Edited by: Rajeev D. Raizada, Cornell University, USA
Reviewed by: Claudia Buss, University of California Irvine, USA; Przemyslaw Tomalski, University of Warsaw, Poland
*Correspondence: Kimberly G. Noble, GH Sergievsky Center, Columbia University, 630 W. 168th St., P&S Box 16, New York, NY 10032, USA. e-mail:
This is an open-access article distributed under the terms of the
Socioeconomic disparities—and particularly differences in educational attainment—are associated with remarkable differences in cognition and behavior across the life-span. Decreased educational attainment has been linked to increased exposure to life stressors, which in turn have been associated with structural differences in the hippocampus and the amygdala. However, the degree to which educational attainment is directly associated with anatomical differences in these structures remains unclear. Recent studies in children have found socioeconomic differences in regional brain volume in the hippocampus and amygdala across childhood and adolescence. Here we expand on this work, by investigating whether disparities in hippocampal and amygdala volume persist across the life-span. In a sample of 275 individuals from the BRAINnet Foundation database ranging in age from 17 to 87, we found that socioeconomic status (SES), as operationalized by years of educational attainment, moderates the effect of age on hippocampal volume. Specifically, hippocampal volume tended to markedly decrease with age among less educated individuals, whereas age-related reductions in hippocampal volume were less pronounced among more highly educated individuals. No such effects were found for amygdala volume. Possible mechanisms by which education may buffer age-related effects on hippocampal volume are discussed.
Socioeconomic disparities are associated with remarkable differences in cognition and behavior (Noble et al.,
Socioeconomic status (SES) is typically characterized by multiple factors, including educational attainment, occupation, and income level (McLoyd,
Different components of SES may operate differentially on specific life outcomes, via different mechanisms (Duncan and Magnuson,
Educational attainment may have differential effects on particular brain regions over the life course. Of course, SES in general, and educational attainment specifically, is a marker for a broad conglomerate of experiences and exposures. Many environmental factors have been shown to affect regionally specific brain development (Rosenzweig,
One recent study found that higher educational attainment was associated with decreased white matter mean diffusivity in the hippocampus (Piras et al.,
In the amygdala, some investigators have reported positive relationships between educational attainment and regional volume (Laakso et al.,
One way to reconcile these seemingly disparate findings is to note that, although a number studies have examined the effects of educational disparities on regional brain structure, the majority have done so within a relatively narrow age range. To our knowledge, no study has assessed whether any effect of educational attainment on these structures may be moderated by the age of participants across the lifespan. As the absence of a main effect is uninterpretable in the presence of an interaction (Pedhazur,
The theory of “brain reserve” suggests that higher levels of education may confer benefits in brain structure or function that may buffer against age-related changes (Stern,
Based on this reasoning, we hypothesized that educational attainment may be associated with regional volumetric differences in the hippocampus and amygdala across the life-course. Further, we predicted that the effects of educational attainment would not be consistent across all ages, but rather would be most pronounced in buffering against age-related decline. To test these hypotheses, we employed structural magnetic resonance imaging (MRI) to assess regional hippocampal and amygdala volume in an educationally diverse sample of adults across a seven-decade age range.
