Abstract

The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer's disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE ε4 with better episodic memory compared with APOE ε2 and ε3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas ε2 and ε3 carriers increased activity. This smaller neural investment of ε4 carriers into learning reappeared during retrieval: ε4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE ε4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.

Introduction

The APOE ε4 allele (APOE4) has an extensive record of deleterious effects on several biological processes. The possession of at least one ε4 allele increases the risk of Alzheimer's disease (AD) (Saunders et al. 1993) 3-fold, presumably through an association of APOE4 with the pathological hallmarks of AD, amyloid plaque deposition, and neurofibrillary tangle formation (Ghebremedhin et al. 1998, 2001; Bennett et al. 2003, 2005; Tiraboschi et al. 2004; Thal et al. 2005). In contrast, the possession of an ε2 allele appears to confer a protective effect against AD and AD-related neuropathology (Corder et al. 1994). Moreover, APOE2 is associated with a reduced decline of episodic memory in older persons (Wilson et al. 2002), whereas APOE4 exerts detrimental effects in middle-aged and older subjects on memory performance (Hyman et al. 1996; Baxter et al. 2003), visual attention (Greenwood et al. 2000), executive functions (Rosen et al. 2005), memory-related brain activity (Bookheimer et al. 2000; Bondi et al. 2005; Trivedi et al. 2006), and resting brain glucose metabolism (Reiman et al. 2001, 2005). APOE4 has also been experimentally related to impaired hippocampal plasticity (Levi et al. 2003) and lower density of dendritic spines (Ji et al. 2003) in aged transgenic mice and to increased neurotoxicity (Qiu et al. 2003) in vitro.

Although the frequency of the APOE4 allele is low in humans (15% in Caucasians), studies in primates suggest that it is the ancestral allele (Finch and Sapolsky 1999). The common (75% in Caucasians) and uniquely human APOE3 allele appeared as a mutation, and its frequency increased during human evolution (Finch and Sapolsky 1999). Because the APOE4 allele has been related to several deleterious biological effects, the question arises why it existed in the first place (Finch and Sapolsky 1999). From an evolutionary point of view, a possible advantageous effect of the APOE4 allele in childhood and early adulthood could explain its existence and further persistence in humans. Support for this notion comes from studies where APOE4 has been associated with higher IQ scores (Yu et al. 2000), a higher educational level (Hubacek et al. 2001), a reduced cardiovascular response to experimentally induced stress (Ravaja et al. 1997), and a protective effect against spontaneous abortion during embryogenesis (Zetterberg et al. 2002) and against perinatal death (Becher et al. 2006). Advantageous effects of the APOE4 allele have also been found for memory-related functions in young animals. Hippocampal long-term potentiation (LTP) was enhanced at a young age in knock-in mice lacking mouse APOE but instead expressing human APOE4 (Kitamura et al. 2004). This LTP enhancement was age dependent and disappeared in adult knock-in mice. Moreover, APOE4, but not APOE3, stimulated the transcriptional activity of cyclic adenosine 3′,5′-monophosphate response element-binding protein (CREB) by activating the extracellular signal-regulated kinase (ERK) cascade in rat primary hippocampal neurons (Ohkubo et al. 2001).

As yet, APOE effects on human memory at young age are unexplored. Here we combined human genetics with memory assessments and functional magnetic resonance imaging (fMRI) and structural magnetic resonance imaging (sMRI) to address the following questions: Does the APOE ε4 allele have an effect on episodic memory performance in young adults? Do APOE ε4 carriers exhibit altered learning- and memory-related brain activity compared with APOE ε4 noncarriers within the medial temporal lobe? Our a priori hypothesis focused on the medial temporal lobe for 3 reasons: 1) the medial temporal lobe is the region where first neurofibrillary tangles can be detected in the course of AD (Ohm et al. 1995; Braak H and Braak E 1996; Delacourte et al. 1999), 2) alterations in the memory-related fMRI signal have been detected in the medial temporal lobe of healthy elderly APOE ε4 carriers (Bookheimer et al. 2000; Bondi et al. 2005), and 3) hippocampal LTP has been found enhanced in young knockin mice expressing human APOE4 (Kitamura et al. 2004). We also measured brain activity during a working memory task to find out whether potentially altered brain activity levels in APOE ε4 carriers are restricted to episodic memory or extend to other forms of memory. Furthermore, we examined whether the APOE ε4 allele influences brain morphology and cognitive functions other than memory functions.

We were testing for behavioral effects of the APOE gene's 3 allelic variants on verbal episodic learning and retrieval in a large sample of 340 healthy young adults. Effects of the APOE gene's allelic variants on memory-related neurophysiology and brain morphology were then examined with fMRI and sMRI in 34 memory-matched subjects (see Materials and Methods) of the 340 original subjects. These 34 subjects underwent one fMRI experiment on episodic memory (Fig. 1) and a second fMRI experiment on working memory. Finally, the 34 subjects underwent an extensive neuropsychological assessment to uncover potential associations of APOE allele status with intelligence, executive functions, and spatial cognition.

Figure 1.

Study design. Left side (encoding fMRI time series): Displayed are examples of stimuli presented for associative learning, single-face learning, and the visual baseline task. Each stimulus appeared once in each run. Right side (retrieval fMRI time series): Displayed are examples of stimuli presented for associative retrieval, face recognition, and the visual baseline task. Alex Kayser granted us permission to use and reproduce faces from his book “Heads,” 1985, New York: Abbeville Press.

Figure 1.

Study design. Left side (encoding fMRI time series): Displayed are examples of stimuli presented for associative learning, single-face learning, and the visual baseline task. Each stimulus appeared once in each run. Right side (retrieval fMRI time series): Displayed are examples of stimuli presented for associative retrieval, face recognition, and the visual baseline task. Alex Kayser granted us permission to use and reproduce faces from his book “Heads,” 1985, New York: Abbeville Press.

Materials and Methods

Subjects

The large sample consisted of 340 healthy human subjects with an age of 22.8 ± 4 (mean ± standard deviation [SD]) years. There were no significant differences between APOE ε4 carriers and APOE ε4 noncarriers regarding age, gender, and education (P ≥ 0.2; APOE ε4 carriers [n = 87]: age 22.8 ± 3.9 years, sex 62 [71%] females, education 54 [62%] academics; APOE ε4 noncarriers [n = 253]: age 22.8 ± 4.2 years; sex 171 [68%] females, education 177 [70%] academics). Information on genotyping procedures is provided elsewhere (de Quervain et al. 2003).

34 subjects (mean age 22.3, SD 2.53) participated in the fMRI experiments; 11 carried the ε2/ε3 genotype, 10 the ε3/ε3 genotype, and 13 the ε3/ε4 genotype (Table 1). Importantly, these subjects were drawn from the large sample such that no statistically significant differences resulted between groups for age, years of education, the His452Tyr polymorphism of the 5-HT2a receptor–encoding gene (the His452Tyr polymorphism has been associated with poorer memory, see de Quervain et al. 2003), and the 5-min words recall performance in the previously applied verbal memory test (Table 1). The reason why we matched the 3 genotype groups for memory performance was to eliminate performance-related brain activity differences in order to sample only genetic effects on brain activity. The subjects reported neither past nor current psychiatric or neurological problems and denied taking illegal drugs or prescription medication. All subjects gave written informed consent to participate in the study after the nature and possible consequences of the study had been explained. The experiments were approved by the local ethics committee.

Table 1

Matched APOE groups

APOE ε2/ε3 (n = 11) ε3/ε3 (n = 10) ε3/ε4 (n = 13) 
Agea 22.7 ± 1.7 21.6 ± 1.7 22.6 ± 3.5 
Years of educationa 14.5 ± 1.3 13.8 ± 1.5 14.3 ± 1.7 
Words delayed recalla 7.2 ± 1.7 7.6 ± 2.7 7.7 ± 2.9 
Sex (m/f)b 2/9 4/6 7/6 
Handedness (R/L/A)b 11/0/0 8/2/0 11/1/1 
His452Tyrb 
APOE ε2/ε3 (n = 11) ε3/ε3 (n = 10) ε3/ε4 (n = 13) 
Agea 22.7 ± 1.7 21.6 ± 1.7 22.6 ± 3.5 
Years of educationa 14.5 ± 1.3 13.8 ± 1.5 14.3 ± 1.7 
Words delayed recalla 7.2 ± 1.7 7.6 ± 2.7 7.7 ± 2.9 
Sex (m/f)b 2/9 4/6 7/6 
Handedness (R/L/A)b 11/0/0 8/2/0 11/1/1 
His452Tyrb 

Note: His452Tyr, polymorphism in the 5HT2a receptor–encoding gene. Carriers of this rare variant (His/Tyr) showed reduced memory performance (see de Quervain et al. 2003) when compared with homozygous carriers of the common variant (His/His). m/f, male/female; R/L/A, right/left/ambidextrous.

a

values = means ± SD.

b

values = number of subjects.

