APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study

Neurobiology of Aging 33 (2012) 832.e15– 832.e22 www.elsevier.com/locate/neuaging

APOE ␧4 differentially influences change in memory performance depending on age. The SMART-MR study Hadassa M. Jochemsena, Majon Mullera,b, Yolanda van der Graafa, Mirjam I. Geerlingsa,* a

University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht, the Netherlands b VU University Medical Center Amsterdam, Department of Internal Medicine, Amsterdam, the Netherlands Received 10 May 2011; received in revised form 11 July 2011; accepted 28 July 2011

Abstract The apolipoprotein E (APOE) gene may act differently in young and old persons, known as antagonistic pleiotropy. We therefore examined the prospective associations between the APOE ␧4 allele and cognitive functioning, and the modifying effect of age, in 375 nondemented adults (mean age 57 ⫾ 10 years; follow-up period 3.8 ⫾ 0.2 years) with available data on APOE genotype and cognitive functioning, within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) cohort study. Neuropsychological tests assessing memory performance and executive functioning were performed at baseline and follow-up, and composite z-scores were calculated. Age significantly modified the association of APOE ␧4 with change in memory performance (p interaction ⫽ 0.02). In persons ⱕ 57 years (median split), an APOE ␧4 allele was associated with an increase in immediate recall (B ⫽ 0.42; 95% confidence interval [CI], 0.17 to 0.66) and delayed recall (B ⫽ 0.37; 95% CI, 0.09 to 0.64), while in persons ⬎ 57 years, an APOE ␧4 allele was associated with decline in immediate recall (B ⫽ ⫺0.25; 95% CI, ⫺0.52 to 0.01). Our findings suggest that the APOE ␧4 allele has a differential effect on change in verbal memory performance depending on age, consistent with the hypothesis of antagonistic pleiotropy. © 2012 Elsevier Inc. All rights reserved. Keywords: Antagonistic pleiotropy; Cognition; Memory performance; APOE ␧4 allele; Age; Cohort

1. Introduction The apolipoprotein E (APOE) ␧4 allele is a well known genetic risk factor for Alzheimer’s disease (AD) (Farrer et al., 1997). However, some studies indicate that the APOE ␧4 allele might have a beneficial effect on cognitive performance at younger age (Alexander et al., 2007; Mondadori et al., 2007; Wright et al., 2003). It could therefore be an example of antagonistic pleiotropy (Schultz et al., 2008), which means that a gene may have beneficial effects at younger age, but deleterious effects later in life (Albin, 1993). Numerous longitudinal studies in older, cognitively impaired people showed that possession of an APOE ␧4 * Corresponding author at: University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Stratenum 7.128, PO Box 85500, 3508 GA Utrecht, the Netherlands. Tel.: ⫹31 (0)88 755 9394; fax: ⫹31 (0)88 755 5485. E-mail address: [email protected] (M.I. Geerlings). 0197-4580/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2011.07.016

allele is associated with cognitive decline (Dik et al., 2000; Farlow et al., 2004) and an increased risk to develop AD (Bondi et al., 1999; Corder et al., 1993). In cognitively healthy older people, the effect of the APOE ␧4 allele on cognitive functioning is less consistent, with some studies showing no association and others showing a worse performance in APOE ␧4 carriers (Bunce et al., 2004; Caselli et al., 2009; Honea et al., 2009; Kim et al., 2002; Small et al., 2004). Moreover, some studies in young adults and children have found evidence of better cognitive performance in APOE ␧4 carriers (Alexander et al., 2007; Mondadori et al., 2007; Wright et al., 2003) although these studies are few and some also found no association (Bloss et al., 2008; Deary et al., 2002). However, prospective data on the association of APOE ␧4 with cognitive decline in a population with a wide age range are scarce (Kozauer et al., 2008). To further investigate this phenomenon of antagonistic pleiotropy, the objective of this study was to examine the

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prospective association between APOE ␧4 and change in cognitive functioning in a cohort of nondemented adults with a wide age range, and to examine the modifying effect of age in this relationship. We hypothesized that APOE ␧4 was associated with better cognitive functioning over time in younger subjects, and with worse cognitive functioning in older subjects.

