Abstract
The Apolipoprotein-E (APOE) gene is now known to be associated with individual differences in cognitive health in ageing. However, while the APOE ε4 allele confers significantly increased risk of developing Alzheimer’s disease (AD), the APOE ε2 allele is hypothesized to be protective against the development of AD. This is in line with neuroimaging and pathological findings associated with ε2 APOE allele, which go in the opposite direction to those observed in AD-related pathology. However, the precise impact of this allele on cognition remains inconclusive, with some small-cohort studies raising the possibility of an advantageous memory performance in these individuals. Here, we tested short-term memory (STM) performance in a large cohort of individuals, 300 of which were ε2/ε3 carriers. Their performance was compared to 554 ε3/ε3 carriers. We included participants from a wide age range spanning young, middle-aged and elderly adults. All of them performed a STM task that has previously been shown to be sensitive to subtle changes in memory in various patient and at-risk cohorts. Individuals carrying the APOE-ε2 allele exhibited a significant memory advantage, regardless of STM task difficulty and across all ages. The observed memory advantage was present across the age range, suggestive of a phenotypical effect of this allele on cognition, possibly independent of any effects of this genetic allele that occur later life in these individuals.
Highlights
The Apolipoprotein-E (APOE) ε4 gene allele, the highest known genetic risk factor for Alzheimer’s disease, has paradoxically been well preserved in the human population
Why has this genetic allele, which has such obvious detrimental effects in old-age, been preserved in the human population world-wide? One possible explanation is rooted in a concept that has emerged in evolutionary biology[14]
Strong evidence for this does not currently exist. To address these shortcomings and to investigate the existence of a potential cognitive advantage associated with APOE ε4 gene across ageing, we examined the largest cohort of genotyped individuals to be tested on a highly sensitive test of short-term memory (STM)
Summary
The Apolipoprotein-E (APOE) ε4 gene allele, the highest known genetic risk factor for Alzheimer’s disease, has paradoxically been well preserved in the human population. The task, previously shown to detect subtle changes in performance in healthy ageing and in APOE ε4 gene carriers in small sample sizes, is a more sensitive measure of memory compared to classical neuropsychological assessments[31] and allows separating out the different kinds of error that people make[32,33]. The current study provides the first evidence in a large sample of participants for a memory advantage over brief durations in APOE ε4 carriers, across ageing.
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