Experimental Procedure—Large Sample

The 340 subjects viewed 6 sets of words, each set containing 5 semantically unrelated nouns. These nouns were visually presented at a rate of one word per second. Subjects were instructed to learn the 5 nouns of a set for immediate free recall from short-term memory. An immediate free recall test followed the presentation of each of the 6 sets. In cognitive psychology, short-term memory is conceived as a limited capacity store capable of holding only about 7 “items” by the operation of rehearsal. Should rehearsal be interrupted, the material has a half-life of about 10–20 s (Reber 1995). Following the completion of the 6 sets, subjects performed a distracter task that kept them busy over 5 min. Thereafter, subjects engaged in a surprise delayed free recall test of the 30 studied nouns. Because this free recall followed a 5-min interval of distraction, it clearly exceeds short-term memory capacity and instead challenges episodic memory. Episodic memory is dependent on the intact functioning of the hippocampus (Scoville and Milner 1957; Squire and Alvarez 1995).

Association studies in outbred populations such as the present one may be prone to false positivity because nonrandom genetic heterogeneity within the study sample (i.e., hidden population structure) can lead to spurious associations between a candidate marker and a phenotype. Hidden population structure within the study sample may be a result of sampling bias (an extreme example for such a condition would be to recruit both Caucasian participants and participants of Asian origin and to consider them as one homogenous group). In this case, alleles of high frequency in one subpopulation would be associated with any phenotype that is most prevalent in this one subpopulation. Thus, a subtle and unequal ethnic admixture may lead to spurious, false-positive associations with the phenotype of interest. Because allele frequencies at random marker loci may differ among ethnic groups, a consistent pattern of allele frequency differences between phenotypic groups will be detected if these groups are not well matched. Conversely, if the phenotypic groups are well matched, significant allele frequency differences will be located only near phenotype-related loci. We calculated the hidden population structure with the structured association method that uses unlinked genetic markers to detect possible population stratification (Pritchard and Rosenberg 1999). To this aim, we genotyped each subject for 55 random single nucleotide polymorphims distributed over the autosomes. This analysis revealed a low allele frequency divergence in our population (Kullback-Leibler distance = 0.15) and excluded nonrandom, gross genetic heterogeneity as a potential source of false positivity.

Experimental Procedure—Small Sample

Subjects were examined in 2 sessions. The first session took place in the magnetic resonance (MR) center and comprised the fMRI and sMRI examinations. Upon arrival, subjects took a medical questionnaire and practiced the fMRI tasks outside the scanner till they felt comfortable with task instructions and response mode. Then they were placed in the MR scanner and underwent the 2 fMRI experiments. The first fMRI experiment was the episodic memory experiment and the second the working memory experiment. In both fMRI experiments, trials were blocked per condition. Stimuli were the same for all subjects to avoid intersubject variance caused by stimulus-generated effects. Responses were collected with a response box that subjects held in their dominant hand. Finally, 2 anatomical brain scans were performed for the volumetric analyses. The second session followed 1–3 months (mean: 1 month) later and included an extensive neuropsychological assessment.

The fMRI Experiment on Episodic Memory—Encoding

We presented 16 face–profession pairs in the associative learning condition, 16 faces in the single-face–learning condition, and 24 head contours without physiognomy in the visual baseline condition (Fig. 1). All stimuli of the 3 conditions were presented in 12 task blocks (4 blocks per condition) in a first learning run consisting of one fMRI time series that ran over 6 min. This learning run/time series was repeated twice such that each stimulus was presented a total of 3 times within its condition—a condition comprising the stimulus presentations in all learning runs/fMRI time series. The 3 learning runs allowed us to monitor genotype-induced brain activity differences during the progressively deeper encoding of the material. The sequence of task blocks within a learning run/time series was counterbalanced across subjects but kept constant within subjects over learning runs/time series. In the 2 learning conditions, a task block contained 4 trials of 6 s each. In the visual baseline condition, a task block contained 6 trials of 4 s each. Consequently, each task block took 24 s. Instruction slides were presented for 6 s to announce each task block. The instruction for associative learning of the face–profession pairs was to imagine the presented person acting in a scene of the written profession. Subjects answered by button press whether they found it easy or hard to imagine a scene. The imagination of a scene automatically leads to the establishment of semantic person–occupation associations and activates the hippocampal formation (Degonda et al. 2005). Importantly, subjects were requested to imagine the same scene for a given face–profession pair during learning runs 2 and 3 as during run 1. This additional retrieval component in runs 2 and 3 was to enhance potential memory-related differences between genotype groups. The instruction for the learning of single faces was to decide whether a face was pleasant or unpleasant. This task leads to a semantic encoding of faces. The visual baseline task was to decide whether the area of the left or right ear was larger.

The fMRI Experiment on Episodic Memory—Retrieval

We applied a single fMRI time series for the retrieval of the previously learned face–profession associations and faces. This time series included an associative retrieval condition, a face recognition condition including the studied faces, a new face (distracter faces) detection condition, and the same visual baseline condition that was used for the encoding time series (Fig. 1). For the retrieval of the associations, the previously presented faces were shown again (without the professions) as retrieval cues with the instruction to recall each person's occupation and to indicate the superordinate professional category by button press: academic or workman. For the retrieval of the faces, we used a recognition test including the remember–know procedure (Tulving 1985; Gardiner 1988) to separate between full recollection (remember) and mere familiarity (know) with faces. Subjects were instructed to indicate by button press whether a face was fully remembered (remember) or appeared just familiar (know) or was completely new (Tulving 1985; Gardiner 1988). To conform to the standard fMRI block design, studied faces and new faces were presented in separate blocks. This procedure allowed for the measurement of fMRI signal solely related to either the recognition of old faces or the detection of new faces. A randomized presentation sequence of old and new faces, as typically used for recognition tasks, would have necessitated an event-related fMRI design. Yet, the number of stimuli required for the statistical analysis of event-related fMRI data exceeds normal mnemonic capacities in our difficult paired-associates learning task.

The sequence of task blocks within the fMRI time series was counterbalanced across subjects. All conditions, except for the visual baseline condition (see above), consisted of 4 blocks, each block including 4 trials of 6 s each. All task blocks took 24 s and were announced by an instruction slide.

The fMRI Experiment on Working Memory

The experiment included one fMRI time series with a 2-back task for the assessment of working memory and a baseline task (x-target) for the assessment of concentration. The 2-back task required subjects to respond to a letter repeat with one intervening letter (e.g., S–f–s–g). The “x-target” task required subjects to respond to the occurrence of the letter “x.” Each task was given in 5 blocks of 26 s each. Blocks were announced by an instruction slide. Stimuli were 50 upper- or lowercase letters typed in black on a white background. Thirteen upper- or lowercase letters were presented per block for the duration of 2 s each.

The fMRI Data Acquisition

MR measurements were performed on a 3-T Philips Intera whole body MR scanner equipped with an 8-channel Philips sensitivity-encoded (SENSE) head coil. Functional data were obtained from 32 transverse slices parallel to the AC–PC plane covering the whole brain with a measured spatial resolution of 2.8 × 2.8 × 4 mm3 (acquisition matrix 80 × 80) and a reconstructed resolution of 1.7 × 1.7 × 4 mm3. Data were acquired using a SENSE-single-shot echo planar imaging (Schmidt et al. 2005) sequence with an acceleration factor of R = 2.0. Other scan parameters were echo time (TE) = 35 ms, repetition time (TR) = 3000 ms, and flip angle θ = 82°. A standard 3-dimensional (3D) T1-weighted scan was obtained for anatomical reference with a measured spatial resolution of 1 × 1 × 1.5 mm3 (acquisition matrix 224 × 224) and a reconstructed resolution of 0.9 × 0.9 × 0.8 mm3, TE = 2.3 ms, TR = 20 ms, θ = 20°, and no interslice gaps. A multislice T1-weighted inversion-recovery anatomical scan, oriented perpendicularly to the long axis of the hippocampus, was obtained for hippocampal and parahippocampal volumetry over 33–39 slices with a measured spatial resolution of 0.5 × 0.6 × 1.5 mm3 (acquisition matrix 400 × 320) and a reconstructed spatial resolution of 0.4 × 0.4 × 1.5 mm3, TE = 15 ms, TR = 4200 ms, θ = 20°, inversion recovery delay = 400 ms, and no interslice gaps.

