declaration of Helsinki, and all methods were carried out in accordance with the relevant is intrinsically taken into account as a measure of survival guidelines and regulations. Participants who were alive at time [29]. Survival curves were then produced to graphically 1993, were followed up for 9 years (median, 7 years), and had depict incident events with diﬀerences among groups genotype data together with measures of cognitive function assessed by means of the log-rank test. Adjusted hazard ratios were included in the current analysis. (HRs) and 95% conﬁdence intervals (CIs) for mortality were APOE genotypes were assessed by restriction fragment calculated using Cox proportional hazards regression. Four models with progressive adjustments were used. Model 1 was length polymorphism analysis of polymerase chain reaction products, as previously developed [24, 25]. +e assays were adjusted for demographic variables such as age, sex, educa- tion, and marital status. Model 2 comprised model 1 with conducted in the Aging and Genetic Epidemiology (AGE) laboratory [23]. Of the 577 individuals who participated at further adjustment for levels of triglyceride, BMI, bone mineral density, and diastolic blood pressure. Model 3 further baseline, 519 had APOE genotyped successfully. To distin- guish unambiguously the eﬀect of the APOE allele and adjusted for psychological factors such as scores on both the genotype, we further excluded participants with APOE 2/4 Geriatric Depression Scale and the Modiﬁed Mini-Mental (n � 15), resulting in an analytic sample of 504 participants. State Examination. Finally, model 4 also adjusted for incident Cognitive function was evaluated by using the modiﬁed medical conditions, including all cancers, nonvertebral or version of the Mini-Mental State Examination (3MS) [26]. vertebral fractures, diabetes, ischemic heart disease, and Depression was measured using the short form of the Ge- cerebrovascular disease. APOE status was identiﬁed with dummy coded indicator variables with the 3/3 genotype used riatric Depression Scale [27], with a score of 5 or higher suggestive of depressive symptomatology. as the referent. Interactions of APOE ε4 allele and educational as well as other statistically signiﬁcant covariates on the risk of Educational status was assessed using a questionnaire with possible responses being less than 12 years of education mortality were explored using the likelihood ratio test to compare models with and without the interaction terms. +e (high school), high school graduate or passed the tests of general educational development, some college or technical assumptionof proportionalhazards wasassessed bygraphical Journal of Aging Research 3 Table 1: Baseline characteristics of participants in the New Mexico Aging Process Study. Apolipoprotein E genotype group Characteristics p value APOE 2 carriers (N � 71) APOE 3/3 (N � 336) APOE 4 carriers (N � 97) Age, years 73.8 (6.4) 73.5 (6.5) 72.4 (5.8) 0.261 Sex, % 0.110 Male 45.1 32.1 36.1 Female 54.9 67.9 63.9 Education, % 0.642 High school or less 16.9 17.2 15.5 Some college or trade 36.6 28.3 27.8 College degree or higher 46.9 54.5 56.7 Marital status, % 0.160 Single 30.4 42.9 40.4 Married 69.6 57.1 59.6 Current smoker, % 7.3 3.9 3.2 0.361 Depressive symptoms, % 4.2 4.5 4.1 0.988 Diastolic blood pressure (mmHg) 80.4 (10.2) 79.5 (11.3) 79.5 (10.8) 0.805 Total cholesterol (mmol/l) 5.10 (0.75) 5.47 (0.93) 5.49 (1.04) 0.008 Triglycerides (mmol/l) 1.61 (0.82) 1.62 (0.99) 1.55 (0.86) 0.820 Body mass index (kg/m ) 25.4 (3.49) 25.5 (4.01) 24.7 (3.91) 0.252 Waist to hip ratio 0.92 (0.11) 0.88 (0.1) 0.89 (0.11) 0.062 Bone mineral density 1.10 (0.13) 1.07 (0.12) 1.09 (0.11) 0.145 Mini-Mental State Exam scores 94.6 (4.91) 95.2 (4.28) 94.1 (5.73) 0.107 Medical conditions at follow-up Diabetes 4.2 3.3 4.1 0.817 Fractures 12.7 13.4 11.3 0.867 Cancers 5.6 12.5 15.5 0.144 Ischemic heart disease 7.0 7.4 10.3 0.626 Cerebrovascular disease 5.6 4.5 9.3 0.190 Deceased at the end of study 9.9 11.0 17.5 0.183 Values are mean (standard deviation) for continuous variables and percentages for categorical variables; p values based on the chi-square test for categorical variables and ANOVA for normally distributed continuous variables or the Kruskal–Wallis test for nonnormally distributed continuous variables. methods using Schoenfeld residuals. To assess the robustness common genotype was APOE 3/3 found in 66.7% of par- of the estimates, we performed a sensitivity analysis which ticipants with 13.9% and 