Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response☆
Introduction
Subtle changes in episodic memory can be an early indicator of the development of Alzheimer's disease (AD) in non-demented older adults [1], [2], [5], [10], [21], [23], [24], [27], [43]. These early “preclinical” memory changes are more likely to occur in those with a genetic susceptibility marker for AD, the apolipoprotein E (APOE) ɛ4 allele [11], [37], than in those without this risk factor. In parallel with these findings, structural [32], [44] and functional [4], [6], [15], [20], [34], [42] neuroimaging alterations are more evident in non-demented elderly with the ɛ4 allele than in those without this allele type.
These results suggest that the combined use of functional neuroimaging and genetic assessments may offer a promising avenue for early and accurate recognition of preclinical AD. The need for such sophisticated and sensitive multimodal approaches for early detection has increased with the advent of treatments that may be most effective when applied in the earliest stages of AD, before significant neuronal loss has accrued [31]. A few studies have investigated the relationship between APOE genotype and functional neuroimaging of memory processes in non-demented elderly, but the interpretation of these results has been confounded by a number of factors. These include: (1) poorer memory in the ɛ4 group than in the non-ɛ4 group [6], (2) questions of interpretability of signal change via the subtraction method, particularly when contrasting two higher-level conditions such as novel versus familiar items, (3) no assessment for differential atrophy [6], [20], or (4) the use of general standard space region of interest (ROI) analyses rather than specific individualized native space renderings [4], [20] (see also Vandenbroucke et al. [46] for discussion).
The present study served to address these concerns by examining APOE genotype-related differences in functional brain response to verbal paired-associate encoding and consolidation by controlling for equivalent behavioral performances and examining structural volumetry, including manually outlined hippocampal ROIs defined in native space, in ɛ4 and non-ɛ4 non-demented older adults. Given that elderly with the ɛ4 allele are more likely than those without the allele to be in a preclinical stage of AD, we hypothesized that the ɛ4 group would require more brain activation than the non-ɛ4 group to maintain the same level of memory performance. In addition, we expected an over-recruitment of right medial temporal lobe (MTL) activation during verbal paired-associate encoding and consolidation consistent with [26] finding that greater right MTL engagement is associated with better verbal list learning, and with the findings from a growing number of fMRI studies of at-risk older adults [4], [15], [16], [20], [25], [26]. Thus, in the context of equivalent learning performance, we predicted that more right hemisphere response would be required by ɛ4 individuals.
Section snippets
Subjects
Twenty-five healthy and independently living older adults were recruited with institutional review board-approved procedures from a larger pool of volunteers participating in the UCSD Alzheimer's Disease Research Center as well as from a longitudinal study of aging. Participants were selected without regard to ethnicity, race, or socioeconomic status. The recruitment and study procedures were approved by the UCSD institutional review board and written informed consent was obtained from all
Behavioral performances
There were no significant differences in performance between those with and without an APOE ɛ4 allele on post-MRI cued recall accuracy for the word pairs (Table 1). Both groups averaged better than 60% accuracy for cued recall following their scanning sessions (APOE ɛ4 group = 62.2%, S.D. = 18.1; APOE non-ɛ4 group = 67.8%, S.D. = 19.7; p = 0.47). Additionally, of those pairs correctly recalled, there were no significant differences in performance between groups with respect to correctly recalled new word
Conclusion
APOE ɛ4 non-demented older adults showed greater BOLD response in multiple right hemisphere brain regions (anterior cingulate, lingual gyrus, middle temporal gyrus, middle frontal gyrus, posterior cingulate, precuneus, and cerebellar tonsil) during a verbal paired-associate learning task than their demographically similar non-ɛ4 counterparts. These differences were most salient in the OLD–FIX condition likely due to more successful encoding of familiar word pairs versus novel word pairs, as
Acknowledgements
This work was supported by National Institute on Aging Grants R01 AG12674 (MWB) and P50 AG05131 (JCB; MWB; ASF; DPS), and by the MIRECC grant from the Medical Research Service of the Department of Veterans Affairs (LTE; GGB). The authors gratefully acknowledge the assistance of staff, patients and volunteers of the UCSD Alzheimer's Disease Research Center, and the UCSD Laboratory of Cognitive Imaging.
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There were no actual or potential conflicts of interest for the authors that could have inappropriately influenced the present work. Subjects were recruited in accordance with Internal Review Board (IRB) approved policies and procedures. Standard professional and ethical guidelines were upheld during the research study and manuscript preparation
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