Subjects were compiled from the Brain Resource International Database, accessed via the independently governed 501(c)(3) BRAINnet Foundation (
89 | 83 | 103 | 275 | |
Age: Mean (s.d.) | 48 (19) | 35 (16) | 36 (13) | 39.7 (17) |
Sex | 49 female, 40 male | 42 female, 41 male | 83 female, 89 male | 152 female, 123 male |
This participant cohort represents a community sample found in the major cities of Australia with no known bias in region-wise education or distribution of educational attainment. Although individuals from lower socioeconomic backgrounds are often difficult to recruit to participate in research studies, educational attainment of the sample spanned a wide range (mean 14 years, s.d. 3.1, range 3–18 years). This range of education is due in part to the fact that, across Australia, educational attainment is fairly diverse, with approximately 25% of individuals not earning a high school diploma, approximately 45% of individuals completing high school only, and approximately 30% completing some type of post-secondary education (Pink and Australian Bureau of Statistics,
MRI data sets came from two imaging sites: Westmead Hospital (Sydney, Australia) and Wakefield Imaging (Adelaide, Australia). All participants in the study were recruited from the general population in the Sydney and Adelaide urban and suburban areas within Australia through standard recruitment procedures (e.g., community advertisements). Cross-site reliability has been established (Grieve et al.,
Participants completed WebQ, a standardized computer-based battery of questionnaires that assess medical history, demographics, and psychological function, including current or lifetime diagnosis of neurological and psychiatric (Axis 1) conditions (Heatherton et al.,
All participants provided informed consent in accordance with the National Health and Medical Research Council of Australia guidelines. Participation was voluntary and participants were reimbursed to cover cost for their time and travel to the research center.
One hundred fourteen of the participants had complete data on a Memory Recall and Recognition test. This test is a variant of the Rey Auditory Verbal Learning and Memory task (Rey,
MRI was conducted on a 1.5 Tesla Siemens Sonata system at Westmead Hospital, Sydney and a 1.5 Tesla Siemens Sonata at Perrett Imaging, Flinders University, Australia. The MRI protocol included a 3-D T1-weighted image acquired in the sagittal plane using an MPRAGE sequence (TR = 9.7 ms; TE = 4 ms; echo train 7; flip angle = 12°; TI = 200 ms; NEX = 1). A total of 180 1 mm slices (without gap) were acquired with a 256 × 256 matrix with an in plane resolution of 1 mm × 1 mm. Approximately 1% of the MRI data were excluded from the overall database due to MRI technical acquisition errors/artifact.
Volumetric segmentation was performed on the 3D T1-weighted structural images with the FreeSurfer image analysis suite (version 4.3) (
To assess whether educational attainment influences regional brain volume across the life-span, we conducted a series of regression analyses, with total hippocampal volume or amygdala volume as the dependent variable, and years of educational attainment as the independent variable of interest. Analyses included age, sex, and total brain volume as covariates. We hypothesized that educational attainment would account for variation in regional brain volume, adjusting for age, sex, and total brain volume. Additionally, we examined the extent to which age-related regional brain volumetric differences would be modified by educational attainment. Specifically, we predicted a significant education × age interaction, such that age-related decreases in regional brain volume would be less steep among more highly educated individuals.
For ease of presentation, results in tables and figures are at times presented using categorical bins of age and educational attainment. However, unless otherwise noted, statistical analyses considered age in years and years of education as continuous variables, to take advantage of the full level of detail provided by the dataset.
Table
Males <35 | 9004 (871) | 3421 (352) |
Males 35 and up | 8187 (1063) | 3103 (455) |
Females <35 | 8248 (711) | 2968 (306) |
Females 35 and up | 7893 (830) | 2847 (329) |
Both hippocampal and amygdala volumes were normally distributed across the sample, without outliers (Hippocampus: skewness = −0.089 (SE 0.147), kurtosis = 1.175 (SE 0.293), Kolmogorov–Smirnov normality statistic = 0.041,
Initial bivariate correlations showed that age was significantly negatively associated with hippocampal size across the entire age range (
Additionally, across the entire age range, educational attainment was positively and linearly associated with hippocampal size (
Similar to the findings in the hippocampus, bivariate correlations revealed a significant negative association between amygdala volume and age (
A significant linear association between amygdala volume and educational attainment was also observed (
Of interest next was the extent to which the effect of age on regional volume varied by an individual's educational attainment. To assess this hypothesis, models above were extended to include terms for an age × education interaction. We first assessed the hippocampus. A significant age × education interaction was present (
When considered separately, both left and right hippocampi showed a similar interaction (left hippocampus: Beta = 0.508,
Figure
Of note, there was a wide span of educational attainment across the entire age range, with the educational spectrum represented across each age range, from young adults to elderly individuals (see Table
No significant education × age interaction was observed in total amygdala volume, or left or right hemispheres considered separately, regardless of whether influential points were included or excluded, suggesting that the effect of age on amygdala volume is independent of educational attainment.
