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/lp/springer-journals/apoe-status-and-its-association-to-learning-and-memory-performance-in-QkMcjY0Ye5
- Publisher
- Springer Journals
- Copyright
- Copyright © 2007 by Wehling et al; licensee BioMed Central Ltd.
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
- eISSN
- 1744-9081
- DOI
- 10.1186/1744-9081-3-57
- pmid
- 17974013
- Publisher site
- See Article on Publisher Site
Abstract
Background: We examined the hypothesis that deficits in learning, memory, and other cognitive functions are associated with the ε4 allele of the Apolipoprotein E (APOE) gene in a non-demented sample with memory complaints recruited from a population with a high prevalence of this allele. Methods: The study group comprised 70 consecutively referred patients aged 50–75 seeking assessment due to memory complaints. They were screened for dementia, for neurological and psychiatric disease, and for cerebral infarction using Magnet Resonance Imaging (MRI). Participants were classified as non-demented based on clinical evaluation and results on cognitive tests. Results: APOE ε4 carriers (56% of the sample) showed poorer performance than non-carriers on the Mini Mental State Examination, a number of measures of verbal memory function from the California Verbal Learning Test, and visual recall. In 46% of the participants, psychometric criteria for amnestic Mild Cognitive Impairment (aMCI) were satisfied. Conclusion: Findings may be partly explained by a significant number of participants being in a preclinical phase of Alzheimer's disease. The observed deficits in learning performance and the lack of significant age modulation of the genetic association suggest a more general genetic effect. The findings are consistent with known neurobiological function of APOE ε4, including both increased risk of neurodegenerative disease and reduced synaptic integrity in older age. which has been characterized by subjective memory com- Background Alzheimer's disease (AD) is the most prevalent form of plaints and clinical criteria of cognitive impairment with- dementia in all age groups, with less than 1% incidence out being demented [2,3]. Memory may be the only before age 65, but with an exponential increase with age cognitive function affected (amnestic MCI), but MCI may [1]. Prior to diagnosis of AD many patients go through a also affect other cognitive domains in isolation or in com- clinical phase termed mild cognitive impairment (MCI), bination with memory impairment [3]. Patients with MCI Page 1 of 10 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:57 http://www.behavioralandbrainfunctions.com/content/3/1/57 are shown to be at high risk of progression to AD [4]. techniques [20-22] and reaction time based attention However, non-demented elderly persons with subjective tasks [23,24]. memory complaints are found quite frequently in the population at large and are a heterogeneous group. The studies above indicate that the APOE ε4 allele may Koivisto and collaborators [5] found a prevalence of 76% affect cognition and brain function in both clinical and in a randomly selected population sample aged 60–78 non-clinical groups. Memory complaints are prevalent in years, with the highest frequency in the younger part of the middle aged population, and the risk for developing the sample. Studies of population prevalence of MCI in AD based on memory complaints alone is low. The pro- similar age groups, using age adjusted psychometric crite- portion of study participants with ε4 allele will also vary ria of memory impairment, yield lower estimates, typi- with recruitment and inclusion criteria in relation to base cally 2–5% [6,7]. rates in the general population. Although APOE ε4 has been shown to be a risk factor for AD in many popula- The risk of developing AD is significantly increased by car- tions, the APOE ε4 - AD association was shown to be rying one or more ε4 alleles of the Apolipoprotein E weaker among African Americans and Hispanics than in (APOE) gene [8], and the risk increases in a dose depend- Caucasians and Japanese [10,25]. The prevalence of ε4 ent manner in relation to debut of AD before age 70 alleles also varies significantly between European popula- [9,10]. APOE ε4 is also associated with reduced memory tions, from a low incidence (10–15%) of ε4 alleles in function in clinically defined MCI patients [11]. Smith southern European populations to a high incidence (40– and collaborators [12] studied a group of MCI patients 50%) in northern European populations [26]. The func- diagnosed on the basis of memory deficits and found that tional consequences of the genetic variation have not APOE ε4 was associated with poorer performance on tests been fully explored. One consequence might be a differ- of learning and recall in MCI patients, but not in normal ence in incidence of early debut of AD between southern controls. They suggested that APOE-related memory defi- and northern European countries. This has not been con- cit is a specific cognitive phenotype in patients with AD firmed by comparative epidemiological studies (ERO- pathology. In a group of non-demented older adults, DEM) [27], but methodological differences across the Bondi and collaborators [13,14] found memory impair- studies preclude definite conclusions. ment at study