Regular articleAPOE moderates compensatory recruitment of neuronal resources during working memory processing in healthy older adults
Introduction
Carrying the APOE ε4 allele is a risk factor for sporadic, late-onset Alzheimer's disease (AD) in a dose-dependent fashion, whereas the ε3 allele is not associated with an increased risk for AD and ε2 seems to be protective from the disease (Corder et al., 1993, Farrer et al., 1997). Therefore, investigating healthy older adults with different APOE variants is of importance to detect subtle APOE effects before the onset of neurodegenerative disease. Interestingly, there is evidence that cognitive differences between APOE ε4 and non-ε4 carriers appear across several domains such as episodic memory, working memory (WM), and executive functions (for meta-analyses, see Small et al., 2004, Wisdom et al., 2011). These differences seem to change across the lifespan, as ε4 carriers show performance advantages at younger age (Alexander et al., 2007, Evans et al., 2014, Mondadori et al., 2007, Rusted et al., 2013), whereas ε4 appears disadvantageous in late life (Caselli et al., 2011, Greenwood et al., 2014). Concomitant neural underpinnings of these changes are yet to be determined.
APOE genotype impacts on neuronal recruitment as measured with functional magnetic resonance imaging (fMRI; Chen et al., 2015; for reviews, see Bookheimer and Burggren, 2009, Trachtenberg et al., 2012). In the current report, we will focus on neuronal underpinnings of WM in different APOE variants, as intact WM is a crucial determinant of everyday functioning. WM is associated with brain activation patterns in a frontoparietal network (for meta-analyses, see Owen et al., 2005, Rottschy et al., 2012), and it declines at older age and in neurodegenerative disease (Hale et al., 2011, Salthouse and Babcock, 1991, Wilson et al., 2011). The increased recruitment of prefrontal areas with increasing WM load is particularly pronounced in older adults (for reviews, see Reuter-Lorenz, 2013, Spreng et al., 2010). There is limited evidence that APOE ε4 carrier status modifies WM-related brain activations (Trachtenberg et al., 2012). In a sample with a large age span, Wishart et al. found increased brain activity in frontal and parietal regions in ε4 compared with non-ε4 carriers in the absence of behavioral differences (Wishart et al., 2006). There are further accounts of increased frontal recruitment in young as well as older ε4 carriers (Filbey et al., 2006, Filbey et al., 2010), whereas a separate study in middle-aged adults suggests that such increased recruitment might occur only at low WM load, albeit in a rather small sample (Chen et al., 2013).
The interpretation of such increases in brain activation has not been resolved yet. For instance, an increase in older ε4 carriers might constitute a compensatory response (Bondi et al., 2005, Han et al., 2007), such that increased effort helps carriers to achieve the same performance level in WM tasks as non-ε4 carriers. This interpretation is supported by observations suggesting a higher impact of disadvantageous genetic variations–among them ε4—with older age (Lindenberger, 2014, Papenberg et al., 2015). On the other hand, ε4 carriers might exhibit excess neural activity that is not beneficial, thus the increased activity might not fulfill a compensatory purpose (Trachtenberg et al., 2012). Separating these 2 possibilities would be an important step for the development of interventions that aim to facilitate compensation. Several models have been suggested to define compensation as a counter-reaction to neuronal decline in healthy aging as well as in neurodegenerative disease (Barulli and Stern, 2013, Cabeza, 2002, Cabeza and Dennis, 2013, Cabeza et al., 2002, Davis et al., 2008, Park and Reuter-Lorenz, 2009, Prvulovic et al., 2005, Reuter-Lorenz and Cappell, 2008, Stern, 2009). However, increased strength of activation per se does not necessarily represent compensation but could constitute a primary effect of degeneration, neuronal dedifferentiation, prolonged reaction times, or altered vascular coupling (D'Esposito et al., 2003, Duverne et al., 2009, Kannurpatti et al., 2010, Price and Friston, 1999). To resolve this issue, Cabeza and Dennis (2013) suggested explicit criteria to rate increased brain activation as compensatory. One of these criteria states that for successful compensation, activation should be positively correlated with task performance. In the present study, we followed the suggested criterion by directly incorporating task performance in our statistical model (Scheller et al., 2014) and addressed potential neuronal compensation using multiple regression models with brain activation as outcome predicted from task performance, APOE variant, and age as well as their interactions. Such interactions in the sense of moderator effects are under-investigated but well suited to shed light on neuronal compensation (Salthouse, 2009, Salthouse, 2010, Salthouse, 2011).