18.1% having ε2/3 and ε3/4 geno- included information for the 15 participants with APOE ε2/4. types, respectively. Additionally, only 19.2% of participants had at least one ε4 allele. +ese percentages are consistent A two-tailed probability value less than 0.05 was considered statistically signiﬁcant, and all analyses were performed using with other prospective population studies among the el- SAS software, version 9.4 (SAS Institute, Inc., Cary, NC) derly, especially those 60 years and older. As expected, total cholesterol levels varied across APOE genotype groups (p � 0.01) with APOE ε2 carriers having the lowest for trend 3. Results levels of total cholesterol. +e mean age of participants at baseline was 73.4 (range During follow-up, 61 (12%) deaths were recorded with 61–91) with 65.3% being women. Approximately half of the fatal events occurring twice as often in men than women. participants reported having a college degree or higher and Figure 1 shows unadjusted Kaplan–Meier cumulative in- only 11.3% had a BMI of 30 or higher. Nearly 5% of the cohort cidence estimates for all-cause mortality according to APOE was identiﬁed as having depressive symptomatology in- genotype and allele. +e log-rank statistic suggests that APOE dicative of depression, and less than 2% of participants were genotype and allele inﬂuenced mortality, with APOE ε4 classiﬁed as having dementia. Several diﬀerences in baseline carriers having a signiﬁcantly higher number of deaths. In multivariable models (Table 2), participants with the APOE characteristics were observed between men and women. Men were more likely than women to be older and have higher ε4/ε4 genotype had a greater risk of mortality (HR � 2.56, 95% CI: 1.33–4.94) compared to persons homozygous for ε3 allele bone mineral density and higher body weight, with a signif- icantly greater proportion reporting having graduated from (model 3). APOE ε4 carriers had a twofold elevated risk of college (66.3% versus 47.1%), currently married (86.2% mortality compared to non-APOE ε4 carriers (HR � 2.21, versus 44.9%), diagnosed with ischemic heart disease (14.3% 95% CI: 1.20–4.09). +ese estimates increased in magni- versus 4.6%), and cancer (16% versus 10%). Women were tude after further adjustment for chronic medical condi- more likely to have higher levels of total cholesterol and tions yielding hazard ratios of 2.61(CI: 1.33–5.14) and 2.76 triglyceride with a signiﬁcantly greater proportion reporting (CI: 1.42–5.37) for APOE ε4/ε4 genotype and e4 allele fractures (15.5% versus 8%). A description of the cohort carriers compared to persons homozygous for ε3 allele and according to APOE genotype is shown in Table 1. +e most non-APOE ε4 carriers, respectively. 4 Journal of Aging Research 100 100 80 80 60 60 p = 0.011 40 40 p = 0.005 20 20 0 0 65 70 75 80 85 90 95 100 65 70 75 80 85 90 95 100 Attained age (years) Attained age (years) APOE genotype APOE e4 allele APOE 3/3 Noncarrier APOE 2/2, 2/3 Carrier APOE 3/4, 4/4 (a) (b) Figure 1: Kaplan–Meier cumulative incidence estimates for all-cause mortality by (a) APOE genotype and (b) APOE ε4 allele. Table 2: APOE genotype and allele as predictors of all-cause mortality. Unadjusted Model 1 Model 2 Model 3 Model 4 Apolipoprotein E genotype APOE ε3/3 1 1 1 1 1 APOE ε2/2, 2/3 0.80 (0.34–1.80) 0.73 (0.32–1.65) 0.73 (0.32–1.68) 0.75 (0.32–1.74) 0.73 (0.31–1.71) APOE ε3/4, 4/4 2.38 (1.33–4.26) 2.34 (1.30–4.36) 2.53 (1.35–4.73) 2.56 (1.33–4.94) 2.61 (1.33–5.14) Apolipoprotein E allele APOE ε4 noncarrier 1 1 1 1 1 APOE ε4 carrier 1.99 (1.17–3.38) 2.20 (1.25–3.86) 2.26 (1.24–4.13) 2.21 (1.20–4.09) 2.76 (1.42–5.37) Model 1: adjusted for age, sex, education, and marital status; model 2: model 1 plus levels of triglyceride, body mass index, bone mineral density, and diastolic blood pressure; model 3: model 2 plus Geriatric Depression Scale and the Modi ed Mini-Mental State Examination scores; model 4: model 3 plus incident medical conditions occurring during follow-up (cancers, nonvertebral or vertebral fractures, diabetes, ischemic heart disease, and cerebrovascular disease). Educational status appeared to be negatively associated important confounders. However, this elevated mortality risk with mortality with persons who had college education or was oŽset by higher educational status. To our knowledge, this more having lower risk of mortality compared to participants is the rst study to report that APOE (genetic factor) and with high school education or less (HR 0.79, 0.35–1.76). education (environmental factor) act interactively to in- Howbeit, this did not approach statistical signi cance. Finally, ’uences survival in the elderly. we observed a signi cant interaction between educational While the underlying mechanism by which education status and APOE ε4 allele on the risk of mortality (p 0.027). ameliorates the in’uence of APOE genotype on mortality †e HR of mortality among ε4 carriers compared to non- among elderly adults is a topic of major interest, it is not fully carriers was 1.59 (0.64–3.96) for those with ≥college educa- understood. It is possible that education may exert some tion; 6.66 (1.90–23.4) for those with some college or trade; and bene cial eŽects on survival through two main avenues. †at 14.1 (3.03–65.6) for participants with ≤high school education. is, either through increased socioeconomic resources over the No signi cant interaction was identi ed between APOE life course that could aid in the prevention of chronic diseases genotype and cognitive function for mortality risk. †ese or through neuroprotective mechanism involved in reducing results remained unchanged when information from the 15 age-related or pathological changes in the structure and participants with APOE ε2/4 was included in the analysis, and function of the brain which in the long term might in’uence APOE ε2/4 was not signi cantly associated with mortality longevity [30, 31]. On the one hand, higher education, more which could possibly be attributed to the small sample size often than not, provides numerous resources such as higher (data not shown). income, stable employment, better social networks, health- related self-e˜cacy, and access to safe neighborhoods [32]. Accordingly, a large body of evidence has shown that higher 4. Discussion educational attainment, whether measured as years of edu- In this community-based sample of elderly adults, we ob- cation or degree completion, is associated with reduced in- served that the APOE ε3/4 and ε4/4 genotypes were associated cidence of chronic morbidities [33], delayed mortality [34], with higher incidence of all-cause mortality, independent of and improved overall health primarily due to better access Incidence (%) Incidence (%) Journal of Aging Research 5 persons who were predominantly Caucasians and gener- and utilization of health care and the adaption of health- promoting behaviors and lifestyles [14]. ally in good health. +us, the results may not be generalizable to other ethnic/racial groups or elderly community-dwelling On the other hand, education may moderate the ex- pression of the APOE ε4 allele on the risk of mortality in the persons. Second, not all participants enrolled in the study elderly by inﬂuencing age-related or pathological changes in consented to give blood for genotyping. Although such brain-matter and cognitive reserve. Some [35], but not all participants were older, there was no diﬀerence with respect [36, 37], neuroimaging studies of cognitively healthy elders to mortality and chronic medical conditions between those have found higher education to be associated with low ac- who did and did not have genotype data. In any case, the eﬀect cumulation of amyloid-beta deposition [38]; physiologically of any diﬀerence on our results cannot be estimated. Because the distribution of APOE genotype was similar to that re- increasing regional cortical thickness [39]; increasing white and gray matter volume [35] in the superior temporal gyrus, ported in other prospective cohort studies of elderly persons, we believe that our results are not seriously biased. +ird, the insula, and anterior cingulate cortex [18]; decreasing mean diﬀusivity in the bilateral hippocampus [40]; and inﬂuencing sample size of the cohort was relatively smaller, and with the occurrence of fatal events not being common, the statistical a greater metabolism in the anterior cingulate cortex [18]. Furthermore, higher education is reported to be positively power to detect very weak associations is limited. None- related with anterior cingulate connectivity which in turn is theless, the associations detected were strong and statistically associated with improved cognitive performances [18]. +ese signiﬁcant. Finally, we did not observe any eﬀect modiﬁcation results and several others provide profound evidence that of chronic ailments such as cancer, impaired cognitive brain and cognitive reserve delays the clinical manifestations function, diabetes, ischemic heart disease, and cerebrovas- of dementia [18]. Compared to persons