Apolipoprotein E genotype does not predict decline in intelligence in healthy older adults

doi:10.1016/S0304-3940(02)00135-0

Neuroscience Letters

Volume 324, Issue 1, 10 May 2002, Pages 74-76

https://doi.org/10.1016/S0304-3940(02)00135-0 Get rights and content

Abstract

There is evidence of a genetic influence on the decline in cognitive performance of older adults, although the mechanisms responsible are unknown. A group of 767 subjects of the Manchester University Age and Cognitive Performance longitudinal study volunteer group, followed up from 1985 to the present, were genotyped for apolipoprotein E (APOE). The data from this were related to cross-sectional and longitudinal trends in the Heim intelligence test score (AH4-1) using previously reported random-effects models (Neuropsychologia 39 (2001) 532). There were no significant differences in mean scores for presence compared with absence of the APOE4 or APOE2 genotypes (P=0.48 and P=0.51, respectively). This research does not demonstrate a link between intelligence and APOE genotype in older adults.

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Cited by (41)

APOE genotype and cognition in healthy individuals at risk of Alzheimer's disease: A review
2018, Cortex
Citation Excerpt :
The lower frequency of APOE-ε4 in the population, compared to APOE-ε3, has resulted in consistently smaller APOE-ε4 samples in most studies, unless specifically matched between groups (e.g., Caselli et al., 2001, 1999; Salvato et al., 2016; Zokaei et al., 2017). There are also relatively few investigations of the specific effect of APOE-ε2 on cognition, due to the low occurrence of the ε2 allele in the population (although see Bartrés-Faz et al., 1999; Batterham et al., 2013; Blair et al., 2005; Bloss et al., 2010; Bunce et al., 2014; Chey et al., 2000; Chiang, Raptentsetsang, & Jack, 2010; Greenwood et al., 2000; Helkala et al., 1995, 1996; Hofer et al., 2002; Marioni et al., 2016; Pendleton et al., 2002; Quintas et al., 2014; Salo et al., 2001; Staehelin et al., 1999; Ward et al., 2014; Wilson, Bienias, et al., 2002; Lancaster, Forster, et al., 2017). Table 1 also illustrates the variability in sample size across studies.
APOE-ε4 is best known as a risk factor for Alzheimer's disease (AD). Consequently, there is considerable research interest in understanding whether APOE-ε4 influences cognition in healthy adults. Despite a substantial literature reporting effects of APOE genotype on cognition, findings are inconsistent. In particular, it is challenging to separate whether cognitive deficits in APOE-ε4 carriers reflect the influence of prodromal dementia pathology (“prodromal hypothesis”), or a direct contribution of APOE genotype to individual differences (“phenotype hypothesis”). Variable methodology across studies further complicates the issue. These challenges have limited what can be learnt about the processes underlying cognitive ageing and dementia by studying the influence of APOE genotype on cognition. In this review, we focus on the two compatible neurobiological mechanisms by which APOE genotype may influence cognition in healthy adults (prodromal and phenotype). We summarise the behavioural evidence for the influence of APOE on cognition in non-demented adults and explore key methodological challenges for disentangling the cognitive effects of different neurobiological mechanisms of APOE. Evidence suggests that at least some APOE-ε4 cognitive deficits are due to early AD pathology, whilst sensitive measures of cognition are beginning to reveal subtle cognitive differences between APOE genotypes in mid-adulthood, prior to the onset of the AD prodromal period. We conclude with recommendations for future research to investigate the cognitive consequences of neurobiological processes affected by APOE and maximise the translational potential of this research.
Posterior cortical atrophy
2012, The Lancet Neurology
Citation Excerpt :
In some studies, significant differences between apolipoprotein E (APOE) genotypes have been noted in patients with PCA versus amnestic Alzheimer's disease.14,18,59 However, in other studies, no difference in APOE was recorded between PCA and typical Alzheimer's disease (table).17,21–23,60–64 Discrepancies between these studies could be attributable to differences in the inclusion criteria used to define PCA and typical Alzheimer's disease and age at onset.
Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterised by progressive decline in visuospatial, visuoperceptual, literacy, and praxic skills. The progressive neurodegeneration affecting parietal, occipital, and occipitotemporal cortices that underlies PCA is attributable to Alzheimer's disease in most patients. However, alternative underlying causes, including dementia with Lewy bodies, corticobasal degeneration, and prion disease, have also been identified, and not all patients with PCA have atrophy on clinical imaging. This heterogeneity has led to inconsistencies in diagnosis and terminology and difficulties in comparing studies from different centres, and has restricted the generalisability of findings from clinical trials and investigations of factors that drive phenotypic variability. Important challenges remain, including the identification of factors associated not only with the selective vulnerability of posterior cortical regions but also with the young age of onset of PCA. Greater awareness of the syndrome and agreement over the correspondence between syndrome-level and disease-level classifications are needed to improve diagnostic accuracy, clinical management, and the design of research studies.
Influence of apolipoprotein e ε4 on rates of cognitive and functional decline in mild cognitive impairment
2010, Alzheimer's and Dementia
Citation Excerpt :
Several longitudinal studies have reported that APOE ɛ4 is associated with cognitive decline among those without dementia [6,10–15], and have shown APOE ɛ4 to be predictive of the progression from aMCI to AD [8,16]. In contrast, a few studies have reported no association between APOE ɛ4 and cognitive decline [17–19] or found it not to be predictive, by itself, in the progression of aMCI to AD [7,20]. Our current longitudinal cohort, derived from a randomized placebo-controlled treatment trial, allows us to better establish and define APOE ɛ4-associated effects over time on specific cognitive and functional measures.