Taken together, automatically concluding a compensatory role of increased activations in APOE ε4 carriers is not justified. Therefore, we aimed at examining brain activity during a working memory task in healthy older adults with different APOE variants constituting an at-risk group for neurodegeneration. We implemented multiple regression models allowing for moderating effects of APOE and age on the relationship between task performance and fMRI activity to investigate neuronal compensation. As a first hypothesis, we expected to identify neuronal compensation in APOE ε4 carriers. Compared with non-ε4 carriers, ε4 carriers should exhibit increased brain activation, hence APOE variant would moderate the positive relationship between task performance and brain activation (hypothesis 1: 2-way performance × APOE variant interaction). Similar to previous studies (Chen et al., 2013, Filbey et al., 2006, Filbey et al., 2010, Wishart et al., 2006), we expected effects to be located primarily in the prefrontal cortex. Second, we hypothesized that activation patterns differing between APOE variants would further depend on age as our sample covered individuals from the seventh to ninth life decade suggesting inter-individual variability (Salthouse, 2010). Hence, both APOE and age could moderate the relationship between task performance and brain activation (hypothesis 2: 3-way performance × APOE variant × age interaction). Third, as an addition to compensation-related activation patterns, we investigated the interaction of APOE variant and age irrespective of task performance, as existing evidence suggests such an interaction in AD-relevant brain regions (Filbey et al., 2010, Filippini et al., 2011; hypothesis 3: 2-way APOE variant × age interaction).
Section snippets
Sample
Thirty-five community-dwelling healthy older adults (20 females, mean age 68.82 years, SD 5.33, range 61–80) were recruited as part of a project investigating neuronal plasticity in aging and early neurodegeneration at the University Medical Center Freiburg. All were right-handed, had normal or corrected-to-normal visual acuity and no history of psychiatric or neurological disease as well as adequate performance in a sensitive cognitive test (Montreal Cognitive Assessment score ≥24; Nasreddine
Behavioral data
Participants performed well across task conditions (Table 1). One participant with good performance in the 1-back and 2-back condition (92% and 87%) achieved only 37% correct in the 0-back condition and presumably misunderstood the instruction. This participant was therefore excluded from the sample. Kolmogorov-Smirnov tests of age, 2-back accuracy, and 1-back as well as 2-back reaction times indicated compatibility with a normal distribution (page = 0.11, pacc_2-back = 0.06, pRT_1-back = 0.20
Discussion
In the present study, we hypothesized to find differential neuronal compensation in APOE ε4 carriers compared with non-ε4 carriers in prefrontal cortex (hypothesis 1). Indeed, we identified activation patterns compatible with successful neuronal compensation in ε4 carriers. The effect was most pronounced in lsOG/vmPFC. Exploratory analyses revealed a similar effect in rIFG/insula. Importantly, carriers and noncarriers did not differ in performance and the employed WM task was strongly
Conclusion
As hypothesized, we observed several significant interactions between WM task performance, APOE variant, and age in task-positive as well as task-negative brain areas in a sample of healthy older adults. These brain activation patterns are well in line with several models of neuronal compensation as well as models describing the impact of detrimental genetic variants across the lifespan. In contrast to previous studies, we were able to unambiguously associate an increase in prefrontal
Disclosure statement
The authors have no conflicts of interest to disclose.
Acknowledgements
The authors wish to thank Hansjoerg Mast and Verena Landerer for their help in fMRI data acquisition. The study was partly supported by the BrainLinks-BrainTools Cluster of Excellence (German Research Foundation grant no. EXC 1086).
References (97)
- et al.
The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades
Biol. Psychol.
(2007) A fast diffeomorphic image registration algorithm
NeuroImage
(2007)- et al.
Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve
Trends Cogn. Sci.
(2013) - et al.
Aging gracefully: compensatory brain activity in high-performing older adults
NeuroImage
(2002) - et al.