entry in APOE ε4 carriers, affecting meas- ures of recall, recognition discriminability, and learning In the present study we examined neuropsychological per- slope as measured by the California Verbal Learning Test formance associated with variants of APOE alleles in non- (CVLT). No group differences between APOE ε4 carriers demented middle aged and older Norwegian participants, and non-carriers were found in other cognitive domains. who are part of a population with high incidence of APOE Follow-up data [14] showed that a subgroup developed ε4. Earlier studies have reported a high prevalence of sub- dementia, and that the risk was related to APOE status and jective memory complaints in 60–70 year olds [5] and a memory performance at study entry. low risk of developing AD before age 75 [28]. This indi- cates that a clinically recruited non-demented group of APOE is a cholesterol transporting protein coded on chro- participants younger than 75 years will include a signifi- mosome 19, with complex functions [15] that may affect cant proportion of participants with age related reduction cognition and brain function in clinical as well as non- of cognitive functions that are not primarily due to degen- clinical groups. A meta-analysis of population based stud- erative pathology. Based on the high prevalence of ε4 alle- ies by Small et al. [16] concluded that the ε4 allele is asso- les in the Norwegian population [26], we expected a high ciated with reduction in global cognitive functioning, incidence of these alleles in our study group, and we asked episodic memory, and executive functioning. Their results if the pattern of cognitive function confirmed the results revealed that APOE ε4 effects may vary with age, having a in samples from populations with lower base rates of ε4. larger impact in middle aged individuals than in the very old. Longitudinal studies of elderly, healthy participants Methods have found that APOE ε4 was associated with more rapid Patients memory decline, but not with memory performance at Participants were referred by their primary physician to a any given time of testing [17,18]. Mortensen and Høgh clinical research project on age related cognitive impair- [19] showed that the APOE ε4 allele was significantly ment and risk for dementia at the Department of Neurol- associated with a decline in tests of speeded attention and ogy, Buskerud Hospital, Drammen, Norway. Only visuo-construction in women, in particular those between patients in the age range 50–75 years were candidates for 70 and 80 years of age. Evidence for an effect of APOE on the project. Each individual underwent an extensive brain function in healthy individuals is reinforced by assessment based on the Consortium to Establish a Regis- studies using metabolic and functional brain imaging try on Alzheimer's Disease (CERAD) protocol [29], including a comprehensive neuropsychological investiga- Page 2 of 10 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:57 http://www.behavioralandbrainfunctions.com/content/3/1/57 tion that was supplemented by the Norwegian version of recall). All other scores were regarded as background vari- the CVLT [30]. All patients underwent full neurological ables. and medical examination, including Magnet Resonance Imaging (MRI) brain scan and laboratory tests. Inclusion Intellectual function criteria were complaints of memory problems of at least 6 Two subtests (Vocabulary and Matrix Reasoning) from the months duration, an estimated IQ score >80, and a score Norwegian version of the Wechsler Abbreviated Scale of of 24 or higher on the Mini Mental State Examination Intelligence (WASI) [36] were administered to estimate an (MMSE) [31]. Patients with a neurological, psychiatric, or IQ score. In the Vocabulary subtest, participants were another diagnosis which might affect cerebral function asked to define orally presented words. In the Matrix Rea- were excluded as well as patients with a known history of soning subtest, incomplete patterns were presented and alcohol or substance abuse. All cases were reviewed by a the participants were asked to complete the patterns by panel including a neurologist and a neuropsychologist pointing to one of five available response alternatives. after completion of the study protocol, and patients who received a dementia diagnosis according either to the Memory function The California Verbal Learning Test (CVLT) [37] was DSM-IV [32] or the ICD-10 [33] criteria were excluded. The final sample included in the present study consisted included to obtain measures of verbal learning, recall and of 70 individuals, 33 men and 37 women. The average age recognition, as well as learning strategies, error types, and was 63.9 years (SD = 7.7). All participants had completed serial position effects. In the learning task, the participants obligatory basic education (7 years in this cohort). The were presented to a list of 16 words (list A), where each average number of years of education for the sample was word belonged to one of four categories. The list was pre- 11.2 years (SD = 3.0), the average IQ was 106 (SD = 14), sented and recalled five times before a second list (list B) and the sample's average MMSE score was 27.89 (SD = was presented. The participants were immediately after 1.78). All individuals were living independently at the the recall of list B asked to recall the words from list A, time of participation in this study. The study was per- both in a free and cued recall condition. After an interval formed according to the Declaration of Helsinki [34] on of 20 minutes, the participants were again asked to recall guidelines for biomedical research involving human sub- the words from list A in a free and cued recall and recog- jects. nition condition. The Verbal Paired Associates Test [38] was included as another measure of verbal learning and Apolipoprotein E memory function. 