APOE effects on cognition from childhood to adolescence (original) (raw)
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Molecular Psychiatry, 2012
Carriers of the APOE E4 allele have an increased risk of developing Alzheimer's disease. However, it is less clear whether APOE E4 status may also be involved in non-pathological cognitive ageing. The present study investigated the associations between APOE genotypes and cognitive change over 8 years in older community-dwelling individuals. APOE genotype was determined in 501 participants of the Lothian Birth Cohort 1921, whose intelligence had been measured in childhood in the Scottish Mental Survey 1932. A polymorphic variant of TOMM40 (rs10524523) was included to differentiate between the effects of the APOE E3 and E4 allelic variants. Cognitive performance on the domains of verbal memory, abstract reasoning and verbal fluency was assessed at mean age 79 years (n = 501), and again at mean ages of 83 (n = 284) and 87 (n = 187). Using linear mixed models adjusted for demographic variables, vascular risk factors and IQ at age 11 years, possession of the APOE E4 allele was associated with a higher relative rate of cognitive decline over the subsequent 8 years for verbal memory and abstract reasoning. Individuals with the long allelic variant of TOMM40, which is linked to APOE E4, showed similar results. Verbal fluency was not affected by APOE E4 status. APOE E2 status was not associated with change in cognitive performance over 8 years. In nondemented older individuals, possession of the APOE E4 allele predicted a higher rate of cognitive decline on tests of verbal memory and abstract reasoning between 79 and 87 years. Thus, possession of the APOE E4 allele may not only predispose to Alzheimer's disease, but also appears to be a risk factor for non-pathological decline in verbal memory and abstract reasoning in the ninth decade of life.
APOE Genotype and Cognitive Change in Young, Middle-Aged, and Older Adults Living in the Community
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2013
We examined whether the APOE ɛ4 allele was associated with cognitive benefits in young adulthood but reversed to confer cognitive deficits in later life ("antagonistic pleiotropy") in the absence of dementia-related neuropathology. We also tested whether the ɛ2 allele was associated with disadvantages in early adulthood but offered protection against cognitive decline in early old age. Eight-year cognitive change was assessed in 2,013 cognitivelynormal community-dwelling adults aged either 20 to 24, 40 to 44, or 60 to 64 years at baseline. Although cognitive decline was associated with age, multilevel models contrasting the ɛ2 and ɛ4 alleles provided no evidence that APOE genotype was related to cognitive change in any of the age groups. The findings suggest that in the absence of clinically salient dementia pathology, APOE ɛ2 and ɛ4 alleles do not exhibit antagonistic pleiotropy in relation to cognition between the ages of 20 and 72 years.
Translational Psychiatry, 2022
Cognitive decline is part of the normal aging process. However, some people experience a more rapid decline than others due to environmental and genetic factors. Numerous single nucleotide polymorphisms (SNPs) have been linked to cognitive function, but only a few to cognitive decline. To understand whether cognitive function and cognitive decline are driven by the same mechanisms, we investigated whether 433 SNPs previously linked to cognitive function and 2 SNPs previously linked to cognitive decline are associated with both general cognitive functioning at baseline and general cognitive decline up to 20-years follow-up in the Doetinchem Cohort Study (DCS). The DCS is a longitudinal population-based study that enrolled men and women aged 20-59 years between 1987-1991, with follow-up examinations every 5 years. We used data of rounds 2-6 (1993-2017, n = 2559). General cognitive function was assessed using four cognition tests measuring memory, speed, fluency and flexibility. With these test scores, standardized residuals (adjusted for sex, age and examination round) were calculated for each cognition test at each round and subsequently combined into one general cognitive function measure using principal component analyses. None of the 435 previously identified variants were associated with baseline general cognitive function in the DCS. But rs429358-C, a coding apolipoprotein E (APOE) SNP and one of the variants previously associated with cognitive decline, was associated with general cognitive decline in our study as well (p-value = 1 × 10 −5 , Beta = −0.013). These findings suggest that decline of general cognitive function is influenced by other mechanisms than those that are involved in the regulation of general cognitive function.
A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing
Molecular Psychiatry, 2014
Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP-rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)-had a genome-wide significant association with cognitive ageing (P ¼ 2.5 Â 10 À 8 ). This result was replicated in a meta-analysis of three independent Swedish cohorts (P ¼ 2.41 Â 10 À 6 ). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P ¼ 2.18 Â 10 À 8 ; females, P ¼ 1.66 Â 10 À 11 ; males, P ¼ 0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P ¼ 3.66 Â 10 À 11 ) and TOMM40 (rs11556505; P ¼ 2.45 Â 10 À 8 ) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.
International Journal of Geriatric Psychiatry, 2014
Objective: This study aimed to investigate the correlation between apolipoprotein E (APOE) ε4 and the mini-mental state examination (MMSE) dimension in an elderly population, using baseline data from the Bambui (Brazil) Cohort Study of Aging. Design: We conducted a community-based cross-sectional study. Setting: The study took place at Bambui city, Minas Gerais State, Southeast Brazil. Participants: A total of 1408 (87.7%) cohort participants had complete information on the MMSE and health measures. Measurements: The association between each of five dimensions (concentration, language/praxis, orientation, attention, and memory) underlying the MMSE and APOE ε4 allele was assessed using multivariate linear regression models. Potential confounding variables included sociodemographic factors and selected biomarkers. Results: The main finding is a strong negative association between the presence of APOE ε4 allele and memory dimension in the MMSE (fully adjusted β coefficient = À0.14; 95% confidence interval: À0.27 to À0.04; p = 0.016). No other cognitive dimensions showed significant associations with the APOE ε4 allele.
Change in Cognitive Functioning Associated With ApoE Genotype in a Community Sample of Older Adults
Psychology and Aging, 2002
The influence of a genetic risk factor, apolipoprotein E (apoE) 4 variant, was assessed in older adults aged 70 to 94 on 3 occasions over 7 years. The results of latent growth curve analyses are reported for individuals genotyped for apoE at the 2nd measurement occasion (n ϭ 601) and for a subsample of individuals without probable or definite dementia during the 1st or 2nd occasion (n ϭ 434). ApoE-4 status was a significant predictor of level and change in memory performance and change in speed performance in the full sample, and of initial level and change in memory performance in the nondemented subsample. These results support previous findings that apoE-4 is associated with accelerated memory deterioration in individuals without clinical dementia.
Assessing for interaction between APOE ε4, sex, and lifestyle on cognitive abilities
Neurology, 2019
Objective To test for interactions between APOE e4 genotype and lifestyle factors on worse cognitive abilities in UK Biobank. Methods Using UK Biobank cohort data, we tested for interactions between APOE e4 allele presence, lifestyle factors of alcohol intake, smoking, total physical activity and obesity, and sex, on cognitive tests of reasoning, information processing speed, and executive function (n range = 70,988-324,725 depending on the test). We statistically adjusted for potential confounders of age, sex, deprivation, cardiometabolic conditions, and educational attainment. Results There were significant associations between APOE e4 and worse cognitive abilities, independent of potential confounders, and between lifestyle risk factors and worse cognitive abilities; however, there were no interactions at multiple correction-adjusted p < 0.05, against our hypotheses. Conclusions Our results do not provide support for the idea that e4 genotype increases vulnerability to the negative effects of lifestyle risk factors on cognitive ability, but rather support a primarily outright association between APOE e4 genotype and worse cognitive ability.