Dissociable effects of the apolipoprotein-E (APOE) gene on short- and long-term memories

Zokaei, Nahid; Čepukaitytė, Giedrė; Board, Alexander G.; Mackay, Clare E.; Nobre, Anna C.

doi:10.1016/j.neurobiolaging.2018.09.017

Cited by 23 publications

(60 citation statements)

References 72 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results complement and extend and strengthen observations in far smaller samples of superior STM performance in middle-aged and older participants 24,25,47 . Most importantly, they show that the effect is consistent across a wide age group, and hence distinguishable from AD-related effects of this gene on cognition.…”

supporting

confidence: 85%

“…Contrary to this advantage for brief durations, carriers of the APOE ε4 gene exhibited a greater rate of forgetting as demonstrated by comparable performance between the two groups following longer memory delays of only 4 seconds. Previously, studies have reported increased forgetting in middle-aged and older APOE ε4 carriers on long-term memory tasks 4,5,9,26,28,34,[57][58][59] . Here, we demonstrate an increase in rapid forgetting in these individuals at much faster time scales, in a matter of seconds, in line with the possible prodromal effect of the APOE gene on longer-term memory.…”

mentioning

confidence: 98%

“…Participants first picked the fractal they recalled seeing in the memory array (identification performance) and then dragged it to its remembered location (localization performance). The OMT is a tablet task based on an identical task previously used to examine STM performance in carrier and non-carriers of the APOE ε4 24,34 .…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Zokaei

Grogan

Fallon

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

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...

show abstract

supporting

confidence: 85%

mentioning

confidence: 98%

See 1 more Smart Citation

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

Zokaei

Grogan

Fallon

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…APOE is a well-known apolipoprotein that functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids (44). As a secreted protein, APOE has been implicated in lipoprotein metabolism and the pathogenesis of Alzheimer's disease and atherosclerosis (45)(46)(47). However, its association with tumors has rarely been reported.…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics analysis of the association between apolipoprotein E expression and patient prognosis in papillary thyroid carcinoma

et al. 2020

View full text Add to dashboard Cite

The prognosis of most patients with papillary thyroid carcinoma (PTC) is excellent despite some cases of tumor progression or relapse. The present study was designed to reveal possible prognostic risk indicators for PTC. Differentially expressed genes (DEGs) extracted from 4 Gene Expression Omnibus (GEO) cohorts were subjected to functional enrichment analyses by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis. A dataset from The Cancer Genome Atlas (TCGA) was obtained to filter and validate significant genes using cytoHubba, followed by analysis of their association with clinicopathological characteristics and prognosis. In total, 240 DEGs were identified after data preprocessing. These DEGs were enriched in 'intracellular redox equilibrium', 'release of exosome', 'cell adhesion', 'regulation of extracellular matrix', 'collagen binding' and 'energy metabolism' based on GO analysis which including cellular component, molecular function and biological process. KEGG pathway analysis revealed that the DEGs were enriched in thyroid hormone synthesis, pathways in cancer, focal adhesion, metabolic pathways, apoptosis, PPAR signaling pathway and PI3K/AKT signaling pathway. Using cytoHubba, the following hub genes were identified: Apolipoprotein E (APOE); hemoglobin subunit α1 (HBA1); angiotensin II receptor 1 (AGTR1); collagen I α1 (COL1A1); galectin 3 (LGALS3) and TIMP metallopeptidase inhibitor 1 (TIMP1). The expression of these genes was found to be consistent in TCGA datasets. Kaplan-Meier analysis revealed that APOE was significantly associated with overall survival (P=0.00067) and disease free survival (P=0.00220). Additionally, low expression of APOE was significantly associated with older age (P<0.001) and higher TNM stage (P<0.001) compared with the high expression group. Therefore, APOE may function as a predictive risk indicator for progression as well as prognosis of PTC.

show abstract

“…While these models were designed for WM tasks, they can be used for other types of tasks including long-term memory tasks for spatial locations (e.g. Zokaei et al, 2019). There is also no reason why the models cannot be extended into the third dimension, should experiments require it, for example in virtual reality navigation tasks.…”

Section: Discussionmentioning

confidence: 99%

A new toolbox to distinguish the sources of spatial memory error

Grogan¹,

Fallon²,

Zokaei³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Studying the sources of errors in memory recall has proven invaluable for understanding the mechanisms of working memory (WM). While non-spatial memory features (e.g. colour, orientation) can be analysed using mixture models to separate the influence of imprecision, guessing, and misbinding (the tendency to confuse features that belong to different memoranda), such methods are not currently available for spatial WM tasks.Here we present a method to isolate sources of spatial error in tasks where participants have to report the spatial location of an item in memory, using two-dimensional mixture models. The method recovers simulated parameters well, and is robust to the influence of response distributions and biases, and number of distractors and trials. The recovered parameters are better estimates of the true parameters than the previously available behavioural metrics used in these tasks, such as mean target distance or nearest neighbour distance, suggesting our method is more sensitive to underlying error sources. To demonstrate the model, we fit data from a complex spatial WM task, and show the recovered parameters correspond well with previous spatial WM findings, and with recovered parameters on a one-dimensional analogue of this task, suggesting convergent validity for this two-dimensional modelling approach. Because an extra dimension is available for every response, spatial tasks turn out to be much better for separating misbinding from imprecision and guessing than in one-dimensional tasks. Code for these models is freely available in the MemToolbox2D package and is integrated to work with the commonly used Matlab package MemToolbox.

show abstract

Dissociable effects of the apolipoprotein-E (APOE) gene on short- and long-term memories

Cited by 23 publications

References 72 publications

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

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

Integrated bioinformatics analysis of the association between apolipoprotein E expression and patient prognosis in papillary thyroid carcinoma

A new toolbox to distinguish the sources of spatial memory error

Contact Info

Product

Resources

About