Cognitive reserve moderates the association between hippocampal volume and episodic memory in middle age
Highlights
► Hippocampal volume is related to memory in those with low cognitive reserve. ► Hippocampal volume is not related to memory in those with high cognitive reserve. ► Reserve effects can be seen in midlife if a direct measure of reserve is used.
Introduction
Why can some individuals with noticeable brain pathology maintain a relatively high level of cognitive performance while others with the same amount of brain damage have remarkable deficits in cognitive performance? (see e.g., Stern, 2009). This question, along with the observation that brain pathology and cognitive functioning do not always correlate (see e.g., Katzman et al., 1988), has led to the development of the concepts of cognitive and brain reserve. Cognitive and brain reserve may be viewed as buffers against the effects of brain pathology and protective factors against Alzheimer's disease (AD) or other forms of dementia. Reserve may also explain individual differences in cognitive functioning in the context of AD. While there is evidence for the effect of reserve in healthy older adults (Brickman et al., 2011) and in context of AD (Stern, Albert, Tang, & Tsai, 1999) and other dementia-causing conditions like vascular pathology (Zieren et al., 2013), it is not clear whether the effect of reserve is present throughout adulthood or if it becomes apparent only later in life.
According to Stern, 2002, Stern, 2009, the concept of reserve can be divided into passive (structural) and active (functional) models as represented by brain reserve and cognitive reserve, respectively. The passive model refers to a threshold at which brain pathology starts to affect cognition. An example of brain reserve would be the neuroanatomical measure of overall brain size (e.g., brain or intracranial volume), the idea being that larger brains can tolerate more pathology before the threshold where cognitive deficits start to occur is reached. The active model refers to compensatory processes that are invoked in order to tolerate or circumvent brain pathology. An example of cognitive reserve would be pre-existing cognitive or compensatory abilities (e.g., higher general intelligence or ability to use different cognitive strategies); in many studies these are approximated by the proxy measure of educational level. In contrast to the passive model, there is no certain threshold of brain pathology when cognition begins to be affected. Instead, higher cognitive reserve helps the individual to compensate and thus maintain a certain level of cognitive functioning despite brain pathology.
Two individuals can have the same amount of brain reserve (e.g., overall brain size), but can still differ in how much they can tolerate brain pathology because they differ in their cognitive reserve (e.g., premorbid general cognitive ability). Because cognitive functions do not operate in isolation from brain anatomy and brain structures are plastic throughout development, the distinction between active and passive models of reserve is not clear-cut. In sum, the reserve hypothesis states that individuals with higher levels of reserve, compared to individuals with lower levels of reserve, can better maintain cognitive functioning in the presence of brain pathology.
As suggested by Christensen et al. (2007), a full model to test the reserve hypothesis should include: (1) a direct or proxy measure of reserve, (2) a measure of brain pathology, and (3) a cognitive outcome. Their review showed that most studies to date have failed to include all of these measures when testing a reserve hypothesis. Instead, many studies have tested the main effects of measures of reserve on cognitive functioning. Such studies have demonstrated, for example, that higher education is related to better cognitive performance at middle age and at old age. These kinds of studies only report the main effect of a measure of reserve on later cognitive performance. Simply showing that more highly educated people (e.g., Le Carret et al., 2003, Singh-Manoux et al., 2011) or those with higher general cognitive ability (e.g., Corral, Rodríguez, Amenedo, Sánchez, & Díaz, 2006) perform better on cognitive tests later in life does not address the question of whether people with higher levels of cognitive reserve tolerate brain pathology better than those with lower levels of reserve. Although this main effect is consistent with the reserve hypothesis, we think it is unnecessary – and therefore less parsimonious – to invoke the reserve hypothesis to account for this finding because those with more education or higher general cognitive ability will perform better on cognitive tests at any point in development, including childhood and young adulthood.