Apolipoprotein E ɛ4 (APOE ɛ4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE ɛ4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE ɛ4 allele status on measures of cognitive and functional decline in subjects with amnestic MCI (aMCI).
A total of 516 aMCI participants aged 55–90 years who received placebo or vitamin E from the Alzheimer's Disease Cooperative Study's MCI treatment trial were evaluated. During the 36-month study period, neurocognitive and functional measures were collected. These measures were assessed over time for change and association with APOE ɛ4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period.
APOE ɛ4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE ɛ4 positive had significantly more rapid decline in performance on all cognitive and functional measures except Number Cancellation and Maze tracing (P < .05). The greatest decline was seen in global measures of cognition and function including the Clinical Diagnostic Rating scale, followed by the Mini-Mental State Examination, Global Deterioration scale, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale.
These findings demonstrate that APOE ɛ4 genotype is predictive of increased general rates of decline with global measures of cognition and function most affected. With accelerated declines in common clinical trial primary efficacy measures, APOE ɛ4 status needs to be accounted for in treatment trials of MCI.
Challenges in phenotype definition in the whole-genome era: Multivariate models of memory and intelligence
2009, Neuroscience
Citation Excerpt :
The apolipoprotein E gene and associated protein are involved in the breakdown of beta-amyloid deposits and has been implicated in Alzheimer's disease (Bertram and Tanzi, 2008). Three relatively large studies report no significant effect of the e-4 allele on IQ using different tests (Turic et al., 2001; Pendleton et al., 2002; Deary et al., 2004). In contrast, Ferguson and colleagues (2003), reported worse performance on WAIS-R-test for those with a copy of e-4, however, they studied 96 women all with type I diabetes.
Refining phenotypes for the study of neuropsychiatric disorders is of paramount importance in neuroscience. Poor phenotype definition provides the greatest obstacle for making progress in disorders like schizophrenia, bipolar disorder, Attention Deficit/Hyperactivity Disorder (ADHD), and autism. Using freely available informatics tools developed by the Consortium for Neuropsychiatric Phenomics (CNP), we provide a framework for defining and refining latent constructs used in neuroscience research and then apply this strategy to review known genetic contributions to memory and intelligence in healthy individuals. This approach can help us begin to build multi-level phenotype models that express the interactions between constructs necessary to understand complex neuropsychiatric diseases. These results are available online through the http://www.phenowiki.org database. Further work needs to be done in order to provide consensus-building applications for the broadly defined constructs used in neuroscience research.
Predicting memory decline in normal elderly: Genetics, MRI, and cognitive reserve
2007, Neurobiology of Aging
Citation Excerpt :
Some studies likewise have reported that AD patients with APOE-ɛ4 exhibited poorer performance on memory tasks [36,54,66], whereas others have not [4,52,53]. Many (reviewed by Nilsson et al. [67]) but not all [4,7,14,15,25,45,61,67,72,73,80] cross-sectional studies of non-demented middle-aged and elderly subjects with APOE-ɛ4 have reported poorer learning and memory [8,9,13,21,27,44,56,78,84,92] and other impairments in cognitive performance [6,32,44,82,101]. Longitudinal MRI studies of hippocampal changes in association with APOE-ɛ4 have been relatively sparse but have suggested that APOE-ɛ4 is associated with accelerated hippocampal-volume loss in healthy controls [15,63].
Major predictors of Alzheimer's disease (AD) include apolipoprotein E (APOE)-ɛ4, hippocampal atrophy on magnetic resonance imaging (MRI), and memory dysfunction prior to diagnosis. We examined 159 normal elderly subjects with MRI and the California Verbal Learning Test (CVLT); 84 returned for longitudinal follow-up 5 years later. Analyses at baseline revealed significant variance in hippocampal volume accounted for by cerebral volume and age but not by APOE isoform. However, interactions involving APOE isoform and laterality were observed. As hypothesized, an APOE × time interaction was revealed for CVLT long-delay free recall: APOE-ɛ3/4 subjects had significantly poorer performance than APOE-ɛ3/3 subjects at follow-up. Forward stepwise multiple regression analysis predicting follow-up long-delay free recall selected baseline recall, followed by number of APOE-ɛ4 alleles, followed by left-hippocampal volume. Age and sex did not enter into the model. We conclude that APOE-ɛ4 predicts longitudinal memory decline in healthy controls and that MRI morphometry of hippocampus adds slightly to predictive value.
The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades
2007, Biological Psychology
Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy ɛ2 and ɛ4 carriers and matched ɛ3/ɛ3 controls, spanning ages 6–65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. ɛ4 subjects had better verbal fluency compared to ɛ3, an effect that was strongest in 51–65 year-olds. No ɛ4 deficits in cognition were found. In 6–15 year-olds, there were differences in total spatio-temporal wave activity between ɛ3 and ɛ4 subjects in the theta band, approximately 200 ms post-stimulus. Differences in brain function in younger ɛ4 subjects and superior verbal fluency across the entire age range suggest that the APOE ɛ4 allele is an example of antagonistic pleiotropy.

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Apolipoprotein E genotype does not predict decline in intelligence in healthy older adults

Abstract

Neurosci. Lett.

Neurobiol. Aging

Neuropsychologia

Apolipoprotein e4 allele and cognitive decline in elderly men

Br. Med. J.

Apolipoprotein E and cognitive change in an elderly population

Ann. Neurol.

Association between apolipoprotein E epsilon4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia

Arch. Neurol.