The fMRI Data Analysis

Image pre- and postprocessing and the statistical analyses were performed with SPM2 (http://www.fil.ion.ucl.ac.uk/spm). Standard preprocessing procedures were applied, realignment, normalization, and spatial smoothing (8 mm) (Friston, Ashburner, et al. 1995). On the single-subject level, data were analyzed according to the fixed effects model (SPM2). The 6 head movement parameters were included in the model as confounding factors. Data were high-pass filtered with a specific filter value for each fMRI time series. This value was determined according to 2 × stimulus onset asynchrony × TR. On the second level, within-subject contrasts were entered into random effects analyses (analyses of variance [ANOVAs], T-tests, SPM2), which account for variance between subjects (Friston, Holmes, et al. 1995). We also computed correlations between the within-subject encoding contrasts (learning run 1–run 3) and behavioral measures (simple regression, SPM2). To determine the brain areas commonly activated in all APOE groups during working memory (2-back task vs. x-target task), we computed a conjunction analysis. To this aim, we inclusively masked the summed activation maps of all APOE groups in the ANOVA with the activation maps of each single APOE group in the ANOVA. The mask P value was 0.001, uncorrected. All thresholds were set at P = 0.001, uncorrected for multiple comparisons. An exception was made for the region of interest, the hippocampus, where the analyses were also run with the lower threshold of P = 0.005. This lower threshold is indicated where applicable. No region-of-interest analyses were computed with the fMRI data.

Analysis of Anatomical Magnetic Resonance Imaging Data

Based on the 3D T1-weighted sMRI images, which covered the whole brain, volumes of the total gray and white matter were computed with SPM2. Images were first normalized to the Montreal Neurological Institute T1 template using a standard bounding box and then segmented into gray matter, white matter, and cerebrospinal fluid. Standardized gray and white matter volumes were then multiplied by the determinant of the linear transformation matrix to obtain gray and white matter volumes in cubic centimeter. Based on the multislice T1-weighted high-resolution sMRI images, 2 independent raters (A.B. and H.M.) manually delineated the hippocampal formation (Henke, Kroll, et al. 1999) [cornu ammonis CA] regions, dentate gyrus, and subiculum, excluding the fimbria) and the parahippocampal gyrus using the software Pmod (http://www.pmod.com.). Cerebrospinal fluid was carefully excluded that resulted in conservative volume estimates. Raters relied on descriptions of anatomical landmarks and subdivisions of the medial temporal lobe as described by Duvernoy (1998) and Insausti et al. (1998). Interrater reliabilities ranged between r = 0.8 and 0.98. ANOVAs with APOE genotype and sex as independent variables were computed to determine group differences in brain volumes. Thresholds were set at P < 0.05 level, uncorrected for multiple comparisons (6 subjects were excluded from this analysis because of data loss).

Neuropsychology

Memory functions were assessed with the Wechsler Memory Scale Revised (Härting et al. 2000) in German and with a difficult verbal paired-associates word-learning test (Henke, Weber, et al. 1999). Intelligence was measured with the Hamburg Wechsler Intelligence Scale Revised Test (Tewes 1991). Spatial thinking abilities were tested with the Luria Mental Rotation Test (Christensen 1979). Executive functions were assessed with a verbal (S words) and nonverbal (5 point) fluency task (Regard et al. 1982), with the Kramer Card Sorting Test (Kramer 1970), which measures concept finding and shifting abilities, and with the Stroop Test (Stroop 1935), which measures the suppression of interference. ANOVAs with the APOE genotype as an independent variable were computed to determine group differences in cognitive performance. Thresholds were set at P < 0.05 level, uncorrected for multiple comparisons (one subject was excluded from this analysis because of noncompliance).

Results

Behavioral Results—Large Sample

The APOE4 carriers, compared with APOE4 noncarriers, exhibited better performance in the delayed but not the immediate recall (IR) of the 30 studied words (odds ratio = 1.6, P = 0.009; Fig. 2a). This result remained significant after excluding 6 homozygous ε4 allele carriers from the analysis (odds ratio = 1.6, P = 0.023). Because the delayed recall of 30 words following only one stimulus presentation is difficult, our subjects' performance was rather low ranging around 25%. The recalled words derived from all sets of nouns, not just the last set. Multiple linear regression analysis revealed a significant linear relationship between the presence of no, 1, or 2 ε4 alleles and the delayed recall of words (βstandardized = 0.118, P = 0.023; Fig. 2b). These performance differences in the delayed recall test are probably not attributable to differences in motivation or attention because the IR of words was comparable between genotype groups.

Figure 2.

APOE effects on verbal memory in 340 subjects. (a) Displayed are forward and backward logistic regression analyses after median split for the 5-min recall of words (dependent variable). Factors significantly associated with better memory performance (>median of 8) were female sex, good immediate recall (IR), and the APOE ε4 allele. Dotted line indicates odds ratio of 1. Error bars reflect 95% confidence interval of odds ratio per independent variable. Edu, education. (b) Displayed are multiple forward and backward linear regression analyses with the 5-min recall performance as the dependent variable, adjusted for sex, education, immediate recall and the His452Tyr substitution of the HTR2A gene, which has been related to memory performance (de Quervain et al. 2003). Dots depict mean, bars depict standard error of mean. Forty subjects carried either the ε2/ε2 or the ε2/ε3 variant, 214 subjects the ε3/ε3 variant, 80 subjects the ε3/ε4 variant, and 6 subjects the ε4/ε4 variant.

Figure 2.

APOE effects on verbal memory in 340 subjects. (a) Displayed are forward and backward logistic regression analyses after median split for the 5-min recall of words (dependent variable). Factors significantly associated with better memory performance (>median of 8) were female sex, good immediate recall (IR), and the APOE ε4 allele. Dotted line indicates odds ratio of 1. Error bars reflect 95% confidence interval of odds ratio per independent variable. Edu, education. (b) Displayed are multiple forward and backward linear regression analyses with the 5-min recall performance as the dependent variable, adjusted for sex, education, immediate recall and the His452Tyr substitution of the HTR2A gene, which has been related to memory performance (de Quervain et al. 2003). Dots depict mean, bars depict standard error of mean. Forty subjects carried either the ε2/ε2 or the ε2/ε3 variant, 214 subjects the ε3/ε3 variant, 80 subjects the ε3/ε4 variant, and 6 subjects the ε4/ε4 variant.

Behavioral Results—Small Sample

In the fMRI experiment on episodic memory, response latencies decreased significantly from learning run 1 to run 3 within each APOE group for both faces and face–profession pairs confirming effective learning in each APOE group. APOE group differences in response latencies occurred neither within nor between runs (Table 2). The number of “easy” (to imagine) answers during associative learning increased over learning runs for each APOE group (Table 2; effect did not quite reach significance in APOE ε3/ε4 carriers with P = 0.06). This facilitation of imagining a scene was also indicative of effective learning over runs. There were no APOE group differences in the number of easy answers within or between runs. The number of “pleasant” decisions for the single faces remained constant over the 3 learning runs for each APOE group. APOE groups did not differ in the number of given pleasant answers within or between runs (Table 2). Retrieval accuracies and response latencies for faces and face–profession associations were statistically equal between APOE groups (Table 2).