Some studies have suggested that the effect of reserve is supported by the findings that at any level of cognitive performance, people with higher reserve exhibit more brain pathology and will develop dementia later than people with lower levels of cognitive reserve. For example, by studying the Alzheimer's Disease Neuroimaging Initiative sample, Vemuri et al. (2011) found that the level of AD-related biomarkers (beta-amyloid, tau, and brain atrophy) was more pronounced at any level of cognitive functioning among people with higher cognitive reserve (based on the proxy measure of National Adult Reading Test [NART] performance) compared to those with lower cognitive reserve. This finding is important as it clearly shows that people with higher prior general cognitive ability develop dementia later and thus require more brain pathology before clinical manifestation of dementia than people with lower general cognitive ability. However, the effect of general cognitive ability was only on the intercepts, not on the slopes (i.e., individuals with higher cognitive reserve performed better at any level of pathology whereas the effect of pathology on cognition did not differ as a function of cognitive reserve).
The simplest explanation is that people who started out with higher prior cognitive ability will continue to have higher cognitive performance at any point before developing dementia. Also, they develop dementia later simply because they have farther to fall before they reach that threshold of cognitive impairment, just as an object dropped from the sixth floor will take longer to reach the ground than one dropped from the third floor. We argue that it is not necessary or particularly useful to invoke the reserve hypothesis to account for these findings. Like the objects being dropped from different heights, the outcome is virtually guaranteed. It is difficult, if not impossible, to conceive of a situation in which individuals with higher pre-existing general cognitive capacity (cognitive reserve) would not have better cognitive performance than those with lower reserve when they both have the same level of current pathology. If one shifts the scale so that two individuals with different cognitive reserve levels are equated on current cognitive performance, it is self-evident that the one with higher reserve will have greater pathology.
What is more meaningful is to test the hypothesis of a moderating effect of cognitive reserve, which means testing for the presence of a significant interaction between measures of cognitive reserve and brain pathology in prediction of cognitive performance (as suggested by Christensen et al. (2007), see also Stern (2012)). A significant interaction would suggest that the association between a brain (or biomarker of dementia or age) and the cognitive measure differs as a function of cognitive reserve. In terms of the cognitive reserve hypothesis, one would expect that greater brain atrophy would be associated more strongly with poorer cognitive performance among people with low levels of cognitive reserve compared to people with high levels of cognitive reserve. If the effects of brain atrophy on cognitive functioning were less pronounced among people with high cognitive reserve, it would suggest that individuals with high cognitive reserve can compensate more in the presence of brain atrophy, thus resulting in a weaker or zero correlation between brain atrophy and the cognitive measure.
An interaction between education and white matter pathology on cognitive functions has been reported among older adults. A significant relationship between white matter hyperintensities and cognition has been reported to be stronger in individuals with low levels of education compared to those with higher levels of education (Dufouil et al., 2003, Nebes et al., 2006). Similarly, senile plaques have been reported to be more strongly associated with poorer cognitive functioning among those with lower education levels (Bennet et al., 2003). These findings support the cognitive reserve hypothesis because the brain pathology and cognition relationships were more pronounced among people with lower cognitive reserve. However, a longitudinal study found no significant interaction between brain atrophy/white matter hyperintensities and education on cognitive functioning, either at baseline (60–64 years) or at follow up after four years (Christensen et al., 2007, Christensen et al., 2009). One important reason for the conflicting reports on the effects of cognitive reserve may be the use of education, which may be too crude an estimate, particularly in relatively younger adults who have less brain atrophy and greater ability to compensate than their older counterparts.
As noted, relatively few studies have tested the interaction model. To our knowledge, no studies have tested whether cognitive reserve moderates the more specific relationship between hippocampal volume and episodic memory performance, despite the well known importance of these measures in the context of aging and AD. Impaired episodic memory performance is characteristic of AD and common in persons with mild cognitive impairment (MCI) (Petersen et al., 1999). Age has been shown to affect episodic memory performance among healthy individuals (Kramer, Yaffe, Lengenfelder, & Delis, 2003), but there are large individual differences in episodic memory performance change in older adults (Christensen et al., 1999). Hippocampal structure and function are both crucial to episodic memory. People with AD show hippocampal atrophy and there is also evidence of hippocampal atrophy in normal aging (Jack et al., 2000, Jernigan et al., 2001). Individuals with MCI have also been reported to have smaller hippocampal volume compared to cognitively healthy older adults (Wolf et al., 2004). A study by Petersen et al. (2000) suggested that smaller hippocampal volume is related to poorer episodic memory performance in persons with AD, but not among non-AD individuals. On the other hand, Kramer et al. (2007) found that decrease in hippocampal volume was related to decrease in episodic memory among healthy older adults.