15 word pairs were presented, and the The APOE genotype was determined with polymerase number of recalled pairs was recorded. chain reaction (PCR) according to standard methods. Individuals were classified as APOE ε4-positive (ε4 carri- The Rey Complex Figure Test (RCFT) [39], recall condi- ers) or APOE ε4-negative (non-carriers) based on the pres- tion, was included as a test of visual memory function. ence or absence of at least one ε4 allele. The ε4 carrier The participants were asked to copy the Rey-Osterrieth fig- group (56% of the study group) comprised 39 patients, ure (a visuo-constructive task). After an interval of 20 min- with allele combinations ε 2/4 (n = 4), ε 3/4 (n = 24) and utes, the participants were then asked to draw the figure as ε 4/4 (n = 11). Thus, 16% of the sample was ε 4/4 they remembered it from the copy-task. homozygote. In the non-carrier group of 31 patients the Attention and psychomotor speed allele combinations were ε 2/3 (n = 4) or ε 3/3 (n = 27). No patient had the allele combination ε 2/2. Two visuo-motor tests of attention and psychomotor speed were included, the Digit Symbol Test [40] and the Neuropsychological tests Trail Making Test A [41]. In the Digit Symbol Test, a sheet The neuropsychological test battery was administered containing rows of blank squares were presented, each according to the CERAD protocol [29]. Main areas of cog- square being paired with a randomly assigned number nitive functioning were assessed. The areas and test meas- (1–9). The task was to fill in as many blank squares as pos- ures are shortly described below. For a more detailed sible within 90 seconds. In the Trail Making Test A, the description, see [35]. Since impaired performance on ver- participants were requested to draw lines to connect con- bal memory acquisition and recall have been demon- secutively numbered circles (1–25) as fast as possible. The strated particularly sensitive measures to discriminate time to complete the tasks was recorded. between ε4 carriers and non-carriers and in addition are well known markers for identifying early stages of AD The Trail Making Test B [41] was included as a measure of [13,14], we considered specific measures on tests of verbal cognitive flexibility. The participants were asked to draw memory function as primary outcome measures (i.e. total lines to connect circles by alternating between circles with learning score, short and long delay free recall (all from numbers and letters (1-A-2-B etc.). The time to complete the CVLT), Verbal Paired Associate Test – learning and the test was recorded. The third subtest of a Stroop Color Page 3 of 10 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:57 http://www.behavioralandbrainfunctions.com/content/3/1/57 Word Test [42] was used as a measure of cognitive flexibil- Data analyses ity/inhibition. In the first subtest, the participants were For all statistical analyses, SPSS version 14.0 was used asked to name color patches (1), then to read color words [46]. Independent samples t-tests were used to test the dif- (2), and in the third condition to name the color of color- ferences in demographic characteristics of the ε4 carrier words printed in an ink of a different color (3) as fast as and non-carrier groups. Categorical data was analyzed possible. Time to complete the tasks was recorded. using chi-square test. When data met the assumption of normality, independent samples t-tests were used to Verbal function examine group differences on neuropsychological meas- Fluency of speech was assessed using the Controlled Word ures. When basic assumption for parametric tests, i.e. nor- Association Test (COWAT)[43]. Participants were asked to mal distribution, was violated, Mann-Whitney U name as many words as possible with a given first letter nonparametric tests were used. These analyses were com- within one minute, using the letters F, A, and S. After- pleted with calculations of effect sizes, i.e. Cohen's d for wards, participants were asked to name as many animals parametric tests and r as an approximate effect size when as possible within a minute. The Boston Naming Test was nonparametric tests were utilized. Additionally, repeated used to provide information about ease and accuracy of measures ANOVAs were used to assess general effects of word retrieval. 15 items of the Boston Naming Test [44] learning, retention and recall, respectively. Learning was were presented, including five words with low, medium assessed by entering the performance on learning trial 1 to and high frequency of occurrence, respectively. 