2. Methods 2.1. SMART-MR study Data were used from the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) study, a prospective cohort study aimed to investigate brain changes on magnetic resonance imaging (MRI) in 1309 independently living persons with symptomatic atherosclerotic disease (Geerlings et al., 2010; Muller et al., 2011). In brief, between May 2001 and December 2005, all persons newly referred to the University Medical Center Utrecht (UMCU) with manifest coronary artery disease, cerebrovascular disease, peripheral arterial disease, or an abdominal aortic aneurysm, and without magnetic resonance (MR) contraindications were invited to participate. Coronary artery disease was defined as myocardial infarction, coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty in the past or at inclusion. Patients with a transient ischemic attack or stroke at inclusion and patients who reported stroke in the past were considered to have cerebrovascular disease. Peripheral arterial disease was defined as surgery or angioplasty of the arteries supplying the lower extremities in history or intermittent claudication or rest pain at inclusion. Abdominal aortic aneurysm (AAA) was defined as present AAA (distal aortic diameter ⱖ 3 cm) or previous AAA surgery. During a 1-day visit to our medical center, an MRI of the brain was performed, in addition to a physical examination, ultrasonography of the carotid arteries, and blood and urine sampling. Risk factors, medical history, and functioning were assessed with questionnaires that the persons completed before their visit to the medical center. Neuropsychological testing was introduced in the SMART-MR study starting in January 2003 and was performed on the same day as the MRI and other investigations, and was available in 831 of the 1309 persons. Between January 2006 and May 2009, all participants still alive were invited for follow-up measurements. The SMART-MR study was approved by the ethics committee of the UMCU and written informed consent was obtained from all participants. 2.2. Study sample Of the 831 persons, APOE genotyping was performed in all persons included between January 2003 and April 2005 (n ⫽ 671). Of these, 378 (59% of the persons still alive) participated in the follow-up examination. Three persons

with dementia (see below) were excluded. As a result, the prospective analyses were performed in 375 persons. Compared with these 375 persons, the 296 persons excluded from the present analyses were, at study entry, on average older (mean age [SD]: 60 [10] vs. 57 [10] years; p ⫽ 0.001), more often female (26% vs. 20%; p ⫽ 0.041), had higher systolic and diastolic blood pressure levels (respectively 149 [25] vs. 142 [20] mm Hg; p ⬍ 0.001; and 85 [12] vs. 83 [11] mm Hg; p ⫽ 0.021), more often had hyperlipidemia (82% vs. 75%; p ⫽ 0.021) and diabetes mellitus (24% vs. 14%; p ⫽ 0.001), had poorer global cognitive performance (z-score global cognitive functioning: ⫺0.29 [1.08] vs. 0.19 [0.87]; p ⬍ 0.001), and were somewhat more often APOE ␧4 carriers, although not statistically significant (37% vs. 31%; p ⫽ 0.076). 2.3. APOE genotype DNA was isolated from 10 mL of ethylenediaminetetraacetic acid (EDTA) (citrate)-augmented blood stored at ⫺80 °C, and amplified with polymerase chain reaction (PCR). To determine the APOE genotype (APOE ␧2, ␧3, and ␧4 alleles) 2 single-nucleotide polymorphisms (SNPs: National Center for Biotechnology Information (NCBI) SNPs rs7412 and rs429358) were genotyped. Genotyping was performed with the 5= nuclease/Taqman assay (Applied Biosystems, Foster City, CA, USA) (Livak, 1999). Polymerase chain reactions with fluorescent allele-specific oligonucleotide probes (Applied Biosystems, Foster City, CA, USA) were performed on a PTC-225 thermal cycler (Biozym, Hessisch Oldendorf, Germany), and fluorescence end point reading for allelic discrimination was performed on an ABI 7900 HT (Applied Biosystems 7900 highthroughput). Genotyping for APOE was performed on coded DNA specimens without knowledge of the diagnosis. 2.4. Cognition and dementia Cognitive functioning was assessed with a set of standard neuropsychological tests, sensitive to mild impairments. Verbal memory was assessed with the 15-word learning test, a modification of the Rey Auditory Verbal Learning test (Brand and Jolles, 1985). In 5 consecutive trials immediate recall was assessed and after 20 minutes delayed recall was assessed. Visual memory was assessed with the Rey-Osterrieth Complex Figure delayed recall test in which the recall of a complex figure, copied 30 minutes before, is requested (Rey, 1941). A composite score for memory performance at baseline was calculated by averaging the z-scores (individual test score minus mean test score divided by the standard deviation of that score) for the mean score of the 5 trials of the immediate recall, the z-score for the delayed recall, and the z-score for the Rey-Osterrieth Complex Figure delayed recall test. A composite score for memory performance at follow-up was calculated by averaging the z-scores (individual follow-up test score minus mean baseline test