No specific clinical testing was done to assess whether participants may have had early signs of a neurodegenerative disease. However, the scores of the 114 participants who had valid data for the Memory Recall and Recognition test were extremely similar to those of the 1007 participants in the full BrainNet International Database, from which our sample was drawn (Clark et al.,
Immediate | Present sample | 32.13 | 4.31 | 33.19 | 4.80 |
recall | ( |
||||
Full database | 30.76 | 6.98 | 31.78 | 7.17 | |
Short delay | Present sample | 7.96 | 1.96 | 8.41 | 1.88 |
recall | ( |
||||
Full database | 7.52 | 2.62 | 8.04 | 2.60 | |
Long delay | Present sample | 7.41 | 1.93 | 7.90 | 2.17 |
recall | ( |
||||
Full database | 7.34 | 2.40 | 7.89 | 2.52 | |
Recognition | Present sample | 11.16 | 1.04 | 11.14 | 1.57 |
( |
|||||
Full database | 10.96 | 1.40 | 11.06 | 1.30 |
On the total immediate recall score, 100% of participants in the present study performed within one standard deviation of the full sample mean. On the short delay score, 98% of participants scored within one standard deviation of the full sample mean, and 100% scored within two standard deviations. On the long delay score, 95% of participants scored within one standard deviation, and 98% scored within two standard deviations of the full sample mean. On the recognition accuracy score, 96% scored within one standard deviation, and 98% scored within two standard deviations of the full sample mean. When excluding participants who scored more than two standard deviations below the database mean on any memory subtest, the age × education interaction in hippocampal volume remained significant (Beta = 0.504;
Here we found that educational attainment buffers against age-related differences in hippocampal volume. Similar results were not found in the amygdala, a nearby medial temporal lobe structure, suggesting that results may be at least somewhat specific to the hippocampus.
The idea that, among older individuals, higher levels of education confer benefits in brain structure or function that buffer against age-related changes or brain pathology is often referred to as “brain” or “cognitive” reserve (Stern,
The present study provides some support for this theory. A “dose-dependent” effect of education was found, such that age-related decreases in hippocampal volume were steepest among the least educated individuals. In contrast, age-related decrease in hippocampal volume was less pronounced among individuals with higher educational attainment. It is thus possible that, among this sample of healthy individuals, higher levels of education were able to counteract typical age-related changes in hippocampal structure. The functional significance of these differential rates of decline may reflect greater retention of the cognitive functions, including declarative memory performance, which rely on this structure (Grieve et al.,
Many components of SES tend to vary with educational attainment and may themselves be important factors in understanding mechanistic pathways. Other objective socioeconomic indicators include measures of income and occupation, which were not available in the dataset studied here. Although education, occupation and income tend to be highly correlated (McLoyd,
Socioeconomic variables—including differences in educational attainment—likely represent relatively distal forces operating on cognitive and neural outcomes. However, SES has been associated with many factors that have been shown to exert more proximal effects on regional brain structure. One well described pathway includes differences in exposure to stress or allostatic load (McEwen,
In both animals and humans, the experience of stress has been linked to differences in the structure of the hippocampus (Rao et al.,
In studies of human adults, self-reported stress exposure, stress-related mental illness, and the prior experience of child abuse have all been associated with decreased hippocampal volume (Sheline et al.,
In the socioeconomically diverse sample of adults studied here, one possibility is that differences in the experience of stress may mediate the association between educational attainment and hippocampal volume. Future research will be necessary to directly test this putative mediating pathway.