without the APOE ε4 cular disease with APOE genotype on longevity. +is may primarily be due to the low prevalence of these conditions in variant, those with two copies of the ε4 variant are known to have more than a sevenfold elevated risk of developing our cohort. Serious chronic medical conditions were the main reason for dropout from the NMAPS, followed by migration. Alzheimer’s disease [38], the 6th leading cause of mortality in the United States. Taken together, these results and that of the However, persons who dropped out still contributed in- formation to the analysis since they were censored at the last present study suggest that higher education may oﬀset the negative eﬀects of the APOE ε4 on mortality by increasing date known to be alive. Also, follow-up for mortality status in cerebral reserve capacity against Alzheimer’s disease and the cohort was nearly complete. Nonetheless, it remains other late-life cognitive-related diseases. Even among elderly possible that these medical conditions may play a moderating adults with Alzheimer’s disease, a history of higher education role in the relationship between APOE and mortality. has been reported to aid in coping better with the eﬀects of In summary, we observed that APOE ε4 allele is positively brain atrophy by increasing cognitive reserve [39]. related to mortality risk with this elevated mortality oﬀset by higher educational status; however, the mechanism un- +ere is a strong, positive, and well-documented relation between APOE genotype and morbidity and mortality, and derlying this association is not fully understood. Discovering candidate genes that inﬂuence longevity has great public our results are consistent with some [12, 41–46] but not other studies [2, 8–11, 13, 47, 48] conducted among the elderly. For health importance. With almost 15% of the general pop- instance, the Cache County study with 4701 participants aged ulation known to have the APOE ε4 variant and this pro- 65 and older found a greater mortality risk in persons carrying portion increasing to about 40% among persons with the ε3/4 and ε4/4 genotype which persisted even after ac- Alzheimer’s disease [38], the moderating eﬀects of education, counting for the eﬀect of Alzheimer’s and cardiovascular lifestyle, and behavioral factors on genes should be studied to disease [42]. One of the several reasons for the diverging achieve a better understanding of their inﬂuence on longevity. results for APOE and mortality may pertain to small samples. +is will go a long way to aid in targeting interventions to- +e improvement in statistical power oﬀered by studies with wards high-risk individuals which will in turn reduce mor- bidity and improve longevity as well as quality of life among longer follow-up, such as the NMAPS, is important because thereis agreaterchance of identifyingan eﬀectif ittruly exists. such persons. +e Rotterdam study which followed 6852 participants for a mean of 5.4 years [47] did not identify any association Conflicts of Interest between APOE genotype and longevity. However, after follow-up was extended to a mean of 11.1 years [4], with +e authors declare that there are no conﬂicts of interest improved risk factor adjustments, APOE ε2 carriers with regarding the publication of this article. normal weight were found to have a reduced risk of mortality. Other reasons for the divergent results could be due to the Acknowledgments heterogeneity in the relative frequency of the APOE ε4 allele among ethnic/racial groups, as well as methodological +e authors wish to acknowledge and thank Dr. Philip Garry issues including selection bias and inadequate adjustment who served as the Principal Investigator of the NMAPS and for confounders, which can all potentially inﬂuence study originally collected the data for APOE genotypes used in this results [49]. analysis. +is study was conducted within the New Mexico +is study has several potential limitations. 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The Influence of Education and Apolipoprotein ε4 on Mortality in Community-Dwelling Elderly Men and Women

The Influence of Education and Apolipoprotein ε4 on Mortality in Community-Dwelling Elderly Men and Women

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The Influence of Education and Apolipoprotein ε4 on Mortality in Community-Dwelling Elderly Men and Women

The Influence of Education and Apolipoprotein ε4 on Mortality in Community-Dwelling Elderly Men and Women

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