5 as within subject variables. Retention was examined by entering learning trial 5 and the delayed free recall score, Subjective memory complaints and the recall measure included the scores on the short A standardized interview was performed by the examining delay and long delay free recall subtests as within subject physician, according to a Norwegian translation of the variables. All analyses tested interaction effects of geno- CERAD Clinical History protocol. The information type with gender and of genotype with age. The sample obtained from the patient was scored by the physician at was split by the median (65 years) into two age groups, the time of the interview. In addition to the two items on entering age and genotype as fixed factors. In case of a sig- memory complaints and their impact on everyday life, the nificant group effect between ε4 carriers and non-carriers, protocol itemized 7 specific domains of non-memory the dose effect was explored by comparing the results in ε4 complaints. homozygotes and ε4 heterozygotes. All statistical tests were two tailed. The alpha level was generally set at 0.05. Amnestic MCI Since several measures of cognitive functioning were Amnestic MCI (aMCI) was defined when a participant included, it seemed appropriate to control for Type I error obtained a result on the long delay free recall CVLT subtest rate for the primary outcome measures, i.e. the measures that was at least 1.5 standard deviations (SD) below the of verbal memory function. For those analyses, correcting age and gender adjusted norm. These norms are the stand- according to Bonferoni, a p value of 0.01 was regarded as ard norms presented by the test-developers [37]. statistically significant. MRI protocol Results Magnet Resonance Imaging (MRI) was included to detect The demographic characteristics of the ε4 carriers and and exclude patients with gross morphological changes. non-carriers are shown in Table 1. There were no signifi- Imaging was initially performed with a 0.5 T Philips scan- cant group differences in age, education, or gender distri- ner, replaced at a later stage with a Philips 1.0 T scanner. bution between the group of ε4 carriers and non-carriers. Standard T1 and T2 clinical scanning sequences were used MRI findings were noted in 67% of non-carriers and 71% and visually rated from a hard copy by the departmental of ε4 carriers. The frequency of MRI findings was not sig- chief radiologist, who was blinded with regard to other nificantly different between the groups. The most frequent study parameters [45]. finding was subcortical hyperintensities, reported in 57% Table 1: Demographic characteristics in APOE ε4 carriers and non-carriers non-carriers (n = 31) ε4-carriers carriers (n = 39) t-values p-values M (SD) M (SD) Age at test 62.9 (8.81) 64.7 (7.15) -0.979 0.331 Years of education 11.4 (3.11) 10.8 (2.98) 1.123 0.266 Sex (M/F) 16/15 17/22 0.631* * Chi-square test statistic Page 4 of 10 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:57 http://www.behavioralandbrainfunctions.com/content/3/1/57 of the non-carriers and 47% of the ε4 carriers. Cortical or Learning measures subcortical atrophy was found in 20% of the non-carriers A repeated measures ANOVA, including the five CVLT and 27% of the ε4 carriers. learning trials, showed that the non-carriers showed an overall better learning performance than ε4 carriers (F Subjective memory problems of at least 6 months dura- (1,68) = 5.46, p = 0.022). There was no interaction tion were present in all patients, and more than half of the between group and learning trial. On average, participants sample (57%) reported duration of memory problems in both APOE groups recalled more items on trial 5 than longer than 2 years. Typical mode of onset was gradual on trial 1. Consistent with this finding, the APOE groups progression (59%), but 13% reported that the impair- showed no significant difference in slope of the learning ment had been stable, and the rest reported a fluctuating curve, characterizing performance increment across trials course. ε4 carriers did not complain of more severe mem- (Figure 1). To explore strategies used in the learning proc- ory problems or of having more non-memory cognitive ess, we compared semantic and serial clustering, recall problems than the non-carriers. consistency, and serial position effects in the two APOE groups (Table 3). ε4 carriers showed a significantly lower There were no statistically significant differences between consistency across learning trials (MW, p = 0.01, r = -0.3) the group of ε4 carriers and non-carriers on tests of intel- as well as significantly more intrusions in the learning tri- lectual function, verbal function, attention/psychomotor als (MW, p = 0.03, r = -0.25). There was no significant dif- speed and visuo-constructive function (Table 2). There ference between the groups regarding clustering strategies was, however, a significant difference in the MMSE score and serial position effects. between the APOE groups, showing that ε4 carriers obtained a statistically significant lower performance Recall and rate of forgetting score than the non-carriers (p = 0.032). Follow-up calcu- A repeated measures ANOVA, entering the short delay free lation of Cohen's d revealed an effect size of (d = 0.53), recall and long delay free recall scores from CVLT as representing a medium sized effect according to Cohen's within-subject factors, showed no statistically significant definition [47]. Statistically significant differences difference between the