Table 2

ANOVA on the groups' latency and accuracy values in the learning and retrieval tasks

 ε2/ε3 ε3/ε3 ε3/ε4 F P 
Associative learning 
    # easy (run 1) 8.9 ± 2.2 8.6 ± 2.5 8.8 ± 2.1 0.5 0.951 
    # easy (run 2) 9.3 ± 2.8 9.9 ± 2.6 8.9 ± 1.8 0.465 0.632 
    # easy (run 3) 10.9 ± 1.9 10.4 ± 2.9 10.8 ± 2.9 0.104 0.902 
    # easy (run 1–run 3) −2 ± 2* −1.8 ± 2.3* −1.7 ± 2.8 0.056 0.946 
    RT run 1 3212.6 ± 841 3179.1 ± 599.5 3164.5 ± 624.9 0.015 0.985 
    RT run 2 2944.8 ± 922 2934.4 ± 514.4 2884.2 ± 639.9 0.261 0.772 
    RT run 3 2628.5 ± 798.5 2725 ± 706.4 2717.8 ± 840.3 0.117 0.89 
    RT run 1–run 3 584 ± 633.3* 454.1 ± 607* 472.9 ± 507.5* 0.158 0.855 
    RT run 1–run 2 267.7 ± 595.7 244.7 ± 423 366.1 ± 332.8* 0.221 0.803 
    RT run 2–run 3 316.3 ± 253.1* 209.5 ± 358.1 116.1 ± 331.2 1.107 0.344 
Single-face learning 
    # pleasant (run 1) 6.8 ± 2.9 7.2 ± 1.2 7.9 ± 3 0.566 0.573 
    # pleasant (run 2) 7.2 ± 3.2 6.8 ± 2.3 7.7 ± 2.8 0.267 0.768 
    # pleasant (run 3) 7.5 ± 2.9 7.1 ± 2 7.5 ± 3.3 0.062 0.94 
    # pleasant (run 1–run 3) −0.6 ± 1.3 0.1 ± 1.2 0.5 ± 1.4 1.758 0.19 
    RT run 1 2132.9 ± 511.9 1945.2 ± 227 2081.5 ± 324.4 0.699 0.505 
    RT run 2 1924.5 ± 477.9 1944.3 ± 343.4 1963.2 ± 402.1 0.025 0.975 
    RT run 3 1541.8 ± 508.9 1702.5 ± 312.4 1581.6 ± 388.6 0.426 0.657 
    RT run 1–run 3 591.1 ± 392.8* 242.7 ± 243.4* 490.3 ± 500.4* 2.075 0.143 
    RT run 1–run 2 208.4 ± 340.1 0.9 ± 222.1 153.4 ± 345.3 1.237 0.305 
    RT run 2–run 3 382.7 ± 207.2* 241.7 ± 244.4* 314.4 ± 273.9* 0.879 0.426 
Associative retrieval 
    # correct 12.3 ± 2.2 11.4 ± 2.3 12.2 ± 2.4 0.442 0.647 
    RT correct answers 2597.1 ± 338.6 2621.9 ± 425.8 2888.1 ± 413 1.928 0.163 
Single-face retrieval 
    Remember answers (hits–false alarms) 10.2 ± 4.5 10.3 ± 3.1 10.2 ± 4.6 0.003 0.997 
    RT hits remember 1609 ± 428 2142.2 ± 415 2163.7 ± 856.1 2.857 0.073 
    Know answers (hits–false alarms) 2.5 ± 4.0 3.4 ± 3.2 3.3 ± 5.9 0.121 0.887 
    RT hits know 2513.4 ± 823 2666.1 ± 594.9 2709.7 ± 538.3 0.248 0.782 
 ε2/ε3 ε3/ε3 ε3/ε4 F P 
Associative learning 
    # easy (run 1) 8.9 ± 2.2 8.6 ± 2.5 8.8 ± 2.1 0.5 0.951 
    # easy (run 2) 9.3 ± 2.8 9.9 ± 2.6 8.9 ± 1.8 0.465 0.632 
    # easy (run 3) 10.9 ± 1.9 10.4 ± 2.9 10.8 ± 2.9 0.104 0.902 
    # easy (run 1–run 3) −2 ± 2* −1.8 ± 2.3* −1.7 ± 2.8 0.056 0.946 
    RT run 1 3212.6 ± 841 3179.1 ± 599.5 3164.5 ± 624.9 0.015 0.985 
    RT run 2 2944.8 ± 922 2934.4 ± 514.4 2884.2 ± 639.9 0.261 0.772 
    RT run 3 2628.5 ± 798.5 2725 ± 706.4 2717.8 ± 840.3 0.117 0.89 
    RT run 1–run 3 584 ± 633.3* 454.1 ± 607* 472.9 ± 507.5* 0.158 0.855 
    RT run 1–run 2 267.7 ± 595.7 244.7 ± 423 366.1 ± 332.8* 0.221 0.803 
    RT run 2–run 3 316.3 ± 253.1* 209.5 ± 358.1 116.1 ± 331.2 1.107 0.344 
Single-face learning 
    # pleasant (run 1) 6.8 ± 2.9 7.2 ± 1.2 7.9 ± 3 0.566 0.573 
    # pleasant (run 2) 7.2 ± 3.2 6.8 ± 2.3 7.7 ± 2.8 0.267 0.768 
    # pleasant (run 3) 7.5 ± 2.9 7.1 ± 2 7.5 ± 3.3 0.062 0.94 
    # pleasant (run 1–run 3) −0.6 ± 1.3 0.1 ± 1.2 0.5 ± 1.4 1.758 0.19 
    RT run 1 2132.9 ± 511.9 1945.2 ± 227 2081.5 ± 324.4 0.699 0.505 
    RT run 2 1924.5 ± 477.9 1944.3 ± 343.4 1963.2 ± 402.1 0.025 0.975 
    RT run 3 1541.8 ± 508.9 1702.5 ± 312.4 1581.6 ± 388.6 0.426 0.657 
    RT run 1–run 3 591.1 ± 392.8* 242.7 ± 243.4* 490.3 ± 500.4* 2.075 0.143 
    RT run 1–run 2 208.4 ± 340.1 0.9 ± 222.1 153.4 ± 345.3 1.237 0.305 
    RT run 2–run 3 382.7 ± 207.2* 241.7 ± 244.4* 314.4 ± 273.9* 0.879 0.426 
Associative retrieval 
    # correct 12.3 ± 2.2 11.4 ± 2.3 12.2 ± 2.4 0.442 0.647 
    RT correct answers 2597.1 ± 338.6 2621.9 ± 425.8 2888.1 ± 413 1.928 0.163 
Single-face retrieval 
    Remember answers (hits–false alarms) 10.2 ± 4.5 10.3 ± 3.1 10.2 ± 4.6 0.003 0.997 
    RT hits remember 1609 ± 428 2142.2 ± 415 2163.7 ± 856.1 2.857 0.073 
    Know answers (hits–false alarms) 2.5 ± 4.0 3.4 ± 3.2 3.3 ± 5.9 0.121 0.887 
    RT hits know 2513.4 ± 823 2666.1 ± 594.9 2709.7 ± 538.3 0.248 0.782 

Note: Values, means ± SD; reaction times (RTs) in milliseconds.

*

Paired t-tests between runs per APOE group (P < 0.05).

In the fMRI experiment on working memory, neither accuracy nor response latency differed significantly between APOE groups for the x-target and the 2-back task (Supplementary Table S1).

Performance measures acquired during the neuropsychological examination of the 34 subjects—measures of memory, intelligence, spatial cognition, and executive functions—were also statistically equal between APOE groups (Supplementary Table S2).

Imaging Results—Small Sample

One-sample t-tests including all 34 subjects revealed brain activation in a memory-related neocortical network and robust bilateral hippocampal activation for face–profession associative learning and for single-face learning (each compared with the visual baseline condition) supporting previous evidence (Degonda et al. 2005) that our tasks reliably activate the hippocampus (Fig. 3). One-way ANOVAs (SPM2) with the APOE genotype as independent variable and contrasts for associative and single-face learning/retrieval and working memory as dependent variables were followed by post hoc t-tests between the ε3/ε4 and ε2/ε3 carriers. We directly compared the ε3/ε4 and ε2/ε3 carriers because the ε4 and the ε2 allele might confer opposite effects not only on the risk of AD (Corder et al. 1994) but also on the normal memory-related neurophysiology. Therefore, we were expecting to see the largest brain activity differences between the ε3/ε4 and the ε2/ε3 carriers.

Figure 3.

Learning-related brain activity in all 34 subjects (all APOE groups). Displayed are sagittal, coronal, and horizontal SPM2 through projections of brain regions that exhibited a significant activation during the first run of associative learning (left side) and the first run of single-face learning (right side), each compared with the visual baseline task. Bilateral hippocampal activity is displayed as color-coded statistical parametric t-map on Montreal Neurological Institute anatomical template.

Figure 3.

Learning-related brain activity in all 34 subjects (all APOE groups). Displayed are sagittal, coronal, and horizontal SPM2 through projections of brain regions that exhibited a significant activation during the first run of associative learning (left side) and the first run of single-face learning (right side), each compared with the visual baseline task. Bilateral hippocampal activity is displayed as color-coded statistical parametric t-map on Montreal Neurological Institute anatomical template.