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score divided by the standard deviation of the baseline test score) for the 3 memory tests. Executive functioning was assessed with 3 tests. The Visual Elevator Test, a subtest of the Test of Everyday Attention, is a timed test of 10 trials that measure mental flexibility and shifting of attention (Robertson et al., 1994). The timing score of the Visual Elevator test is equivalent to time per switch for correct items (seconds per switch). The Brixton Spatial Anticipation test was used to assess the capacity to discover logical rules and mental inhibition and flexibility. The total number of errors made was scored (Burgess and Shallice, 1996). The letter Verbal Fluency test (letter N at baseline and A at follow-up) was used in a 1-minute time frame to assess mental flexibility and employment of strategies (Lezak, 1995). Before calculating the z-score, the scores of the Visual Elevator test and Brixton Spatial Anticipation test were multiplied by ⫺1, so that lower scores represented poorer performance. The composite score for executive functioning at baseline was calculated by averaging the z-score (individual test score minus mean test score divided by the standard deviation of that score) for the Visual Elevator test—timing score, the z-score for the Brixton Anticipation test, and the z-score for the letter Verbal Fluency test. A composite score for executive functioning at follow-up was calculated by averaging the z-scores (individual follow-up test score minus mean baseline test score divided by the standard deviation of the baseline test score) for the 3 executive functioning tests. General cognitive functioning at follow-up was assessed with the Mini Mental State Examination (MMSE), and participants with a score ⬍ 27 were examined by a physician who conducted an additional in-house standardized dementia interview and physical examination. These results, together with the outcome of the neuropsychological testing were discussed in a consensus meeting with a geriatrician to diagnose dementia. 2.5. Covariates An overnight fasting venous blood sample was taken to determine glucose and lipid levels. Height and weight were measured without shoes and heavy clothing, and body mass index was calculated (weight [kg]/height [m2]). Systolic and diastolic blood pressure (mm Hg) were measured twice in sitting position with a sphygmomanometer, and the average was obtained. Diabetes mellitus was defined as a glucose level of ⱖ 7.0 mmol/L or use of oral antidiabetic drugs or insulin. Hyperlipidemia was defined as total cholesterol ⬎ 5.0 mmol/L, low-density lipoprotein cholesterol ⬎ 3.2 mmol/L or use of lipid lowering drugs. Smoking habits and alcohol intake were assessed by using questionnaires. Packyears of smoking were calculated as the average number of cigarettes smoked per day divided by 20 and then multiplied by the number of years of cigarette smoking. Alcohol intake was divided into 3 categories: never, former, and current. Persons who had quit drinking during the past year were