two APOE groups. between the two APOE groups were also found on Boston Naming Test (p = 0.03, r = -0.26) and the RCTF-recall An analysis of the rate of forgetting, including the learning measure (p = 0.02, r = -0.27). trial 5 and the delayed free recall score from CVLT as between subject factors, showed no statistically significant ε4 carriers showed lower performance than non-carriers APOE group difference. on several CVLT measures, as shown in Figure 1 and Table 3. Group differences became statistically significant only Recognition for Learning trial 1 but for none of the other comparisons; Mann-Whitney nonparametric tests were used to analyze however, effect sizes revealed small to medium effects for the differences between ε4 carriers and non-carriers on several measures. recognition measures. The only significant difference Table 2: Mean performance (SDs shown in parantheses) of APOE ε4 carriers and non-carriers on cognitive measures (raw scores) ε 4 non-carriers (n = 31) ε 4 carriers (n = 39) t-values/U-values p-values Effect sizes MMSE 28.4 (1.6) 27.5 (1.8) 2.19 0.03 0.53 b b c,e WASI-IQ 105 (13.4) 106 (15.3) 0.068 0.95 0.01 Stroop Color Word Test (seconds) 94 (54.3) 106 (58.0) -0.840 0.40 0.22 WAIS-R Digit Symbol (items) 35 (10.5) 32 (12.1) 1.166 0.25 0.27 FAS (items) 30 (12.0) 31 (12.8) -0.262 0.79 0.08 Animal fluency (items) 16 (5.8) 17 (5.6) -0.299 0.77 0.18 Trail Making A (seconds) 48 (22.0) 58 (26.9) 477 0.13 -0.18 Trail Making B (seconds) 144 (112.6) 165 (89.4) 479.5 0.14 -0.18 Boston Naming (items) 15 (1.1) 14 (1.1) 539.5 0.03 -0.26 Rey Complex Figure Test – copy (points) 33 (5.4) 31 (7.0) 487 0.16 -0.17 Rey Complex Figure Test – recall (points) 16 (9.0) 11 (7.5) 410.5 0.02 -0.27 Degrees of freedom for all parametric tests was 68 For t-tests, Cohen's d, for nonparametric tests r were calculated Standardized scores Test statistics according to independent t-tests Test statistics according to Mann-Whitney U tests Test statistic based on age-adjusted scores Page 5 of 10 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:57 http://www.behavioralandbrainfunctions.com/content/3/1/57 Table 3: Mean learning and memory performance (raw scores) on the Verbal Paired Associate Test and the California Verbal Learning Test (CVLT) in APOE ε4 carriers and non-carriers (SDs shown in parantheses) ε 4 non-carriers ε 4 carriers t-values/ U-values p-values Effect sizes (n = 31) (n = 39) *Verbal Paired Associate Test – learning (errors) 33 (22.7) 41 (22.2) -1.51 0.14 0.52 *Verbal Paired Associate Test – recall (errors) 7 (4.2) 9 (4.8) -1.80 0.08 0.63 CVLT List A Trial 1 recall 5.8 (2.6) 4.6 (2.2) 2.14 0.04 0.51 List A Trial 5 recall 10.1 (3.8) 8.5 (3.3) 1.85 0.07 0.46 *Total learning (trial 1–trial 5) 42 (15) 34.7 (11) 2.34 0.02 0.57 *Short delay free recall 7.3 (4.3) 6.1 (3.9) 1.20 0.24 0.30 Short delay cued recall 9.3 (3.8) 8.1 (3.4) 1.35 0.18 0.34 *Long delay free recall 8.5 (4.3) 6.8 (3.9) 1.78 0.08 0.44 Long delay cued recall 9.1 (3.5) 8.1 (3.5) 1.18 0.24 0.29 0.07 0.47 Percent recognition discriminability 89 (10.1) 84 (11.4) 1.84 Intrusions learning 0.3 (0.7) 0.8 (1.4) 467 0.03 -0.25 Short delay intrusions 0.2 (0.5) 0.3 (0.6) 559.7 0.45 -0.09 Long delay intrusions 0.4 (0.6) 0.7 (1.5) 545 0.39 -0.10 Recognitions hits 14.3 (1.8) 13.9 (1.9) 521.5 0.32 -0.12 Recognition false alarms 3.0 (4.3) 4.7 (4.2) 413.5 0.02 -0.27 Response bias (recognition) 0.09 (0.4) 0.24 (0.4) 462 0.09 -0.20 Percentage consistency 75.7 (17.1) 67.6 (15.9) 395 0.01 -0.30 Degrees of freedom for all parametric tests was 68 * According to Bonferoni correction, a p-value of 0.01 was regarded as significant for these scores For t-tests, Cohen's d, for nonparametric tests r were calculated Test statistics according to independent t-tests Test statistics according to Mann-Whitney U tests appeared for the false alarm scores (MW, p = 0.02, r = - Even though several mean values indicated that women 0.27). performed better than men, the analysis revealed no sta- tistically significant interaction effect of APOE status and Effects of gender, age, and dose on cognitive performance gender (F (1,68), p = 0.09). When rerunning the analysis To examine modulating effects of gender and age on CVLT by including age and APOE status as between subject fac- performance, we performed repeated measures ANOVAs tors, no statistically significant effect (F (1,68), p = 0.52) including APOE status and gender as between subject fac- was demonstrated. The analyses of dose effects showed no tors and learning trial 1 to trial 5 as within subject factors. statistically significant differences between homozygotes and heterozygotes for ε4 on any measure of learning and memory function. aMCI There were 32 participants who were allocated to the group of aMCI according to our definition (i.e. a free recall performance at least 1.5 standard deviations below ApoE İ 4 carriers ApoE İ 4 non carriers normative mean), 6 homozygotes, 18 heterozygotes and 8 non-carriers of the ε4 allele. Test statistics revealed a sta- tistically significant higher number of ε4 carriers than non-carriers in this aMCI group (χ = 4.06, p = 0.04). The average age in the aMCI group was slightly higher (M = 65.1, SD = 8.1) than the non-aMCI group (M = 62.8, SD = 12 345 7.3), but the difference was not statistically significant (t = trial -0.236, p = 