Significant APOE group differences in the signal change from learning run 1 to run 3 were observed in both the ANOVA and the post hoc t-tests within bilateral hippocampus during associative learning (Table 3 and Fig. 4) and within the left hippocampus during single-face learning (Table 3). Further effects were situated in neocortical areas, namely, within the left orbital gyrus and within a left posterior middle temporal area during associative learning (Fig. 4) and within the middle frontal gyrus during single-face learning (Table 3). Whereas the ε3/ε4 carriers decreased their learning-related hippocampal and neocortical activity from the first to the third learning run, the ε2/ε3 carriers increased their learning-related hippocampal and neocortical activity from the first to the third learning run (Fig. 4). These differences in the slope of activity changes between the ε3/ε4 and ε2/ε3 carriers over learning runs were not caused by unequal starting levels of brain activity during the first run of associative learning and single-face learning because the comparison of run 1 brain activity (vs. the visual baseline condition) barely revealed significant differences between ε3/ε4 and ε2/ε3 carriers (Fig. 5). One-sample t-tests computed for each APOE group revealed that ε2/ε3 and ε3/ε3 carriers exhibited transcortical activity increases (contrast run 3–run 1) during repeated associative and single-face learning, whereas ε3/ε4 carriers exhibited primarily decreases of brain activity from run 1 to run 3 (contrast run 1–run 3) (Fig. 6).

Table 3

Brain activation differences between APOE groups during repeated learning and during retrieval

Brain region Left/right MNI coordinates (mm) kE F t 
  x y z    
One-way ANOVA and post hoc t-tests 
Repeated associative learning (run 1 > run 3) 
    APOE ε3/ε4 > ε2/ε3 
        Hippocampus 30 −16 −16 7.66  
30 −18 −16 182  4.29 
−22 −26 −12 7.07*  
−22 −26 −12 15  4.01 
        Orbital gyrus −24 28 −8 21 10.03  
−24 30 −8 11  3.95 
        Post middle temporal area −40 −54 71 14.67  
−40 −54 232  6.34 
    APOE ε2/ε3 > ε3/ε4 No significant differences 
Repeated single-face learning (run 1 > run 3) 
    APOE ε3/ε4 > ε2/ε3 
        Hippocampus −22 −28 −6 6.03*  
−22 −28 −6  3.7 
        Middle frontal gyrus −30 34 38 25 10.39  
−30 34 38 73  5.14 
    APOE ε2/ε3 > ε3/ε4 No significant differences 
Associative retrieval > face recognition 
    APOE ε3/ε4 > ε2/ε3 No significant differences 
    APOE ε2/ε3 > ε3/ε4 
        Hippocampus 36 −40 −4 13 8.85  
34 −40 −6 16  4.01 
        Fusiform gyrus −42 −36 −22 17 10.20  
−44 −34 −24  3.68 
Single-face retrieval > baseline 
    APOE ε3/ε4 > ε2/ε3 No significant differences 
    APOE ε2/ε3 > ε3/ε4 
        Middle frontal gyrus 36 26 52 102 11.55  
36 26 52 71  4.55 
        Superior frontal gyrus 40 54 1408 20.78  
40 54 10  3.7 
        Precuneus −48 50 10 7.66  
−48 50 122  4.21 
Brain region Left/right MNI coordinates (mm) kE F t 
  x y z    
One-way ANOVA and post hoc t-tests 
Repeated associative learning (run 1 > run 3) 
    APOE ε3/ε4 > ε2/ε3 
        Hippocampus 30 −16 −16 7.66  
30 −18 −16 182  4.29 
−22 −26 −12 7.07*  
−22 −26 −12 15  4.01 
        Orbital gyrus −24 28 −8 21 10.03  
−24 30 −8 11  3.95 
        Post middle temporal area −40 −54 71 14.67  
−40 −54 232  6.34 
    APOE ε2/ε3 > ε3/ε4 No significant differences 
Repeated single-face learning (run 1 > run 3) 
    APOE ε3/ε4 > ε2/ε3 
        Hippocampus −22 −28 −6 6.03*  
−22 −28 −6  3.7 
        Middle frontal gyrus −30 34 38 25 10.39  
−30 34 38 73  5.14 
    APOE ε2/ε3 > ε3/ε4 No significant differences 
Associative retrieval > face recognition 
    APOE ε3/ε4 > ε2/ε3 No significant differences 
    APOE ε2/ε3 > ε3/ε4 
        Hippocampus 36 −40 −4 13 8.85  
34 −40 −6 16  4.01 
        Fusiform gyrus −42 −36 −22 17 10.20  
−44 −34 −24  3.68 
Single-face retrieval > baseline 
    APOE ε3/ε4 > ε2/ε3 No significant differences 
    APOE ε2/ε3 > ε3/ε4 
        Middle frontal gyrus 36 26 52 102 11.55  
36 26 52 71  4.55 
        Superior frontal gyrus 40 54 1408 20.78  
40 54 10  3.7 
        Precuneus −48 50 10 7.66  
−48 50 122  4.21 

Note: Listed are regions with significant effects in both the 1-way ANOVA, which includes the 3 APOE groups, and the post hoc t-tests between APOE ε3/ε4 and ε2/ε3 carriers. t and F, values of peaks within significantly (P < 0.001) activated clusters of voxels; post, posterior; kE, cluster size (in voxels); MNI, Montreal Neurological Institute; mm, millimeters.

*

P < 0.005.

Figure 4.

APOE effects on learning-related brain activity changes (run 3–run 1). Left panel: One-way ANOVA shows APOE effects on the right and left hippocampal signal changes over runs of associative learning (run 3–run 1). Columns indicate mean-corrected parameter estimates, bars depict standard error of mean parameter estimates. Post hoc 2-sample t-tests are showing larger right and left hippocampal signal decreases during associative learning from run 1 to run 3 in APOE ε3/ε4 versus APOE ε2/ε3 carriers. These results are displayed as color-coded statistical parametric t-maps on Montreal Neurological Institute anatomical template. Right panel: One-way ANOVA shows APOE effects on the activity change from run 1 to run 3 of associative learning (run 3–run 1) in the left orbital gyrus and a left posterior middle temporal area.

Figure 4.

APOE effects on learning-related brain activity changes (run 3–run 1). Left panel: One-way ANOVA shows APOE effects on the right and left hippocampal signal changes over runs of associative learning (run 3–run 1). Columns indicate mean-corrected parameter estimates, bars depict standard error of mean parameter estimates. Post hoc 2-sample t-tests are showing larger right and left hippocampal signal decreases during associative learning from run 1 to run 3 in APOE ε3/ε4 versus APOE ε2/ε3 carriers. These results are displayed as color-coded statistical parametric t-maps on Montreal Neurological Institute anatomical template. Right panel: One-way ANOVA shows APOE effects on the activity change from run 1 to run 3 of associative learning (run 3–run 1) in the left orbital gyrus and a left posterior middle temporal area.

Figure 5.

Comparisons between APOE ε3/ε4 and APOE ε2/ε3 carriers during the first associative learning run (upper panel) and during the first single-face learning run (lower panel), each versus the visual baseline task. Activity differences between APOE groups are shown as SPM2 through projections of brain regions in sagittal, coronal, and horizontal views. GFd, medial frontal gyrus; Bas. gangl., basal ganglia; Amygd., amygdala; GFs, superior frontal gyrus.

Figure 5.

Comparisons between APOE ε3/ε4 and APOE ε2/ε3 carriers during the first associative learning run (upper panel) and during the first single-face learning run (lower panel), each versus the visual baseline task. Activity differences between APOE groups are shown as SPM2 through projections of brain regions in sagittal, coronal, and horizontal views. GFd, medial frontal gyrus; Bas. gangl., basal ganglia; Amygd., amygdala; GFs, superior frontal gyrus.

Figure 6.

Brain activity differences between learning runs 1 and 3 per APOE group. Displayed are sagittal, coronal, and horizontal SPM2 through projections of brain regions that exhibited a significant signal decrease (run 1–run 3) or signal increase (run 3–run 1) during associative learning (left side) and single-face learning (right side).

Figure 6.

Brain activity differences between learning runs 1 and 3 per APOE group. Displayed are sagittal, coronal, and horizontal SPM2 through projections of brain regions that exhibited a significant signal decrease (run 1–run 3) or signal increase (run 3–run 1) during associative learning (left side) and single-face learning (right side).

To determine whether the slope of learning-related brain activity changes measured over the 3 learning runs was related to retrieval success in each APOE group, we computed correlations between the signal change from learning run 1 to run 3 and the number of correctly remembered associations or faces (only remember responses for faces: hits–false alarms). The correlations between associative learning–related brain activity changes over learning runs and associative retrieval performance were positive (the more signal decrease during learning, the better the retrieval performance) for the ε3/ε4 carriers but negative (the more signal increase during learning, the better retrieval performance) for the ε2/ε3 carriers within the left hippocampus (ε3/ε4: r = 0.75; ε2/ε3: r = −0.84; Fig. 7 and Table 4) and many neocortical areas (Table 4) that were not always the same between APOE groups. A similar pattern of results was observed for the correlations between face learning–related brain activity changes over learning runs and face recognition accuracy (Table 5).