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assigned to the category current alcohol intake. Premorbid intellectual functioning was assessed using the Dutch version of the National Adult Reading Test (DART) in which persons had to read out loud a list of words with irregular pronunciation (Schmand et al., 1998). Highest attained level of education was assessed with 7 categories, graded from primary school to academic degree, according to the Dutch educational system. 2.6. Data analysis First, baseline characteristics were calculated for the total study population and for APOE ␧4 categories (1 or 2 ␧4 alleles vs. no ␧4 allele). Second, linear regression analysis was used to investigate the prospective associations between APOE genotype (1 or 2 ␧4 alleles vs. no ␧4 allele) and change in measures of cognitive functioning by using cognitive z-scores at follow-up as dependent variable and cognitive z-scores at baseline as independent variable. We adjusted for age, sex, education, the DART score, follow-up time, systolic and diastolic blood pressure, hyperlipidemia, diabetes mellitus, body mass index, packyears of smoking, and alcohol intake. To assess the modifying effect of age on the relation between APOE ␧4 and change in cognitive function, we added interaction terms between APOE ␧4 and age (as a continuous variable) with the z-score of memory and the z-score of executive functioning. If the interaction term was statistically significant (p ⬍ 0.05), we repeated the interaction terms with the z-scores for the individual cognitive tests. If the regression analyses revealed a significant interaction between APOE ␧4 and age, we associated APOE ␧4 with change in cognitive functioning (z-scores and crude scores for the individual tests) within strata of age (median split: age ⱕ 57 and ⬎ 57 years old). Furthermore, predicted values for change in immediate recall and delayed recall (crude scores for the individual tests: number of words) for carriers and noncarriers were plotted with a regression model including age, APOE ␧4, the interaction between age and APOE ␧4, sex, education, DART score, and vascular risk factors. Because the ␧2 allele might have a beneficial effect on cognitive function (Blacker et al., 2007), we repeated the analyses after exclusion of persons with ␧2␧4 genotype (n ⫽ 7). Finally, because some persons may have impaired cognition, the analyses were repeated after exclusion of persons with an MMSE ⬍ 27 (n ⫽ 15). Because missing data on covariates were few (n ⫽ 27) we performed complete case analysis. In all analyses, we report 95% confidence intervals (CI). The statistical package SPSS version 17.0 (Chicago, IL, USA) was used to analyze the data. 3. Results At baseline, the mean (SD, range) age of the study population was 57 (10, 27–79), 80% was male, and 31%

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Table 1 Baseline characteristics for categories of APOE ␧4 genotype and the total population Characteristics

No APOE ␧4 allele (n ⫽ 259)

1 or 2 APOE ␧4 alleles (n ⫽ 116)

Total population (n ⫽ 375)

Agea Male gender, n (%) Educationb DART scoreb Hyperlipidemia, n (%) Diabetes mellitus, n (%) Systolic blood pressure (mm Hg)a Diastolic blood pressure (mm Hg)a Body mass index, kg/m2a Smoking (pack-years)b Current alcohol use, n (%)

58 ⫾ 10 209 (81) 4 (1, 6) 82 (56, 97) 191 (75) 35 (14) 143 ⫾ 20 84 ⫾ 11 27 ⫾ 3 16 (0, 48) 201 (78)

56 ⫾ 9 92 (79) 3 (2, 6) 80 (63, 97) 87 (75) 18 (16) 140 ⫾ 20 81 ⫾ 11 26 ⫾ 3 20 (0, 46) 89 (77)

57 ⫾ 10 301 (80) 3 (2, 6) 82 (58, 97) 278 (75) 53 (14) 142 ⫾ 20 83 ⫾ 11 27 ⫾ 3 19 (0, 48) 290 (78)

Key: APOE, apolipoprotein E; DART, Dutch version of the national Adult Reading Test (range 0 –100). a Mean ⫾ SD. b Median (10th, 90th percentile).

(n ⫽ 116) of the persons carried 1 or more APOE ␧4 alleles, of which 92% (n ⫽ 107) had 1 APOE ␧4 allele and 8% (n ⫽ 9) had 2 APOE ␧4 alleles. Table 1 shows the baseline characteristics of the study sample according to APOE ␧4 allele status. APOE ␧4 carriers had a somewhat higher risk of nonparticipation in the follow-up examination; the crude odds ratio OR (95% CI) was 1.28 (0.93 to 1.77), and the age-adjusted odds ratio (95% CI) was 1.33 (0.96 to 1.84). After a mean (SD, range) follow-up period of 3.8 (0.2, 3.3– 4.6) years, APOE ␧4 was not associated with a change in memory performance or executive functioning; B (95% CI) were 0.05 (⫺0.07 to 0.18) and ⫺0.04 (⫺0.09 to 0.01), respectively. When an interaction term between APOE ␧4 and age was added to the model, we found that age significantly modified the association of APOE ␧4 with a change in z-score of memory performance (p interaction ⫽ 0.02). When looking at the individual memory tests, age significantly modified the association of APOE ␧4 with change in z-score for immediate and delayed recall (p interaction ⫽ 0.01 and 0.04), but not with change in z-score for visual memory (p ⫽ 0.91) (Table 2). Furthermore, age did not modify the association between APOE ␧4 and change in z-score of executive functioning (p interaction ⫽ 0.55).