0.221). However, individuals in the aMCI group performed significantly lower on the MMSE (aMCI Figure 1 Mean number of CVLT in APOE ε wo 4 car rdrs on the f iers and non-ca ive learning trials from rriers the M = 27.3 (SD = 1.7), non-aMCI M = 28.4 (SD = 1.7), t = Mean number of words on the five learning trials from the 2.58, p = 0.01) and had a lower IQ score (aMCI M = 101 CVLT in APOE ε4 carriers and non-carriers. * indicates p = 0.04. (SD = 11.9), non-aMCI M = 110 (SD = 15.1), t = 2.61, p = 0.01). There was no statistically significant group differ- Page 6 of 10 (page number not for citation purposes) No. of words Behavioral and Brain Functions 2007, 3:57 http://www.behavioralandbrainfunctions.com/content/3/1/57 ence with respect to educational level (aMCI M = 10.4 (SD oping dementia [14,48], other have found that measures = 2.7), non-aMCI M = 11.8 (SD = 3.2), t = 1.85, p = 0.07). of learning are equally or more predictive [49,50]. How- ever, the distinction between learning and recall may not be very informative since episodic memory is critically Discussion Results from the present study showed that the APOE ε4 involved both in learning performances across repeated carriers showed a statistically significant lower perform- trials and in delayed recall. ance on a number of measures of verbal learning and memory than the non-carriers. Performance of the ε4 car- In the present study, the APOE status was found to have a riers on the CVLT was characterized by fewer correctly significant effect on the recall measure from the RCFT. reported words on all learning trials, reduced between- This was not found in the Bondi et al. [14] study, although trial recall consistency, a higher number of intrusions dur- the performance on another visual memory test (Wechsler ing learning trials, and an increased frequency of false Memory Scales, visual reproduction) showed a trend alarms in recognition trials than the non-carriers. Recall of towards lower scores in ε4 carriers. Other studies of ε4 car- the verbal material across varying delays was not dispro- riers which have included the RCFT have shown mixed portionately reduced in the ε4 carriers, but further statisti- results [51,52], and our finding was in accordance with cally significant differences between the two groups were the study of Caselli et al. [18], showing lower delayed demonstrated for the Boston Naming Test, the recall recall sores for ε4 carriers on a complex figure test. measure of the RCFT, and on the MMSE. Gross measures of cerebral atrophy or subtle vascular pathology on MRI An atypical finding in our study was the poorer perform- could not distinguish between ε4 carriers and non-carri- ance of the ε4 carriers on the first presentation of the word ers, and the level of subjective complaint of memory prob- list. This may be explained as an attention deficit, a word lems was not significantly related to APOE status. finding or semantic deficit, or a memory problem. Per- According to the selected criteria for MCI, 46% of the par- formance on the Boston Naming Test differed signifi- ticipants were classified as aMCI. The aMCI group showed cantly between ε4 carriers and non-carriers, which could an increased frequency of ε4 alleles than the non-MCI suggest a word retrieval problem. However, we believe group. that this was not the case since both groups obtained results that were more than one standard deviation above The results were generally in accordance to those in previ- age-corrected norms (not shown data) and no other meas- ous studies of clinically recruited aging participants, ures of verbal function (Vocabulary, animal and letter flu- showing that APOE ε4 is associated with impaired per- ency) confirmed such a problem in the ε4 carriers. formance on subtasks from the CVLT [13,14]. There were, Together with the lack of group differences on the remain- however, differences in the profile of test results between ing tests of attention (Digit Symbol Substitution, Trail the study groups. Bondi et al. [14] found that reduced Making Test, Stroop Color Word), we suggest a selective delayed recall and learning slope discriminated well memory problem in the ε4 carriers. between the APOE groups, whereas our results indicated that a pattern of inconsistent retrieval and erratic report- The significant lower performance of ε4 carriers than the ing (intrusions of non-presented words) characterized the non-carriers on the MMSE deserves a comment, because learning and memory function in ε4 carriers. In spite of such a finding could indicate that ε4 carriers showed gen- the fact that the CVLT measure of long delay recall has eral lower cognitive functioning than the non-carriers. We shown to be sensitive to early changes of AD in other stud- argue against such a conclusion, in that the two groups ies [13,14,48], the two APOE groups showed similar performed almost equal on the comprehensive neuropsy- results in the our study. This might be due to the lack of chological test battery, expected to be at least as sensitive statistical power because of the small sample size in the to impairment as the MMSE. Furthermore, the MMSE dif- present study. This argumentation was supported by ference was less than one point and all participants medium effect sizes on scores such as long delay free recall obtained a MMSE score above 24. (CVLT) and