Figure 7.

Simple regression between left hippocampal signal difference during associative learning (run 1–run 3) and associative retrieval performance computed for APOE ε3/ε4 (left panel) and APOE ε2/ε3 carriers (right panel). Y axis, beta values (SPM2) of the most active voxel in hippocampal activation cluster; X axis, number of correctly retrieved associations; black line, regression line.

Figure 7.

Simple regression between left hippocampal signal difference during associative learning (run 1–run 3) and associative retrieval performance computed for APOE ε3/ε4 (left panel) and APOE ε2/ε3 carriers (right panel). Y axis, beta values (SPM2) of the most active voxel in hippocampal activation cluster; X axis, number of correctly retrieved associations; black line, regression line.

Table 4

Correlation between associative learning signal difference (run 1–run 3) and associative retrieval performance

Brain region Left/right MNI coordinates (mm) t r Brain region Left/right MNI coordinates (mm) t r 
  x y z     x y z   
Positive correlations Negative correlations 
APOE ε2/ε3 APOE ε2/ε3 
    Superior parietal lobule −40 −40 64 6.36 0.90     Hippocampus −38 −22 −16 4.57a −0.84 
          Parahippocampal gyrus −30 −14 −28 5.38 −0.87 
          Middle frontal gyrus −32 42 38 5.39 −0.87 
      26 54 4.87 −0.85 
          Superior frontal gyrus 26 62 24 7.54 −0.93 
      −30 −8 62 5.69 −0.88 
          Orbital gyrus −16 26 −18 5.37 −0.87 
          Cingulate gyrus −8 −52 44 8.28 −0.94 
      −32 36 5.44 −0.88 
      −12 −46 34 4.88 −0.85 
          Middle temporal gyrus −56 −56 6.86 −0.92 
      44 −74 22 5.37 −0.87 
          Superior temporal gyrus −60 −54 18 6.5 −0.91 
      −58 −46 18 5.2 −0.87 
          Fusiform gyrus −40 −86 5.73 −0.89 
          Lingual gyrus −16 −90 −8 14.60 −0.98 
      −66 4.98 −0.86 
          Middle occipital gyrus −24 −90 28 5.32 −0.87 
          Basal ganglia −20 16 −6 5.28 −0.87 
          Cerebellum −58 −46 7.53 −0.93 
APOE ε3/ε3 APOE ε3/ε3 
    Fusiform gyrus −26 −82 −20 4.72 0.83     Insula −46 −14 10 5.21 −0.85 
    Inferior temporal gyrus 62 −48 −10 6.29 0.89       
APOE ε3/ε4 APOE ε3/ε4 
    Hippocampus −26 −32 −4 3.56* 0.75     No significant correlations       
    Inferior frontal gyrus 40 42 −20 5.11 0.83        
42 24 −12 4.94 0.82        
−44 36 −20 4.88 0.82        
    Middle frontal gyrus −34 32 44 7.39 0.91        
48 32 18 4.5 0.79        
    Superior frontal gyrus 20 −10 56 6.02 0.87        
    Paracentral lobule −42 58 5.35 0.84        
    Precentral gyrus −8 −24 64 4.55 0.80        
    Insula 30 −22 12 4.75 0.81        
    Putamen −28 −4 5.27 0.84        
Brain region Left/right MNI coordinates (mm) t r Brain region Left/right MNI coordinates (mm) t r 
  x y z     x y z   
Positive correlations Negative correlations 
APOE ε2/ε3 APOE ε2/ε3 
    Superior parietal lobule −40 −40 64 6.36 0.90     Hippocampus −38 −22 −16 4.57a −0.84 
          Parahippocampal gyrus −30 −14 −28 5.38 −0.87 
          Middle frontal gyrus −32 42 38 5.39 −0.87 
      26 54 4.87 −0.85 
          Superior frontal gyrus 26 62 24 7.54 −0.93 
      −30 −8 62 5.69 −0.88 
          Orbital gyrus −16 26 −18 5.37 −0.87 
          Cingulate gyrus −8 −52 44 8.28 −0.94 
      −32 36 5.44 −0.88 
      −12 −46 34 4.88 −0.85 
          Middle temporal gyrus −56 −56 6.86 −0.92 
      44 −74 22 5.37 −0.87 
          Superior temporal gyrus −60 −54 18 6.5 −0.91 
      −58 −46 18 5.2 −0.87 
          Fusiform gyrus −40 −86 5.73 −0.89 
          Lingual gyrus −16 −90 −8 14.60 −0.98 
      −66 4.98 −0.86 
          Middle occipital gyrus −24 −90 28 5.32 −0.87 
          Basal ganglia −20 16 −6 5.28 −0.87 
          Cerebellum −58 −46 7.53 −0.93 
APOE ε3/ε3 APOE ε3/ε3 
    Fusiform gyrus −26 −82 −20 4.72 0.83     Insula −46 −14 10 5.21 −0.85 
    Inferior temporal gyrus 62 −48 −10 6.29 0.89       
APOE ε3/ε4 APOE ε3/ε4 
    Hippocampus −26 −32 −4 3.56* 0.75     No significant correlations       
    Inferior frontal gyrus 40 42 −20 5.11 0.83        
42 24 −12 4.94 0.82        
−44 36 −20 4.88 0.82        
    Middle frontal gyrus −34 32 44 7.39 0.91        
48 32 18 4.5 0.79        
    Superior frontal gyrus 20 −10 56 6.02 0.87        
    Paracentral lobule −42 58 5.35 0.84        
    Precentral gyrus −8 −24 64 4.55 0.80        
    Insula 30 −22 12 4.75 0.81        
    Putamen −28 −4 5.27 0.84        

Note: t, values of peaks within significantly (P < 0.001) activated clusters of voxels; r, correlation coefficient; MNI, Montreal Neurological Institute.

*

P < 0.005.

Table 5

Correlation between single-face–learning signal difference (run 1–run 3) and face recognition performance (for remember responses: hits–false alarms)

