Possible positive effect of the APOE ε2 allele on cognition in early to mid-adult life

Sinclair, Lindsey I; Pleydell-Pearce, Christopher W.; Day, Ian N.M.

doi:10.1016/j.nlm.2017.10.008

Cited by 16 publications

(17 citation statements)

References 67 publications

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“…The present largest single-sample study has not found any association between the ε2 allele and special cognitive ability across all age ranges (Marioni et al, 2016). Sinclair et al (2017) found that the ε2 allele showed positive outcomes on episode memory and executive function in early to mid-adult life (ages 23-67). In the present study, the APOE genotype was associated with general cognitive performance (MMSE and ADAS13 scores) in the MCI group, but was not associated with any cognitive domains in CN elders or MCI patients; this can be attributed to the small sample size in this study.…”

Section: Discussioncontrasting

confidence: 63%

“…A large body of work has focused on the relationship between APOE genotype and AD pathology. Many prior studies have examined the structural and functional differences in the brain, particularly in the hippocampus, resulting from the presence of ε4 (Schuff et al, 2009;Wang et al, 2015;Sinclair et al, 2017). More recently, researchers have paid more attention to the impact of the APOE ε2 allele on the brain.…”

Section: Introductionmentioning

confidence: 99%

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The Specific Impact of Apolipoprotein E Epsilon 2 on Cognition and Brain Function in Cognitively Normal Elders and Mild Cognitive Impairment Patients

Gong

Liu

et al. 2020

Front. Aging Neurosci.

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Variants in the apolipoprotein E (APOE) gene play an important role in the development of Alzheimer's disease (AD). Specifically, the APOE ε4 allele is an established genetic risk factor for AD, while the APOE ε2 allele is a protective factor against AD. However, the mechanism underlying this impact of APOE genotype on the pathogenesis of AD remain unclear. This study sought to investigate the influence of APOE genotype on cognition and neuroimaging features in cognitively normal (CN) elderly individuals and patients with mild cognitive impairment (MCI). A total of 177 participants were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 101 MCI patients and 76 CN individuals. A 2 × 3 (consisting of two groups and three APOE genotypes) analysis of covariance was carried out to measure the influences of diagnosis and APOE genotype on cognition and brain features, assessed based on global functional connectivity density (gFCD) and hippocampal volume. In addition, a mediation analysis was carried out to investigate the indirect influence of neuroimaging features on the relationship between APOE genotype and cognitive performance in the MCI group. This analysis revealed that APOE genotype had an influence on brain function in the bilateral precentral gyrus, right thalamus, and posterior cingulate cortex (PCC). In addition, an interactive influence between diagnosis and APOE genotype was found on general cognition, immediate memory, executive function, hippocampal volume, and gFCD in the right dorsolateral prefrontal cortex and medial prefrontal cortex (MPFC). Finally, this mediation analysis revealed that hippocampal volume and gFCD in the thalamus may mediate the relationship between APOE genotype and cognitive performance in the MCI group. Taken together, our findings provide novel insights into the neural mechanisms underlying the genetically guided pathogenic mechanisms of AD.

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Section: Discussioncontrasting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

The Specific Impact of Apolipoprotein E Epsilon 2 on Cognition and Brain Function in Cognitively Normal Elders and Mild Cognitive Impairment Patients

Gong

Liu

et al. 2020

Front. Aging Neurosci.

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“…The 3 allele displayed a competitive survival advantage sufficiently robust to result in the current predominance of the 3/3 genotype which is now found in over 60% of the US population, presumably because of its protection for memory loss and dementia in progressively older age ranges [23]. Similarly, the 2 allele mutated from the 3 allele about 200,000 years ago, but this protective allele has remained relatively rare with the homozygous 2/2 variant less than 1%, and the 3/2 heterozygote in about 11% of the population [144].…”

Section: Discussionmentioning

confidence: 99%

“…The average effect size of 4 status was non-significant across cognitive domains. Sinclair et al [144] studied 114 participants with the allelic combinations of 3/3 (39 subjects), 3/4 (27 subjects), 4/4 (15 subjects), 3/2 (26 subjects), and 2/2 (7 subjects). The primary outcome was performance on the Rey Auditory Verbal Learning Test (RAVLT).…”

