Dataset Information

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 ?4 allele of the Apolipoprotein E (APOE ?4), the strongest genetic risk factor for late onset Alzheimer's disease. Beyond its association with late-onset dementia, the association between APOE ?4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ?4 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 ?4 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-?4 carriers as the reference, ?4 homozygotes had poorer global cognitive score starting from 65?years; ?4 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 ?4 heterozygotes was primarily attributable to executive function.ConclusionsBoth heterozygous and homozygous ?4 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 ?4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.

Project description:ObjectiveAn Alzheimer's disease (AD) diagnosis is preceded by a long period of cognitive decline. We previously demonstrated increased risk of decline among individuals possessing one or more APOE ?4 alleles together with a family history of AD. The objective of this study is to investigate the possibility that such an increased risk might be due to AD risk genes with small effects in combination with APOE.MethodsParticipants in the Health and Retirement Study (HRS) over the age of 65, who contributed DNA, and had two or more evaluations with an abbreviated version of the modified Telephone Interview for Cognitive Status (TICS-m) were eligible for the study (n = 7451). A genetic risk score (g-score) was derived using AD risk genes' meta-analyses data, assigning risk according to the number of risk alleles and summed over all the risk genes. Trajectories of cognitive function were modeled in four groups of Caucasian participants with and without one or more APOE ?4 alleles and either a high or low g-score: APOE ?4-/low g-score; APOE ?4-/high g-score; APOE ?4+/low g-score; and APOE ?4+/high g-score. Post hoc analyses evaluated interactions between individual genes and APOE.ResultsIndividuals in the APOE ?4+/high g-score group exhibited the greatest cognitive decline over time (p<.0001). This risk appeared to be greater than the sum of the effects of either high g-score or APOE ?4 alone. When gene interactions were individually tested with APOE, a statistically significant interaction with CD33 was discovered (p = 0.04) although the interaction was no longer significant when adjusted for multiple comparisons.ConclusionsIndividuals with multiple AD risk genes in addition to having one or more APOE ?4 alleles are at greater risk of cognitive decline than individuals with either APOE ?4 or a high genetic risk score. Among those with one or more APOE ?4 alleles, having one or more copies of the CD33 C (risk) allele may further increase the risk of cognitive decline.

Dataset Information

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

Publications

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

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