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Apolipoprotein-E (Apoe) ?4 and cognitive decline over the adult life course.

ABSTRACT: We tested the association between APOE-?4 and processing speed and memory between ages 43 and 69 in a population-based birth cohort. Analyses of processing speed (using a timed letter search task) and episodic memory (a 15-item word learning test) were conducted at ages 43, 53, 60-64 and 69 years using linear and multivariable regression, adjusting for gender and childhood cognition. Linear mixed models, with random intercepts and slopes, were conducted to test the association between APOE and the rate of decline in these cognitive scores from age 43 to 69. Model fit was assessed with the Bayesian Information Criterion. A cross-sectional association between APOE-?4 and memory scores was detected at age 69 for both heterozygotes and homozygotes (??=?-0.68 and ??=?-1.38, respectively, p?=?0.03) with stronger associations in homozygotes; no associations were observed before this age. Homozygous carriers of APOE-?4 had a faster rate of decline in memory between ages 43 and 69, when compared to non-carriers, after adjusting for gender and childhood cognition (??=?-0.05, p?=?0.04). There were no cross-sectional or longitudinal associations between APOE-?4 and processing speed. We conclude that APOE-?4 is associated with a subtly faster rate of memory decline from midlife to early old age; this may be due to effects of APOE-?4 becoming manifest around the latter stage of life. Continuing follow-up will determine what proportion of this increase will become clinically significant.

SUBMITTER: Rawle MJ

PROVIDER: S-EPMC5802532 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Apolipoprotein-E (Apoe) ε4 and cognitive decline over the adult life course.

Rawle Mark James MJ Davis Daniel D Bendayan Rebecca R Wong Andrew A Kuh Diana D Richards Marcus M

Translational psychiatry 20180110 1

We tested the association between APOE-ε4 and processing speed and memory between ages 43 and 69 in a population-based birth cohort. Analyses of processing speed (using a timed letter search task) and episodic memory (a 15-item word learning test) were conducted at ages 43, 53, 60-64 and 69 years using linear and multivariable regression, adjusting for gender and childhood cognition. Linear mixed models, with random intercepts and slopes, were conducted to test the association between APOE and t ...[more]

PMID: 29317609

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Project description:BackgroundApproximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOE ε4), the strongest genetic risk factor for late onset Alzheimer's disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age.MethodsA cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) with APOE genotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association of APOE genotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia.ResultsCompared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%) APOE ε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45-85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function.ConclusionsBoth heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect of APOE ε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.

Project description:BackgroundSubjective cognitive decline (SCD) is characterized by self-reported cognitive deficits without measurable cognitive impairment. It has been suggested that individuals with SCD exhibited brain structural alterations in widespread cortical thinning or gray matter loss in the medial temporal and frontotemporal regions. Apolipoprotein E (APOE) ε4 allele is thought to be a genetic marker associated with risk of SCD. Neuropsychiatric symptoms may provide insight in detecting higher-risk elders for early Alzheimer's disease as well. Therefore, we aim to explore the characteristics of brain morphology in SCD and to determine whether it is influenced by APOE ε4 as well as neuropsychiatric symptoms in SCD.MethodsA total of 138 cognitively normal older individuals from the SILCODE cohort underwent a clinical interview, neuropsychological assessments, a blood test, and MRI. A two-sample t-test was used to examine the cortex volume and bilateral cortical surface area alterations between SCD (n = 65) and controls (n = 73). A general linear model analysis was used to test for both main and interaction effects of clinical phenotype (SCD vs. controls) and APOE on global and regional cortex volume and bilateral cortical surface area and thickness. A multiple linear regression analysis was conducted to determine the effects of the APOE genotype on the relationships between morphometric features and neuropsychiatric symptoms in SCD.ResultsCompared with controls, individuals with SCD showed decreased total cortical volumes and cortical surface area. SCD APOE ε4 carriers showed additive reduction in the right cortical surface area. The evaluation scores of anxiety symptoms were negatively associated with the right cortical surface area in SCD APOE 4 non-carriers.ConclusionsIndividuals with SCD had an altered cortical surface area, and APOE genotype and anxiety symptoms are modified factors on the cortical surface area decrease in SCD.Trial registrationClinicalTrials.gov (Identifier: NCT03370744 ). Registered 15 March 2017.

Project description:IntroductionSubjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer's disease prevention trials.MethodsThe PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention + EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color and Word Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium.DiscussionThe use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions.

Project description:ObjectiveTo exam the association of cognitive decline with APOE ε4 allele carriage and dietary protein intake and investigate whether there is a gene-diet (GxD) interaction of APOE ε4 allele carriage and dietary protein intake on cognitive decline in a nationwide cohort of older adults.MethodsA cohort study of participants from Chinese Longitudinal Healthy Longevity Survey was conducted from 2008 to 2014. A total of 3029 participants (mean age of 77.0 years, SD = 9.0; 49.3% were women) was enrolled. We genotyped APOE ε4 allele for each participant and calculated the diversity of dietary protein intake (DDPI) by summing up the frequency of intake of the 6 protein-rich foods (meats, fish, eggs, nuts, dairy products, and bean products). We assessed cognitive function using the Mini-Mental State Examination (MMSE). We used ordinal regression model to estimate the independent and joint effects of APOE ε4 carrier and dietary protein intake on cognitive decline, adjusting for potential confounders of age, sex, education, socio-economic status, lifestyles, BMI, and cardiometabolic conditions.ResultsThere was significant association between carrying APOE ε4 allele and faster cognitive decline (Odds ratio: 1.19, 95% CI = 1.00-1.42), independent of potential confounders. While the associations of DDPI and the intake of 6 protein-rich foods with cognitive decline did not reach any statistical significance. We observed significant interactions of APOE ε4 with DDPI and fish intake, at multiple correction-adjusted Ps < 0.05. In those who were APOE ε4 carriers rather than non-carriers, both high DDPI (OR = 0.54, 95% CI: 0.34-0.88) and daily fish intake (OR = 0.43, 95% CI: 0.22-0.78) were significantly associated with slower cognitive decline, respectively. We also found that frequent intake of fish benefits women more than men regarding the mitigating of cognitive decline among APOE ε4 allele carriers (P for interaction = 0.016).ConclusionsThe results of this study support the hypothesis that diversified protein food intake in addition to frequent fish intake may reduce the detrimental effect of APOE ε4 on cognitive health.

Dataset Information

Apolipoprotein-E (Apoe) ?4 and cognitive decline over the adult life course.

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Apolipoprotein-E (Apoe) ε4 and cognitive decline over the adult life course.

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