Section: Mental Performance In Young Apolipoprotein 4 Carriers (Table 8)mentioning

confidence: 99%

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

Smith

Ashford

Perfetti³

2019

JAD

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Inheritance of a single copy of the apolipoprotein E (APOE) 4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to 3 allele homozygosity. There is a decreased risk associated with the APOE 2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous 4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on 4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the 4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral 4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing 3 allele, at the expense of decreased fitness in old age, which is substantially improved by the 3 allele. However, possession of the 4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion. conceptualization of AD pathology dates from 1968 when Blessed et al. showed in elderly individuals that the NFTs correlated with the severity of the dementia, though the neuritic plaques, which contain cerebral amyloid-␤ (A␤), did not [2]. A major advance in understanding AD pathology was the demonstration that AD pathology predominantly affects the posterior-temporal, inferior parietal, posterior cingulate, and medial temporal region [3], with a characteristic pattern of progression beginning in the entorhinal cortex involving neurofibrillary (NF)

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“…The results from the power analysis were that testing 15 participants would provide at least 80% power to detect a significant difference between-groups with a corrected p-value of p < 0.05. Amongst those invited and subsequently consented to take part: 16 were e3/ e3 carriers (these comprised the e4− group); 11 were e3/e4 and 5 were e4/e4 (these comprised the e4+ group, totaling 16); 1 participant was an e2/e4 and excluded from analyses based on evidence that the e2 allele might be protective 58 Between the two groups, there were no significant differences in age, gender balance, NART IQ, MoCA score or years of education (Table 1). Nevertheless in the imaging analyses, gender was entered as a covariate.…”

Section: Methodsmentioning

confidence: 99%

Mid age APOE ε4 carriers show memory-related functional differences and disrupted structure-function relationships in hippocampal regions

Evans

Dowell

Prowse

et al. 2020

Sci Rep

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Carriers of the APOE e4 allele are at higher risk of age-related cognitive decline and Alzheimer's disease (AD). The underlying neural mechanisms are uncertain, but genotype differences in medial temporal lobe (MTL) functional activity and structure at mid-age might contribute. We tested 16 non-e4 and 16 e4 carriers (aged 45-55) on a subsequent memory task in conjunction with MRI to assess how hippocampal volume (from T1 structural) and microstructure (neurite orientation-dispersion, from NODDI) differs by genotype and in relation to memory encoding. No previous study has investigated APOE effects on hippocampal microstructure using NODDI. Recall performance did not differ by genotype. A genotype by condition interaction in left parahippocampus indicated that in e4 carriers activity did not differentiate subsequently remembered from forgotten words. Hippocampal volumes and microstructure also did not differ by genotype but hippocampal volumes correlated positively with recognition performance in non-e4 carriers only. Similarly, greater hippocampal neurite orientationdispersion was linked to better recall but only in non-e4s. Thus, we suggest that mid-age e4 carriers show a breakdown of normal MTL activation and structure-performance relationships. This could reflect an inability to utilise compensatory mechanisms, and contribute to higher risk of cognitive decline and AD in later life.In humans, the Apolipoprotein E (APOE) gene has 3 variants (e2, e3, e4); the e4 allele has been subject to considerable research interest due to it being a well-established risk factor for late-onset Alzheimer's disease (AD) 1 with e4 carriers being approximately 3 times more likely to develop AD relative to e3 carriers 2 . The e4 allele also affects cognitive ageing trajectories in healthy individuals. Healthy older e4 carriers (from this point referred to as e4+) perform worse than non-e4 carriers (e4−) on measures of episodic memory, executive functioning and overall global cognitive ability 3 . Longitudinal studies in healthy populations point to more rapid age-related cognitive decline in e4+ 4,5 . Small detrimental effects of e4 on cognition appear to be evident at mid age 4,6 with these becoming more pronounced beyond the 6 th decade 7 . However, midlife effects of APOE are not well studied, despite evidence that risk factor exposure during this life stage significantly influences AD risk in later life 8 . With accumulation of AD-related neuropathology beginning some decades before symptom onset 9 , midlife thus likely represents the optimal opportunity to intervene against cognitive decline and AD.Brain structural differences have been detected in healthy e4 carriers. Imaging studies have tended to focus on the medial temporal lobe (MTL) since this structure is amongst the first to evidence AD-related pathology 10 . Reduced hippocampal volumes have been reported in healthy older e4+ 11,12 but studies in younger samples tend

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Possible positive effect of the APOE ε2 allele on cognition in early to mid-adult life

Abstract: HighlightsE4 carriers self reported more memory problems, but no objective differences found.E2 carriers performed slightly better on episodic memory test.E2 carriers were faster in a test of executive function.

Cited by 16 publications

References 67 publications

The Specific Impact of Apolipoprotein E Epsilon 2 on Cognition and Brain Function in Cognitively Normal Elders and Mild Cognitive Impairment Patients

The Specific Impact of Apolipoprotein E Epsilon 2 on Cognition and Brain Function in Cognitively Normal Elders and Mild Cognitive Impairment Patients

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

Mid age APOE ε4 carriers show memory-related functional differences and disrupted structure-function relationships in hippocampal regions

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