Abstract
IntroductionThe APOE e4 allele has been linked to poorer cognitive aging and enhanced dementia risk. Previous imaging studies have used subsequent memory paradigms to probe hippocampal function in e4 carriers across the age range, and evidence suggests a pattern of hippocampal overactivation in young adult e4 carriers.MethodsIn this study, we employed a word‐based subsequent memory task under fMRI; pupillometry data were also acquired as an index of cognitive effort. Participants (26 non‐e4 carriers and 28 e4 carriers) performed an incidental encoding task (presented as word categorization), followed by a surprise old/new recognition task after a 40 minute delay.ResultsIn e4 carriers only, subsequently remembered words were linked to increased hippocampal activity. Across all participants, increased pupil diameter differentiated subsequently remembered from forgotten words, and neural activity covaried with pupil diameter in cuneus and precuneus. These effects were weaker in e4 carriers, and e4 carriers did not show greater pupil diameter to remembered words. In the recognition phase, genotype status also modulated hippocampal activity: here, however, e4 carriers failed to show the conventional pattern of greater hippocampal activity to novel words.ConclusionsOverall, neural activity changes were unstable in e4 carriers, failed to respond to novelty, and did not link strongly to cognitive effort, as indexed by pupil diameter. This provides further evidence of abnormal hippocampal recruitment in young adult e4 carriers, manifesting as both up and downregulation of neural activity, in the absence of behavioral performance differences.
Highlights
| INTRODUCTIONThree variants of the APOE gene exist (e2, e3, e4). The e4 allelic variant has been the focus of considerable recent research activity due to it being a well-established risk factor for Alzheimer’s disease (AD) (Rocchi, Pellegrini, Siciliano, & Murri, 2003)
The APOE e4 allele has been linked to poorer cognitive aging and enhanced dementia risk
We did not anticipate any genotype differences in memory performance: a recent study using a word-based subsequent memory task found that APOE status did not affect performance in young adults (Stening et al, 2016), as did the majority of studies using pictorial stimuli, it should be noted that these imaging studies have typically employed relatively small numbers and might not have sufficient power to detect subtle memory impairment
Summary
Three variants of the APOE gene exist (e2, e3, e4). The e4 allelic variant has been the focus of considerable recent research activity due to it being a well-established risk factor for Alzheimer’s disease (AD) (Rocchi, Pellegrini, Siciliano, & Murri, 2003). Another study reported increased activity in prefrontal, temporal and parietal regions during memory encoding, but coupled with frontal decreases during retrieval, in e4+ aged 55–65 (Kukolja, Thiel, Eggermann, Zerres, & Fink, 2010) These findings have been interpreted as representing compensatory mechanisms: e4+ recruit additional neural resources to maintain cognitive performance (Tuminello & Han, 2011), requiring additional cognitive effort to achieve comparable performance levels to their none peers (Bondi et al, 2005). We reverted to a classic subsequent memory paradigm, and extending the work outlined above, imaged both the acquisition and recognition phases so as to fully characterize hippocampal activation patterns in young adult e4+ during the task. Pupil diameter is enlarged to words that are subsequently remembered,
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