the Verbal Paired Association Test (learning and recall). Furthermore, the age range in the present sam- It may be argued that the displayed problems in the ε4 car- ple may have influenced our results. The participants were riers are a consequence of the inclusion of patients with on average 7 years younger than the ones studied by subjective memory problems. This argument may have Bondi et al. [14] (64 years vs. 71 years). We suggest that some merit if the study population is defined on the basis the younger age of the participants in the present study of reduced performance on memory tests, as is the case in may partly explain why their memory performances were some definitions of MCI [3]. In the present study, we less characteristic of mild AD than the patient group stud- included participants on the basis of widely defined clini- ied by Bondi et al. [14]. Even if several studies concur that cal criteria based on subjective cognitive complaints, with measures of delayed recall are predictive of risk for devel- symptoms and pathological markers of dementia as exclu- Page 7 of 10 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:57 http://www.behavioralandbrainfunctions.com/content/3/1/57 sion criteria. In view of the high incidence of subjective results in the present study. In this respect our results memory complaints in the general population [5], it is resemble those of Caselli et al. [17] in a normal group in likely that patients recruited on the basis of this criterion an age range similar to ours. In accordance with Caselli's will include a heterogeneous group of normal and mildly group [18,58] we noted that while the definition of aMCI pathological cases. Our results confirmed that subjective emphasizes a memory profile resembling mild AD with memory complaint is not associated with APOE status reduction in delayed recall, this was not the pattern of [53], and Fisk et al. [6] found that eliminating the crite- memory performance that best characterized the differ- rion of subjective memory complaint from the definition ence between ε4 carriers and non-carriers in the present of MCI had no impact on the relative risk of subsequent group. Based on all these observations we assume that the cognitive decline. Therefore, it is less likely that subjective whole study group rather than a subgroup with early AD memory complaint has served as a strong factor biasing has contributed to the results in the present study. While the findings of an association of memory dysfunction and the APOE ε4 related mechanisms that are not explicitly APOE ε4 in the present study. linked to AD pathology [15] are thought to affect neuro- nal health in general, it is likely that memory and learning Despite the relatively young age of our sample, 46% of the are domains of cognitive function that are more sensitive patients satisfied psychometric criteria for aMCI. This to impaired synaptic plasticity than other domains. More group showed an increased frequency of APOE ε4 alleles, sensitive and specific tests of attention, as shown by and data from other studies [3,54] suggest that the aMCI Greenwood and Parasuraman using a cued visual discrim- group has an increased risk of developing AD. Thus, the ination task [23], may also reveal effects in this domain. association between APOE status and memory perform- ance may be explained by the presence of a significant Even though we used Bonferoni correction for a number number of preclinical AD patients in the study popula- of analyses, this study can be criticized for the use of mul- tion. This was also the conclusion drawn by Bondi et al. tiple comparisons since some of the neuropsychological [13,14] on the basis of follow-up data for their sample. measures surely tap the same cognitive resources. This and We acknowledge that this is a likely explanation for part the small sample size request caution when interpreting of our findings. Although these authors showed that the the results until these are verified by further North Euro- combination of impaired memory performance and pean studies. Another issue is the clinical impact of our APOE ε4 genotype had a high predictive value in the findings. In the present study, the aim was to investigate course to AD, this has not always been confirmed [49,55]. group differences rather than individual patterns of cogni- It is important to note that in the present study, 25% of tive function. Although group results give indications to a the participants classified as aMCI were non-carriers. This clinician, he or she will still have to assess their patients possibly reduces their risk to progress to AD. Furthermore, individually to take into account the individual differ- this points to an important weakness of the concept of ences in older adults. Follow-up studies are necessary to MCI. A number of authors have demonstrated that elderly answer the question of the predictive value of cognitive individuals showed fluctuating performance when decline in patients with APOE ε4 in Nordic samples and assessed with neuropsychological tests [56], and that characteristics of different developmental pathways. there are individuals classified as MCI who remained sta- ble or even re-obtained normal cognitive function on fol- Conclusion The present study of consecutively referred non-demented low-up [57]. In