Table 3 presents the results of the association of APOE ␧4 with change in memory performance across strata of age (median split: age ⱕ 57 and ⬎ 57 years). In persons ⱕ 57 years (n ⫽ 188), APOE ␧4 was associated with a significant increase in global memory performance and in immediate and delayed verbal recall, after adjusting for age, sex, education, DART score, follow-up time, and vascular risk factors. However, in persons ⬎ 57 years (n ⫽ 187), APOE ␧4 was associated with a decrease in global memory performance, immediate and delayed verbal recall (Table 3). Fig. 1 shows the predicted values for change in immediate recall and delayed recall (number of words) for carriers and noncarriers, adjusted for age, APOE ␧4, the interaction between age and APOE ␧4, sex, education, DART score, and vascular risk factors (Fig. 1A and B). These figures show that APOE ␧4 noncarriers do not considerably change in verbal memory performance during the follow-up period, whereas APOE ␧4 carriers show an improvement of verbal memory compared with noncarriers before their late fifties, and a decline in verbal memory at later age. For instance, at age 40 years APOE ␧4 carriers have a predicted improvement of about 6 words on immediate recall at follow-up, whereas noncarriers show hardly any improvement. On the contrary, at age 75 years APOE ␧4 carriers show a

Table 2 Regression coefficients of the interaction between APOE ␧4 genotype and age in relation to change in memory performance (composite z-score and zscores of individual tests) after 3.8 years of follow-up Change in memory performance (z-scores)

APOE ␧4 allele Age APOE ␧4 ⴱ age p interaction

Memory performance B (95% CI)a

Verbal immediate recall B (95% CI)a

Verbal delayed recall B (95% CI)a

Visual delayed recall B (95% CI)a

0.10 (⫺0.07 to 0.21) ⫺0.01 (⫺0.02 to 0.00) ⫺0.02 (⫺0.04 to ⫺0.00) 0.022

0.10 (⫺0.08 to 0.28) ⫺0.02 (⫺0.03 to ⫺0.01) ⫺0.03 (⫺0.05 to ⫺0.01) 0.007

0.14 (⫺0.05 to ⫺0.33) ⫺0.02 (⫺0.03 to ⫺0.01) ⫺0.02 (⫺0.04 to 0.00) 0.038

0.03 (⫺0.13 to 0.19) ⫺0.01 (⫺0.02 to ⫺0.00) ⫺0.00 (⫺0.02 to 0.02) 0.906

Key: APOE, apolipoprotein E; CI, confidence interval; DART, Dutch version of the national Adult Reading Test. a Adjusted for sex, education, the DART score, follow-up time, baseline cognitive z-score, systolic and diastolic blood pressure, hyperlipidemia, diabetes mellitus, body mass index, pack-years of smoking and alcohol intake.

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Table 3 Association of the APOE ␧4 allele with change in memory performance (composite z-scores, z-scores of the individual tests and crude scores of the individual tests) after 3.8 years of follow-up within strata of age Change in memory performance according to age groups

APOE ␧4 allelea p value

Z-score memory performance B (95% CI)

Z-score verbal immediate recall B (95% CI)

Z-score verbal delayed recall B (95% CI)

ⱕ 57 y (n ⫽ 188)

⬎ 57 y (n ⫽ 187)

ⱕ 57 y (n ⫽ 188)

⬎ 57 y (n ⫽ 187)

ⱕ 57 y (n ⫽ 188)

⬎ 57 y (n ⫽ 187)

0.34 (0.09 to 0.59)

⫺0.16 (⫺0.40 to 0.08)

0.42 (0.17 to 0.66)

⫺0.25 (⫺0.52 to 0.01)

0.37 (0.09 to 0.64)

⫺0.09 (⫺0.35 to 0.17)

0.008

0.193

0.001

0.060

0.010

0.493

APOE ␧4 alleleb p value

Crude score verbal immediate recall B (95% CI)

Crude score verbal delayed recall B (95% CI)

ⱕ 57 y (n ⫽ 188)

⬎ 57 y (n ⫽ 187)

ⱕ 57 y (n ⫽ 188)

⬎ 57 y (n ⫽ 187)

3.96 (1.60 to 6.31)

⫺2.42 (⫺4.94 to 0.10)

1.08 (0.27 to 1.90)

⫺0.27 (⫺1.04 to 0.51)

