Short-term memory advantage for brief durations in human APOE ε4 carriers

Abstract

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. One possible explanation offered by evolutionary biology for survival of deleterious genes is antagonistic pleiotropy. This theory proposes that such genetic variants might confer an advantage, even earlier in life when humans are also reproductively fit. The results of some small-cohort studies have raised the possibility of such a pleiotropic effect for the ε4 allele in short-term memory (STM) but the findings have been inconsistent. Here, we tested STM performance in a large cohort of individuals (N = 1277); nine hundred and fiftynine of which included carrier and non-carriers of the APOE ε4 gene, those at highest risk of developing Alzheimer's disease. We first confirm that this task is sensitive to subtle deterioration in memory performance across ageing. Importantly, individuals carrying the APOE ε4 gene actually exhibited a significant memory advantage across all ages, specifically for brief retention periods but crucially not for longer durations. Together, these findings present the strongest evidence to date for a gene having an antagonistic pleiotropy effect on human cognitive function across a wide age range, and hence provide an explanation for the survival of the APOE ε4 allele in the gene pool. The Apolipoprotein-E (APOE) ε4 gene allele is the highest known genetic risk factor for developing Alzheimer's disease (AD) 1. Approximately 45% of carriers of the gene develop AD by the age of 85 years, compared to 10% of non-carriers 1. It is not surprising therefore that much research has focused on seeking to identify early biomarkers related to the development of AD in ε4 carriers 2-13. But 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. The antagonistic pleiotropy hypothesis proposes that some genetic alleles have different effects on the fitness of an organism at different ages. Therefore, a genetic allele, such as APOE ε4, which confers a disadvantage later in life, might instead provide an advantage, even earlier in life, hence ensuring its survival. Because the power of natural selection to disfavour a genetic allele wanes later in reproductive life, when an animal has less likelihood of passing on its genes, disadvantages in older age have minimal consequences on the survival of a genetic variant. Although there has been little investigation of a potential early advantage in human carriers of the APOE ε4 gene, several authors have argued for the existence of such an advantage, specifically when it comes to brain function 15-17. A few studies on small cohorts have presented mixed evidence for a possible cognitive advantage in young and middle-aged APOE ε4 gene carriers. In children and young adults, better performance on neuropsychological measures of att...

Memory precision of object-location binding is unimpaired inAPOEε4-carriers with spatial navigation deficits

“…2. We fit probabilistic mixture models to the location placement errors expressed as the degrees separating the response from the target (Zhang and Luck, 2008; Bays et al ., 2011; Suchow et al ., 2013; Richter et al ., 2016; Zokaei et al ., 2020). The approach aims to determine the distribution of trial responses in order to examine which retrieval mechanisms best explain the observed responses: i) correctly recalled locations, ii) random guesses or iii) a misbinding error in which the location of the target is confused with that of another object from the same display.…”

“…To maximise comparability with the only other study on the effect of the APOE genotype on location memory precision (Zokaei et al ., 2020), we also used Bayesian modelling implemented with the MemToolbox in MATLAB 2016a (Suchow et al ., 2013). We fit three models to the error data collapsed across all participants by APOE genotype group to test whether which components could explain localisation performance.…”

“…This is a well-established method to probe memory fidelity that has been widely used by both our work and others across short-term and long-term memory studies. 24,66,[73][74][75] The approach aims to determine the distribution of trial responses in order to examine which retrieval mechanisms best explain the observed responses: i) correctly recalled locations, ii) random guesses or iii) a misbinding error in which the location of the target item is confused with that of another object also presented on the same display. Guess trials can be modelled using a uniform distribution.…”

Superior short-term memory in APOE ε2 carriers across the age range

“…Previously we have shown that ε4 carriers can also demonstrate superior STM performance compared to ε3/ε3 carriers across the age range, using an identical task [ 2 , 3 , 34 ]. Crucially, this effect was, however, only observed for the shorter memory delays of 1 s, with higher forgetting rate compared to non-carriers in STM as well as worse LTM performance in the same individuals [ 2 ].…”

“…The Oxford Memory Test (OMT) is a flexible web-based version of a highly sensitive short-term-memory precision task we have previously successfully used to detect subtle changes in performance in healthy ageing, neurodegenerative disorders, and at-risk populations [ 2 , [35] , [36] , [37] ]. The online OMT instantiation is identical to that used in a previous study of APOE ε4 carriers [ 34 ]. The web-app platform is designed for testing in ‘less strict’ environments such as clinics, wards, or individuals’ homes; and can be run on any tablet or touchscreen device.…”