our group, other reasons than underlying neurodegenerative processes could have lead to classifica- patients included 55% of participants with at least one ε4 tion as aMCI. In the present study, the group of individu- allele, and 15 % of the total sample were ε4 homozygotes. als defined as aMCI had significant lower IQ scores and The proportion is high in comparison with MCI samples lower scores on the MMSE. Thus, some of individuals in [4] and with unselected AD cases [59], which reflect the the aMCI group may have been misclassified due to a gen- fact that the general population from which the present eral low cognitive abilities or a more a temporary cogni- patients were recruited also has a high incidence of ε4 alle- tive impairment. les [26]. While APOE has been commonly accepted as a susceptibility gene for late onset AD, with increased risk Proximity to a likely age of debut for AD is expected to be associated with the ε4 allele, it has also become increas- a powerful factor predicting memory deficit. Although the ingly clear that genetic risk is modulated by other factors. average age for the aMCI group was somewhat higher than There is increasing information of gene combinations that the remaining group, we did not find that age as such was may serve to modify APOE effects [24,60]. While the a significant modulator of the relation between APOE sta- present findings are largely consistent with reports based tus and memory performance. Homozygozity for ε4 has on North American and European populations, further been shown to confer another significant increase in risk comparative studies of effects on cognition of APOE and for conversion to AD, but this was not confirmed by the other genes may give information relevant to focusing on Page 8 of 10 (page number not for citation purposes) Behavioral and Brain Functions 2007, 3:57 http://www.behavioralandbrainfunctions.com/content/3/1/57 E genotype and Alzheimer disease. A meta-analysis. APOE APOE. mechanisms as a therapeutic target. Exploiting the and Alzheimer Disease Meta Analysis Consortium. JAMA natural variation in prevalence of at-risk alleles is an 1997, 278:1349-1356. important part of this strategy. 11. Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC: Impact of APOE in mild cognitive impairment. Neurology 2004, 63:1898-1901. Competing interests 12. Smith GE, Bohac DL, Waring SC, Kokmen E, Tangalos EG, Ivnik RJ, Petersen RC: Apolipoprotein E genotype influences cognitive The author(s) declare that they have no competing inter- 'phenotype' in patients with Alzheimer's disease but not in ests. healthy control subjects. Neurology 1998, 50:355-362. 13. Bondi MW, Salmon DP, Monsch AU, Galasko D, Butters N, Klauber MR, Thal LJ, Saitoh T: Episodic memory changes are associated Authors' contributions with the APOE-epsilon 4 allele in nondemented older adults. EW conducted data analyses, literature review and pre- Neurology 1995, 45:2203-2206. pared drafts of the manuscript; ALJ instigated data analy- 14. Bondi MW, Salmon DP, Galasko D, Thomas RG, Thal LJ: Neuropsy- chological function and apolipoprotein E genotype in the ses and contributed to the interpretation of results and preclinical detection of Alzheimer's disease. Psychol Aging drafts of the manuscript; BS and LG examined all partici- 1999, 14:295-303. 15. Mahley RW, Weisgraber KH, Huang Y: Apolipiprotein E4: A caus- pants and made diagnostic judgments; IR was responsible ative factor and therapeutic target in neuropathology, for the design and data collection, data analyses, literature including Alzheimer's disease. Proc Natl Acad Sci USA 2006, review, and contributed substantially to the manuscript. 103:5641-5644. 16. Small BJ, Rosnick CB, Fratiglioni L, Backman L: Apolipoprotein E All authors have read and approved the final manuscript and cognitive performance: a meta-analysis. Psychol Aging and contributed equally to this work 2004, 19:592-600. 17. Mayeux R, Small SA, Tang M, Tycko B, Stern Y: Memory perform- ance in healthy elderly without Alzheimer's disease: effects Acknowledgements of time and apolipoprotein-E. Neurobiol Aging 2001, 22:683-689. All participants gave informed consent according to the standard require- 18. 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Devanand DP, Pelton GH, Zamora D, Liu X, Tabert MH, Goodkind M, Scarmeas N, Braun I, Stern Y, Mayeux R: Predictive utility of "BioMed Central will be the most significant development for Apolipoprotein E genotype for Alzheimer Disease in outpa- disseminating the results of biomedical researc h in our lifetime." tients with mild cognitive impairment. Arch Neurol 2005, Sir Paul Nurse, Cancer Research UK 62:975-980. 56. Palmer BW, Boone KB, Lesser IM, Wohl MA: Base rates of Your research papers will be: impaired neuropsychological test performance among available free of charge to the entire biomedical community healthy older adults. Arch Clin Neuropsychol 1998, 13:503-511. 57. deRetrou J, Wenisch E, Chausson C, Dray F, Faucounau V, Rigaud AS: peer reviewed and published immediately upon acceptance Accidental MCI in healthy subjects: a prospective longitudi- cited in PubMed and archived on PubMed Central nal study. Eur J Neurol 2005, 12:879-885. 58. 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Behavioral and Brain Functions – Springer Journals
Published: Oct 31, 2007