0.001

0.060

0.010

0.493

Adjusted for age, sex, education, the DART-score, follow-up time, baseline cognitive z-score, systolic and diastolic blood pressure, hyperlipidemia, diabetes mellitus, body mass index, pack-years of smoking and alcohol intake. Key: APOE, apolipoprotein E; CI, confidence interval; DART, Dutch version of the national Adult Reading Test. a Regression coefficients represents the adjusted mean difference in z-score between ␧4 carriers and noncarriers. b Regression coefficients represents the adjusted mean difference in absolute number of words recalled between ␧4 carriers and noncarriers.

predicted decline of about 3 words on immediate recall at follow-up, whereas noncarriers show no decline. Analyses were repeated with exclusion of ␧2␧4 carriers (n ⫽ 7), but the results did not change (data not shown). Finally, after exclusion of potentially cognitively impaired persons (MMSE ⬍ 27, n ⫽ 15), the results in persons ⱕ 57 years did not change (data not shown), whereas in persons ⬎ 57 the association with APOE ␧4 and decline in the z-score for immediate verbal recall became slightly stronger (B ⫽ ⫺0.29; 95% CI, ⫺0.58 to ⫺0.01; p ⫽ 0.041). 4. Discussion In a nondemented population with symptomatic atherosclerotic disease we observed that possession of the APOE ␧4 allele was associated with verbal memory improvement during 4 years of follow-up in persons ⱕ 57 years, whereas in persons ⬎ 57 years the APOE ␧4 allele was associated with a verbal memory decline. These associations were independent of demographics and cardiovascular risk factors. To date, an increasing number of studies suggest a beneficial role of the APOE ␧4 allele in younger age on cognition (Mondadori et al., 2007; Wright et al., 2003), educational achievement (Hubacek et al., 2001), and IQ (Yu et al., 2000), whereas the well-documented negative consequences of possessing an ␧4 allele, including greater risk for developing dementia and poorer cognitive aging, may not emerge until after the fifth decade of life (Caselli et al., 2009). This has led to the hypothesis that the APOE gene may be an example of antagonistic pleiotropy (Han and Bondi, 2008). The differential effects of APOE ␧4 in younger and older subjects that we observed in this study are in line with this concept.

Although the mechanisms causing the beneficial effect on cognition of APOE ␧4 in younger age are unclear, it could be hypothesized that this is due to its role in cholesterol metabolism, an underlying contributing mechanism for neurite outgrowth and synaptogenesis, which are processes that are critical to neurodevelopment (Bothwell and Giniger, 2000; Herz and Beffert, 2000). The mechanisms causing the deleterious effect at older age are also still unclear, but the effect of APOE ␧4 on episodic memory is thought to be mediated by hippocampal atrophy (Small et al., 2004), while the general cognitive effects of APOE ␧4 might be related to its link with ␤-amyloid plaques and neurofibrillary tangles (Warzok et al., 1998), the hallmark neuropathologic characteristics of AD. We found that APOE ␧4 in nondemented older persons was associated with immediate verbal memory decline, but not with decline in visual memory or executive functioning. Memory performance as assessed with the 15-word learning test is mainly a function of the hippocampus (O’Brien et al., 2003). Furthermore, memory impairment is most commonly the earliest cognitive symptom of Alzheimer’s dementia. This is in line with our study that shows that memory decline, possibly as a result of the role of APOE ␧4 on hippocampus atrophy, can already be seen in nondemented persons. Yet, whereas most studies in older nondemented persons reported statistically significant cognitive decline with APOE␧4, we found a smaller decline than shown in most studies, and it was not statistically significant, although the interaction between age and APOE was highly significant. An explanation might be that the subgroup of older persons was based on a median split of our study sample at 57 years, while most studies finding a significant decline were performed in persons older than 65 years (Bretsky et al., 2003; Bunce et al., 2004; Jonker et al.,

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Fig. 1. Predicted values of immediate and delayed recall according to age, for carriers and noncarriers. (A) Predicted values of change in immediate recall (number of words) during follow-up for carriers and noncarriers, adjusted for age, apolipoprotein E (APOE) ␧4, the interaction between age and APOE ␧4, sex, education, the Dutch version of the National Adult Reading Test (DART) score and vascular risk factors. (B) Predicted values of change in delayed recall (number of words) during follow-up for carriers and noncarriers, adjusted for age, APOE ␧4, the interaction between age and APOE ␧4, sex, education, the DART score, and vascular risk factors.