Although among all reviewed brain–behavior relationships in healthy older adults, the association of hippocampal volume and memory was one of the more consistent findings (Kaup, Mirzakhanian, Jeste, & Eyler, 2011), a meta-analysis of these studies suggested that the relationship between hippocampal volume and episodic memory performance among healthy older adults is weak and there is variability in findings (Van Petten, 2004). Cognitive reserve could account for the increased individual differences in episodic memory at older ages and explain the inconsistent results regarding relationship between hippocampal volume and episodic memory among non-demented individuals. In the context of cognitive aging, it is important to detect subgroups that might be more vulnerable to brain pathology such as hippocampal atrophy. Indeed, cognitive reserve-based subgrouping might allow detection of individuals whose cognition will be affected by brain pathology before clinical signs of dementia.
Here we investigate the association between hippocampal volume and episodic memory performance among middle-aged men in the context of cognitive reserve. We examined the possible moderating effect of cognitive reserve on the hippocampal volume-episodic memory relationship. In line with the cognitive reserve hypothesis, we hypothesized that smaller hippocampal volume would be more strongly associated with poorer episodic memory performance among individuals with low cognitive reserve relative to those with higher cognitive reserve, or that the hippocampal volume-episodic memory relationship would be evident only among those with lower levels of cognitive reserve. In the context of a full model of reserve (Christensen et al., 2007) we assessed general cognitive ability, hippocampal volume, and episodic memory as measures of cognitive reserve, brain anatomy, and cognitive outcome, respectively. In order to relate our results specifically to cognitive reserve independent of brain reserve, we used total intracranial volume – a measure of brain reserve – as a covariate. Importantly, our study used a direct measure of cognitive reserve in the form of a measure of general cognitive ability administered at an average age of 20 years rather than indirect proxies such as education or the NART. In contrast to previous cognitive reserve studies using relatively general measures, we used specific brain and cognitive measures (hippocampal volume and episodic memory) that are particularly relevant to age-related cognitive decline and progression to dementia, and we tested for moderation effects of cognitive reserve in a middle-aged sample in which early detection and intervention is most relevant.
Section snippets
Participants
Participants were 534 middle-aged males (at the time of recruitment from 51 to 59 years) from the ongoing Vietnam Era Twin Study of Aging (VETSA; Kremen et al., 2006, Kremen et al., 2010). The VETSA participants served in the military but are representative of men of similar age in US (Lyons et al., 2009). The mean level of education in years was 13.8 (SD 2.1). Participants traveled to University of California, San Diego or Boston University for an extensive laboratory study protocol that
Results
As expected, years of education correlated positively with the continuous AFQT20 measure (r=.35, p<.0001). Continuous AFQT20 measure was not significantly related to hippocampal volume when adjusted for age and eTIV (F(1,209)=0.01, p=.92). The APOE ε4+ genotype did not have an effect on continuous AFQT20 measure (F(1,199)=0.05, p=.82). The categorical AFQT20 measure had a significant association with education, showing that those with higher cognitive reserve had higher education compared to
Discussion
Individuals with more cognitive reserve, based on higher general cognitive ability in young adulthood, had better memory performance at middle age. This result demonstrates the expected main effect of a measure of cognitive reserve on cognitive outcome. Also, age was a significant predictor of all episodic memory measures even in our narrow age range with older individuals performing more poorly than younger individuals. More importantly, we tested whether cognitive reserve moderates the
Funding
This work was supported by grants from the National Institute on Aging [R01 AG022982, R01 AG018386, and R01 AG022381, R01 AG018384]; National Institute of Drug Abuse [DA029475]; National Institute of Neurological Disorders and Stroke [NS056883], National Center for Research Resources [P41-RR14075, BIRN002, U24 RR021382 ]; National Institute for Biomedical Imaging and Bioengineering [EB006758 ]; National Center for Alternative Medicine [RC1 AT005728-01]; National Institute for Neurological
Acknowledgements
The Cooperative Studies Program of the U.S. Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. Numerous organizations have provided invaluable assistance in the conduct of this study, including: Department of Defense; National Personnel Records Center, National Archives and Records Administration; the Internal Revenue Service; National Opinion Research Center; National Research Council, National Academy of
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