Interestingly, and contrary to initial predictions, we only found a moderating effect of educational attainment on regional volume in the hippocampus, and not in the amygdala. Research in animals has demonstrated that the experience of stress profoundly affects development of the amygdala (Makino et al.,
Finally, while differences in experience have direct effects on the hippocampus, it should also be noted that interactions between age, educational attainment and hippocampal volume may in part be explained by differences in genes and/or gene-environment interactions. Future research will be necessary to disentangle the various causal pathways.
In a recent study of 60 socioeconomically diverse children and adolescents, we found that parental education levels predicted children's amygdala volumes, but not hippocampal volumes (Noble et al.,
The two studies included a non-overlapping age range of participants: the previous study examined children between the ages of 5 and 17, whereas the present study includes individuals between the ages of 17 and 87. Human neuroimaging studies have suggested that the effects of adversity on amygdala structure may vary based on the age of the population studied. In adulthood, the experience of highly stressful events has been associated with smaller amygdala size (Driessen et al.,
A second possible explanation is that the previous study in children examined
A third possibility is that the previous study, with only 60 participants, had reduced power with which to detect an effect of education on hippocampal volume, whereas the greater sample size in the present study allowed such an effect to be revealed here. This explanation alone would not, however, explain why we failed to find a link between educational attainment and amygdala volume in the present study.
This study suffers from several limitations. First, by nature, it is difficult to draw strong conclusions concerning development and aging in a cross-sectional sample. While a longitudinal study spanning the entire 7-decade range of the present sample is unlikely to be feasible, longitudinal data are currently being acquired on a subset of these individuals, which may provide better evidence concerning rate of change.
Secondly, because this study represented a secondary analysis of an existing dataset, the sample was not originally recruited with the goal of optimizing educational diversity across the age spectrum. Thus, one limitation is the commonly reported negative correlation between age and education in the study participants (Piras et al.,
Third, as mentioned above, we had no information on other aspects of objective or subjective SES, such as income, occupational status, or perceived social standing, which may have differentially predicted regional brain volumes. Nor did we have information on environmental factors, such as exposure to stressors or other putative mechanistic factors, which would have enabled us to directly test the degree to which such factors mediate our findings.
Fourth, although all participants were healthy at the time of testing, no specific screening for neurodegenerative disorders was performed, and it is therefore possible that some participants who would go on to develop neurodegenerative disease later on may have showed early signs of brain atrophy. A subset of participants had complete data on a memory recall and recognition test, and among this subset, scores were very similar to the full database of participants who completed this task, suggesting that at the time of scanning, the vast majority of participants had normal memory performance. Further, results were unchanged when known outliers on this were excluded. Nonetheless, this represents an important limitation given the increased risk of developing AD among individuals with low levels of education (Karp et al.,
Finally, although the moderating effect of education on hippocampal volume across the lifespan is provocative, the direction of causality is unclear. Future work should build upon these findings by collecting longitudinal data on educational attainment, hypothesized environmental mediators, and brain structure over time.
Across a 7-decade age range in adulthood, higher educational attainment buffers age-related decline in hippocampal volume, such that hippocampal volume tends to markedly decrease with age among less educated individuals, whereas hippocampal volumetric decreases with age are less pronounced among more educated individuals. No such effects were found for amygdala volume. This provides some support for “brain reserve theory” and suggests the possibility that higher education may be protective against age-related regional volumetric decreases. Alternatively, it is possible that higher education may allow for better compensatory mechanisms. Future research will be necessary to elucidate the mechanisms that underlie these effects.
Dr. Grieve has received consulting fees from Brain Resource Ltd. Dr. Williams has received consulting fees and stock options in Brain Resource Ltd, and is a stock holder in Brain Resource Ltd. She has received advisory board fees from Pfizer. Other authors report no actual or potential commercial or financial relationships that could be construed as potential conflicts of interest.
We acknowledge the data and support provided by BRAINnet;