1998). Because the results of our study indicate that after the late fifties the function of the APOE ␧4 allele on verbal memory may change, it is possible that some of the persons in the older age group did not yet experience the negative effect of APOE ␧4. In our study the younger persons demonstrated a verbal memory improvement, which might indicate a protective role of APOE ␧4 on the mechanisms underlying verbal memory impairment, such as hippocampus atrophy. The few studies that examined the role of APOE ␧4 in cognitively healthy persons in 2 or more age groups reported inconsistent results. Some studies showed that younger subjects with the APOE ␧4 allele had better cognitive performance (Baxter et al., 2003; Liu et al., 2010; Schultz et al., 2008), whereas other studies found no association (Jorm et al., 2007) or even a decline in cognitive performance in young ␧4 carriers (Kozauer et al., 2008). The reasons for these inconsistent findings may be the short follow-up period (Baxter et al., 2003) or the cross-sectional design of

some studies (Jorm et al., 2007; Liu et al., 2010). The study that showed a decline in young ␧4 carriers, had a very long follow-up period (22 years), and it is possible that the inversion point was missed (Kozauer et al., 2008). Prospective studies in populations with a wide age range, a long follow-up period, and several interim measurements are needed to reliably assess the association between APOE ␧4 and cognition across the lifespan. Strengths of our study include the prospective design and the wide age range of the sample, which facilitated the aim to associate APOE ␧4 with a change in cognitive performance across a wide age range, to examine the concept of antagonistic pleiotropy. A potential limitation is that the patients who participated in the follow-up examination might represent a healthier group due to, for example, selective mortality or morbidity. Although the age-adjusted association between APOE ␧4 and nonparticipation was not statistically significant, it is thus possible that the memory improvement in the younger group is somewhat overestimated, while the memory decline in the older group may have been underestimated. Furthermore, persons with 2 ␧4 alleles are more vulnerable for Alzheimer’s disease than persons with 1 ␧4 allele (Corder et al., 1993), and the detrimental effect of APOE ␧4 on memory decline may start at an earlier age in persons with 2 ␧4 alleles than those with 1 ␧4 allele (Liu et al., 2010). Unfortunately, we could not reliably analyze these groups separately because there were only 9 persons with 2 ␧4 alleles in our study. Finally, our study sample consisted of persons with symptomatic atherosclerotic disease and the majority were male, and our results could therefore not be fully applicable to the general population. However, as the relations were largely independent of the presence of vascular risk factors such as blood pressure and hyperlipidemia, we could argue that the results may also apply for the general population. In summary, in a nondemented population with symptomatic atherosclerotic disease, possession of an APOE ␧4 allele was associated with memory improvement during 4 years of follow-up in younger individuals, whereas in older individuals the APOE ␧4 allele was associated with memory decline. Consistent with the phenomenon of antagonistic pleiotropy, these findings might indicate a differential effect of the ␧4 allele on memory performance, with a change in function after the late fifties. Identification of possible environmental or genetic factors interacting with the APOE ␧4 allele might give new targets for medication to influence the development of Alzheimer’s dementia.

Disclosure statement The authors disclose no conflicts. This study was approved by the ethics committee of the UMCU and written informed consent was obtained from all participants.

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Acknowledgements The authors gratefully acknowledge the members of the SMART Study Group of University Medical Center Utrecht: A. Algra, M.D., Ph.D., Julius Center for Health Sciences and Primary Care and Rudolf Magnus Institute for Neurosciences, Department of Neurology; P.A. Doevendans, M.D., Ph.D., Department of Cardiology; Y. van der Graaf, MD, Ph.D, D.E. Grobbee, M.D., Ph.D., and G.E.H.M. Rutten, M.D., Ph.D., Julius Center for Health Sciences and Primary Care; L.J. Kappelle, M.D., Ph.D., Department of Neurology; W.P.Th.M. Mali, M.D., Ph.D., Department of Radiology; F.L. Moll, M.D., Ph.D., Department of Vascular Surgery, and FLJ Visseren, M.D., Ph.D., Department of Vascular Medicine. This study was supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO: project no. 917-66-311). The funding source had no involvement in the writing of this article or in the decision to submit it for publication.

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