Brain region Left/right MNI coordinates (mm) t r Brain region Left/right MNI coordinates (mm) t r 
  x y z     x y z   
Positive correlations Negative correlations 
APOE ε2/ε3 APOE ε2/ε3 
    Medial frontal gyrus −10 56 4.69 0.86     Amygdala −18 −26 8.14 0.94 
    Fusiform gyrus −38 −56 −26 6.23 0.91     Inferior frontal gyrus 36 30 −16 8.04 0.94 
       −36 34 −4 5.32 0.88 
           Middle frontal gyrus 30 52 −8 5.43 0.89 
       18 60 −8 5.77 0.90 
           Superior frontal gyrus 24 56 34 6.76 0.92 
       −22 62 28 5.62 0.89 
           Precentral gyrus 46 38 4.82 0.86 
           Lingual gyrus −4 −86 −10 5.27 0.88 
       −88 −2 4.76 0.86 
APOE ε3/ε3 APOE ε3/ε3 
    Hippocampus −36 −18 −18 4.15* 0.83     No significant correlations       
22 −14 −14 4.15* 0.83        
    Parahippocampal gyrus 26 −42 −12 8.57 0.95        
    Fusiform gyrus 24 −64 −6 8.58 0.95        
    Inferior frontal gyrus −46 26 26 10.11 0.96        
58 18 32 5.62 0.89        
    Middle frontal gyrus −48 36 7.52 0.94        
−32 42 24 6.95 0.93        
44 44 24 6.3 0.91        
    Medial frontal gyrus 14 54 5.42 0.89        
−6 −4 58 5.19 0.88        
    Superior frontal gyrus −16 12 64 4.87 0.86        
    Middle temporal gyrus 40 −36 6.61 0.92        
48 −4 −20 5.39 0.89        
    Superior temporal gyrus 64 −32 5.52 0.89        
    Inferior parietal lobule 58 −24 30 6.25 0.91        
    Inferior parietal lobule −66 −24 26 5.15 0.88        
    Precentral gyrus −14 −26 66 8.02 0.94        
58 −10 40 6.78 0.92        
32 −28 68 5.11 0.87        
−46 −12 54 5.06 0.87        
    Lingual gyrus −8 −76 −4 7.42 0.93        
20 −94 −16 5.31 0.88        
    Superior parietal lobule 34 −80 42 5.86 0.90        
    Insula 34 −4 −6 5.54 0.89        
    Cerebellum −6 −50 −12 8.21 0.95        
APOE ε3/ε4 APOE ε3/ε4 
    Hippocampus 20 −16 −14 4.35* 0.81     No significant correlations       
    Inferior frontal gyrus −46 38 −12 4.7 0.83        
    Middle frontal gyrus 30 14 42 5.36 0.86        
    Superior frontal gyrus −32 12 62 4.96 0.84        
30 12 58 4.81 0.84        
22 −12 74 4.72 0.83        
18 24 44 4.6 0.82        
    Cingulate gyrus 12 40 −10 4.83 0.84        
−14 −60 22 4.97 0.84        
    Middle temporal gyrus −56 −14 −24 5.32 0.86        
    Superior temporal gyrus 44 −50 16 4.66 0.83        
    Inferior parietal lobule −30 −66 36 8.58 0.94        
−34 −58 38 4.6 0.82        
    Cerebellum −58 −32 4.75 0.83        
Brain region Left/right MNI coordinates (mm) t r Brain region Left/right MNI coordinates (mm) t r 
  x y z     x y z   
Positive correlations Negative correlations 
APOE ε2/ε3 APOE ε2/ε3 
    Medial frontal gyrus −10 56 4.69 0.86     Amygdala −18 −26 8.14 0.94 
    Fusiform gyrus −38 −56 −26 6.23 0.91     Inferior frontal gyrus 36 30 −16 8.04 0.94 
       −36 34 −4 5.32 0.88 
           Middle frontal gyrus 30 52 −8 5.43 0.89 
       18 60 −8 5.77 0.90 
           Superior frontal gyrus 24 56 34 6.76 0.92 
       −22 62 28 5.62 0.89 
           Precentral gyrus 46 38 4.82 0.86 
           Lingual gyrus −4 −86 −10 5.27 0.88 
       −88 −2 4.76 0.86 
APOE ε3/ε3 APOE ε3/ε3 
    Hippocampus −36 −18 −18 4.15* 0.83     No significant correlations       
22 −14 −14 4.15* 0.83        
    Parahippocampal gyrus 26 −42 −12 8.57 0.95        
    Fusiform gyrus 24 −64 −6 8.58 0.95        
    Inferior frontal gyrus −46 26 26 10.11 0.96        
58 18 32 5.62 0.89        
    Middle frontal gyrus −48 36 7.52 0.94        
−32 42 24 6.95 0.93        
44 44 24 6.3 0.91        
    Medial frontal gyrus 14 54 5.42 0.89        
−6 −4 58 5.19 0.88        
    Superior frontal gyrus −16 12 64 4.87 0.86        
    Middle temporal gyrus 40 −36 6.61 0.92        
48 −4 −20 5.39 0.89        
    Superior temporal gyrus 64 −32 5.52 0.89        
    Inferior parietal lobule 58 −24 30 6.25 0.91        
    Inferior parietal lobule −66 −24 26 5.15 0.88        
    Precentral gyrus −14 −26 66 8.02 0.94        
58 −10 40 6.78 0.92        
32 −28 68 5.11 0.87        
−46 −12 54 5.06 0.87        
    Lingual gyrus −8 −76 −4 7.42 0.93        
20 −94 −16 5.31 0.88        
    Superior parietal lobule 34 −80 42 5.86 0.90        
    Insula 34 −4 −6 5.54 0.89        
    Cerebellum −6 −50 −12 8.21 0.95        
APOE ε3/ε4 APOE ε3/ε4 
    Hippocampus 20 −16 −14 4.35* 0.81     No significant correlations       
    Inferior frontal gyrus −46 38 −12 4.7 0.83        
    Middle frontal gyrus 30 14 42 5.36 0.86        
    Superior frontal gyrus −32 12 62 4.96 0.84        
30 12 58 4.81 0.84        
22 −12 74 4.72 0.83        
18 24 44 4.6 0.82        
    Cingulate gyrus 12 40 −10 4.83 0.84        
−14 −60 22 4.97 0.84        
    Middle temporal gyrus −56 −14 −24 5.32 0.86        
    Superior temporal gyrus 44 −50 16 4.66 0.83        
    Inferior parietal lobule −30 −66 36 8.58 0.94        
−34 −58 38 4.6 0.82        
    Cerebellum −58 −32 4.75 0.83        

Note: t, values of peaks within significantly (P < 0.001) activated clusters of voxels; r, correlation coefficient. MNI, Montreal Neurological Institute.

*

P < 0.005.

During retrieval, the ε3/ε4 carriers exhibited less brain activity than the ε2/ε3 carriers in spite of their equivalent retrieval success. The comparison of the retrieval of face–profession associations with the retrieval of single faces isolates brain activity underlying the retrieval of associations alone. In this comparison, the ε3/ε4 carriers exhibited weaker activity increases compared with the ε2/ε3 carriers within the right hippocampus and the left fusiform gyrus (Table 3). In the comparison of single-face retrieval with the visual baseline condition, the ε3/ε4 carriers exhibited weaker activity increases compared with the ε2/ε3 carriers within the right middle and superior frontal gyri and within the right precuneus (Table 3).

The working memory experiment yielded robust bilateral frontoparietal activation in each APOE group (Supplementary Fig. S1). Frontoparietal activity has typically been found in neuroimaging studies of working memory (for a review, see Baddeley 2003). A conjunction analysis confirmed that activity common to all 3 APOE groups was located in frontoparietal areas (Fig. S1 and Table S3). There were no significant MR signal differences between the ε2/ε3 and the ε3/ε4 carriers. Therefore, the above-reported brain activity differences between APOE groups during associative and single-face learning/retrieval were probably specific to episodic memory.

To determine whether APOE group differences in brain activity resulted from interindividual differences in the volume of gray or white brain matter, we performed volumetric analyses of the subjects' brain structures. Both automated whole brain gray and white matter segmentation (SPM2) (Ashburner and Friston 2000) and manual volume measurements of the hippocampal formation and the parahippocampal gyrus yielded comparable volumes between the 3 APOE groups (Supplementary Table S4).

Discussion

APOE4 is the major genetic risk factor for AD, whereas APOE2 appears to confer a protective effect against AD. Although the frequency of the APOE4 allele is low in humans, studies in primates suggest that APOE4 is the ancestral allele (Finch and Sapolsky 1999). Its existence and further persistence in humans might be explained by an advantageous effect of APOE4 in early adulthood. Here, we report an association of APOE4 with better episodic memory performance and with smaller learning- and retrieval-related brain activity increases compared with APOE2 and APOE3 in young and healthy human subjects.

The direct comparison between APOE groups showed that, despite comparable starting levels of learning-related brain activity between APOE groups (Fig. 5), the APOE ε3/ε4 carriers decreased their learning-related bilateral hippocampal, left orbital frontal, left middle frontal, and left middle temporal activities during the progressively deeper encoding of faces and associations over runs, whereas the APOE ε2/ε3 carriers increased their learning-related activity in these regions (Fig. 4 and Table 3). This disparity in the learning-related brain activity slopes between groups was not related to differences in performance levels because all performance measures collected during the learning runs were statistically equal between the 3 APOE groups (Table 2). We therefore assume that the APOE ε4 allele is associated with a more economic use of learning-related neural resources than the APOE ε2 allele. Consequently, the APOE ε4 allele and the APOE ε2 allele do confer opposing effects not only on the development of AD in middle-aged individuals but also on the normal learning-related neurophysiology in young individuals. For patients with an amnestic mild cognitive impairment, that is, a transitional state between the cognitive changes of normal aging and AD (Petersen et al. 2001), Johnson et al. (2004) reported also significant differences in medial temporal activity slopes over repeated face learning compared with healthy subjects. Slopes were more negative in the controls than the patients. Furthermore, using hippocampal depth electrodes in patients with temporal lobe epilepsy, Grunwald et al. (1999) found that medial temporal N400 responses to items decreased with repetition in the intact hippocampus but not in the epileptic hippocampus. These data suggest that an economic use of learning-related neural resources characterizes a well functioning memory system.