Three key regions for supervisory attentional control: evidence from neuroimaging meta-analyses
Neurosci. Biobehav. Rev.
(2015) - et al.
Effects of ApoE-ɛ4 allele load and age on the rates of grey matter and hippocampal volumes loss in a longitudinal cohort of 1186 healthy elderly persons
NeuroImage
(2010) - et al.
A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data
NeuroImage
(2005) - et al.
Cognitive and neural signatures of the APOE E4 allele in mid-aged adults
Neurobiol. Aging
(2014) - et al.
Lateral temporal hyper-activation as a novel biomarker of mild cognitive impairment
Neuropsychologia
(2013) - et al.
Differential effects of the APOE genotype on brain function across the lifespan
NeuroImage
(2011)
Age-related adaptations of brain function during a memory task are also present at rest
NeuroImage
tDCS-enhanced motor and cognitive function in neurological diseases
NeuroImage
Characterizing evoked hemodynamics with fMRI
Neuroimage
Imaging the default mode network in aging and dementia
Biochim. Biophys. Acta
Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response
Neurobiol. Aging
Linking planning performance and gray matter density in mid-dorsolateral prefrontal cortex: moderating effects of age and sex
NeuroImage
Neural and vascular variability and the fMRI-BOLD response in normal aging
Magn. Reson. Imaging
Training and plasticity of working memory
Trends Cogn. Sci.
Neuroanatomic overlap of working memory and spatial attention networks: a functional MRI comparison within subjects
Neuroimage
Aging-related magnification of genetic effects on cognitive and brain integrity
Trends Cogn. Sci.
Longitudinal assessment of default-mode brain function in aging
Neurobiol. Aging
Functional activation imaging in aging and dementia
Psychiatry Res. Neuroimaging
Imaging genetics of cognitive functions: focus on episodic memory
NeuroImage
Comparative accuracies of two common screening instruments for classification of Alzheimer's disease, mild cognitive impairment, and healthy aging
Alzheimers Dement
Modelling neural correlates of working memory: a coordinate-based meta-analysis
NeuroImage
APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures
NeuroImage
When does age-related cognitive decline begin?
Neurobiol. Aging
Age-related alterations in default mode network: impact on working memory performance
Neurobiol. Aging
The potential of functional MRI as a biomarker in early Alzheimer's disease
Neurobiol. Aging
Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
Alzheimers Dement
Reliable differences in brain activity between young and old adults: a quantitative meta-analysis across multiple cognitive domains
Neurosci. Biobehav. Rev.
Cognitive reserve
Neuropsychologia
APOE-epsilon4 and aging of medial temporal lobe gray matter in healthy adults older than 50 years
Neurobiol. Aging
The effects of APOE-ε4 on the BOLD response
Neurobiol. Aging
The effects of apolipoprotein E on non-impaired cognitive functioning: a meta-analysis
Neurobiol. Aging
Magnetic resonance imaging of freely moving objects: prospective real-time motion correction using an external optical motion tracking system
NeuroImage
Advanced magnetic resonance imaging of neurodegenerative diseases
Neurol. Sci.
Cross-frequency coupling supports multi-item working memory in the human hippocampus
Proc. Natl. Acad. Sci.
Sustained neural activity patterns during working memory in the human medial temporal lobe
J. Neurosci.
Probing interactions in fixed and multilevel regression: inferential and graphical techniques
Multivar. Behav. Res.
fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease
Neurology
Salience network integrity predicts default mode network function after traumatic brain injury
Proc. Natl. Acad. Sci.
APOE-4 genotype and neurophysiological vulnerability to Alzheimer's and cognitive aging
Annu. Rev. Clin. Psychol.
The Brain's default network
Ann. N. Y. Acad. Sci.
Hemispheric asymmetry reduction in older adults: the HAROLD model
Psychol. Aging
Frontal lobes and aging: deterioration and compensation
Longitudinal modeling of frontal cognition in APOE ε4 homozygotes, heterozygotes, and noncarriers
Neurology
The road ahead to cure Alzheimer's disease: development of biological markers and neuroimaging methods for prevention trials across all stages and target populations
J. Prev. Alzheimers Dis.
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