The question arises whether the APOE differences in brain activity slopes reflect a differential neurophysiology underlying episodic memory or another form of memory that is simultaneously active during the learning runs. The repeated exposure to material does evoke retrieval (from previous exposure) and reencoding processes in the realm of not only episodic memory but also priming. Priming is a form of implicit/nondeclarative memory that involves a facilitation of the ability to identify, produce, or classify an item as a result of a previous encounter with that item or a related item (Schacter et al. 2004). Priming is often associated with accelerated information processing (shortening of response latencies) and decreasing neural activity over repeated exposures, as observed in our APOE ε3/ε4 group. One could, therefore, speculate that the differential activity slopes over learning runs reflected priming more than episodic memory. We found that neither of the APOE groups exhibited a significant correlation of medial temporal activity slopes with the shortening of response latencies from run 1 to run 3. Instead, medial temporal (Fig. 7) and also neocortical activity slopes were correlated with retrieval success for both faces (Table 5) and face–profession associations (Table 4). Yet, the direction of these correlations appeared to distinguish the ε3/ε4 carriers from the ε2/ε3 carriers. Whereas correlations were positive (the more signal decrease over runs, the better retrieval performance) for the ε3/ε4 carriers, they were negative (the more signal increase over runs, the better retrieval performance) for the ε2/ε3 carriers. Thus, a large signal increase over learning runs denoted the good learners among the APOE ε2/ε3 carriers, but a large signal decrease characterized the good learners among the APOE ε3/ε4 carriers.

The inspection of brain activity slopes over learning runs within each APOE group (no direct comparison between groups) suggests reverse activity slopes in APOE ε3/ε4 carriers versus APOE ε2/ε3 carriers within the whole brain (Fig. 6). The APOE ε3/ε4 group exhibited mostly negative activity slopes in many left and a few right prefrontal areas associated with executive functions (Collette et al. 2006) during both learning tasks, bilateral anterior superior temporal areas related to lexical–semantic processing (e.g., Bright et al. 2004) during associative learning, right middle temporal areas related to the processing of person semantics (Thompson et al. 2004) during single-face learning, and the right fusiform face area (Kanwisher et al. 1997) during single-face learning (Fig. 6). Activity slopes in several of these areas were positively correlated with retrieval success—the greater the activity decrease, the greater retrieval success (Tables 4 and 5). The APOE ε3/ε4 group also exhibited a few spots of activity increases over learning runs within the inferior parietal lobule bilaterally, but these were not correlated with retrieval success. The activity slopes were primarily positive in the APOE ε2/ε3 and the APOE ε3/ε3 groups and were located in large parts of the parietal lobe bilaterally (Fig. 6) and might reflect an increase in the richness of imagery contents over learning runs (Mellet et al. 2000; Ganis et al. 2004; Sack et al. 2005) during the imagination task given for encoding. However, these parietal activity slopes were not correlated with retrieval success in either APOE group. Therefore, we assume that they were not directly relevant for memory storage. Whereas none of the other positive activity slopes in the APOE ε3/ε3 group were correlated with retrieval success, the APOE ε2/ε3 group exhibited further positive activity slopes in the frontal and temporal lobes that were correlated with retrieval success (Tables 4 and 5), suggesting that they were related to memory storage.

We also observed a more economic use of retrieval-related neural resources in the APOE ε3/ε4 carriers versus the APOE ε2/ε3 carriers. The APOE ε3/ε4 carriers invested less neural resources into the retrieval process than the APOE ε2/ε3 carriers within the right hippocampus and left fusiform gyrus during associative retrieval and within the right middle and superior frontal gyri and the right precuneus during face retrieval (Table 3); yet, the 2 groups achieved a comparable retrieval performance in these retrieval tasks (Table 2). This finding suggests that task demands were higher on the APOE2 than the APOE4 carriers—a finding that is intuitive given the better retrieval performance in the APOE4 carriers within the large and nonmatched sample of 340 subjects. Although we had matched participants of the fMRI study for memory performance, task demands might still have been higher on the APOE2 than the APOE4 carriers. It has been demonstrated for a variety of cognitive tasks that increasing task demands are associated with an increase in the spatial extent and the magnitude of brain activity in the task-specialized neural network (Just et al. 1996; Carpenter et al. 1999). Patients with an amnesic mild cognitive impairment exhibited larger memory-related activity enhancements within the medial temporal lobe (Dickerson et al. 2004) compared with healthy individuals. In addition, neuroimaging studies have shown that practice can lead to reductions in brain activation (Raichle et al. 1994; Simpson et al. 2001) and that brains of high performers or people with much practice work more efficiently (less activity with better task performance) than the brains of lower performers or people with less practice (Haier, Siegel, MacLachlan, et al. 1992; Haier, Siegel, Tang, et al. 1992; Neubauer et al. 2005). We conclude, therefore, that brain activity levels may be elevated in response to increasing task demands caused by either an objective increase in task difficulty or a subjective increase in task difficulty due to less practice or less favorable genetic or neurophysiological resources.

Our neuroimaging APOE groups were statistically equal in terms of neuropsychological test performance (Supplementary Table S2) and gray and white matter volumes (Supplementary Table S4)—particularly hippocampal and parahippocampal volumes. It is, therefore, unlikely that the performance and imaging results were biased by morphological or cognitive differences between APOE groups. Moreover, brain activity differences between APOE groups were found only for episodic memory, not for working memory. The APOE ε2/ε3 and APOE ε3/ε4 carriers differed neither in performance (Supplementary Table S1) nor in brain activity levels on the working memory task. It should be noted that the participants in these studies were well-educated (around 14 years of education) and scoring above average on the intelligence test (around 123 IQ points). Whether the reported APOE differences generalize to average functioning individuals must be examined in future studies.

The economic use of neural resources in APOE4 carriers concurs with advantageous effects of the APOE4 allele on the normal neurophysiological functioning in young animals. Hippocampal LTP was enhanced at a younger age in knock-in mice lacking mouse APOE, but instead expressing human APOE4 (Kitamura et al. 2004). This LTP enhancement was age dependent and disappeared in adult knock-in mice. Moreover, APOE4, but not APOE3, stimulated the transcriptional activity of CREB by activating the ERK cascade in rat primary hippocampal neurons (Ohkubo et al. 2001). The influence of APOE4 on this memory-related pathway may provide an explanation for the beneficial effect of APOE4 on human memory in young adults. On the other hand, there is evidence that APOE4 alters intracellular calcium homeostasis, which might ultimately lead to neuronal damage (Qiu et al. 2003). One may speculate that a sustained APOE4-related neuronal calcium increase, which is related to improved memory performance at a young age, finally induces age-associated neuronal damage. Alternatively, the APOE4-associated cognitive impairment and abnormal brain activity/metabolism found in middle-aged and older subjects might be a consequence of the continuous deposition of amyloid plaques and neurofibrillary tangles, which are associated with dysfunction, deafferentation, and degeneration of neurons in the long course of AD. The deposition of amyloid plaques and neurofibrillary tangles has been related to the presence of the APOE4 allele (Ghebremedhin et al. 1998, 2001; Bennett et al. 2003, 2005; Tiraboschi et al. 2004; Thal et al. 2005). Importantly, these neuropathological changes precede the clinical diagnosis of AD by 30–50 years (Ohm et al. 1995; Braak H and Braak E 1996; Delacourte et al. 1999). A single copy of the APOE4 allele in middle-aged and older persons with normal memory performance was associated with lowered parietal and temporal lobe metabolism, which predicted cognitive and metabolic decline after 2 years of longitudinal follow-up (Small et al. 2000; de Leon et al. 2001). Moreover, older APOE4 carriers, compared with APOE3 carriers, exhibited increases in brain activity in response to verbal (Bookheimer et al. 2000) and picture (Bondi et al. 2005) learning, presumably to compensate for AD-related preclinical neuropathology. Indeed, the greater their brain activity increase was, the greater was their memory decline during the following 2 years (Bookheimer et al. 2000). We assume that brain activity abnormalities in middle-aged and older APOE4 carriers reflect ongoing pathophysiological processes of AD. Because of the long preclinical course of AD, a direct effect of the APOE isoforms on the normal memory-related neurophysiology, independently of pathological deposits, can only be studied in subjects as young as those included in the present study.

In conclusion, we suggest that the APOE4 allele is associated with positive effects on episodic memory in young, healthy individuals. Its association with cognitive impairment and abnormal brain activity later in life is probably mediated by AD-related preclinical neuropathology. Future studies need to address a potential link between the APOE4 allele's beneficial effects on normal memory and its role as a risk factor for AD.

Supplementary Material

Supplementary material can be found at: http://www.cercor.oxfordjournals.org/.

We are grateful to Roger Lüchinger for technical assistance and to Guillen Fernandez for comments on the manuscript. The study was supported by the EMDO Foundation, the Helmut Horten Foundation, the Swiss National Science Foundation (3100-067114 to KH, PP00B-68859 to AP, PP00B-106708 to DJFQ), Foundation for Clinical Neuropsychiatric Research and the European Union contract LSHM-CT-2003-503330 (Abnormal Proteins in the Pathogenesis of Neurodegenerative Disorders). Conflict of Interest: None declared.

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