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Apolipoprotein E ?4 allele effects on longitudinal cognitive trajectories are sex and age dependent.

ABSTRACT: INTRODUCTION:Questions remain about whether apolipoprotein E (APOE)-?4 effects on cognitive decline are similar in men and women and how APOE-?4 and age interact to influence decline in different cognitive domains. METHODS:In sex-stratified analyses, baseline age-dependent associations between APOE-?4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). RESULTS:In men, older baseline age was associated with greater effects of APOE-?4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-?4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-?4 effects were found for language, visual-spatial ability, or processing speed. DISCUSSION:Results highlight the importance of considering sex and age when assessing APOE-?4-associated vulnerability to cognitive decline.

SUBMITTER: Williams OA

PROVIDER: S-EPMC7561018 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Apolipoprotein E ε4 allele effects on longitudinal cognitive trajectories are sex and age dependent.

Williams Owen A OA An Yang Y Armstrong Nicole M NM Shafer Andrea T AT Helphrey Jessica J Kitner-Triolo Melissa M Ferrucci Luigi L Resnick Susan M SM

Alzheimer's & dementia : the journal of the Alzheimer's Association 20190924 12

<h4>Introduction</h4>Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains.<h4>Methods</h4>In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments).<h4>Result ...[more]

PMID: 31561966

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Project description:Women are more likely to have Alzheimer's disease (AD) and decline more rapidly once diagnosed despite greater verbal memory early in the disease compared to men-an advantage that has been termed "memory reserve." Resting state functional MRI (fMRI) investigations demonstrate interactions between sex and AD risk factors in default mode network (DMN) connectivity, a network of brain regions showing progressive dysfunction in AD. Separate work suggests connectivity of left prefrontal cortex (PFC) may correlate with more general cognitive reserve in healthy aging. It is unknown whether left prefrontal functional connectivity with anterior and posterior default mode network (aDMN, pDMN) might differ by sex in AD. This study employed group independent component analysis (ICA) to analyze resting state fMRI data from 158 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with baseline diagnoses of normal cognition or early mild cognitive impairment (eMCI). pDMN and aDMN were defined on a subject-specific basis; prefrontal areas were selected from the Brodmann atlas (BA 6, 44, 8, and 9). Moderation regression analyses examined whether sex and amyloid PET positivity (A+/-) moderated effects of apolipoprotein ε4 (APOE ε4) on connectivity between left PFC, aDMN, and pDMN; and between aDMN and pDMN. Significant analyses were followed up with partial correlations assessing relationship of connectivity to verbal memory on the Rey Auditory Verbal Learning Test (RAVLT), and with preliminary analyses within NC and eMCI groups separately. Results showed no sex moderation of effects of A+ and APOE ε4 on left prefrontal/DMN connectivity in the full sample. However, sex significantly moderated impact of A+ and APOE ε4 on connectivity between aDMN and pDMN (p < 0.01). Women with an APOE allele (ε4+) and A+ showed greater aDMN/pDMN connectivity than their ε4- counterparts. No significant results were observed in men. Subgroup analyses suggested the aDMN/pDMN finding was true for those with NC, not eMCI. Partial correlations controlling for age and education showed increased aDMN/pDMN connectivity related to better verbal learning in women (p < 0.01) and not men (p = 0.18). In women at risk for AD or in early symptomatic stages who also have evidence of amyloid burden, stronger aDMN/pDMN connectivity may support verbal learning.

Project description:Many studies have shown that healthy elderly subjects and patients with Alzheimer's disease (AD) who carry the apolipoprotein E (ApoE) ε4 allele have worse cognitive function and more severe brain atrophy than non-carriers. However, it remains unclear whether this ApoE polymorphism leads to changes of cognition and brain morphology in healthy young adults. In this study, we used an established model to measure verbal episodic memory and core executive function (EF) components (response inhibition, working memory and task switching) in 32 ApoE ε4 carriers and 40 non-carriers between 20 years and 40 years of age. To do this, we carried out an adapted auditory verbal learning test and three computerized EF tasks. High-resolution head magnetic resonance scans were performed in all participants and voxel-based morphometry (VBM) was used for image processing and analysis. Multivariate analysis of variance (ANOVA) performed on memory measures showed that the overall verbal episodic memory of ApoE ε4 carriers was significantly worse than non-carriers (Wilk's λ = 4.884, P = 0.004). No significant differences were detected in overall EF between the two groups. Post hoc analyses revealed group differences in terms of immediate recall, recognition and task switching, which favored non-carriers. VBM analysis showed gray matter (GM) bilateral reductions in the medial and dorsolateral frontal, parietal and left temporal cortices in the carrier group relative to the non-carrier group, which were most significant in the bilateral anterior and middle cingulate gyri. However, these changes in GM volume were not directly associated with changes in cognitive function. Our data show that the ApoE ε4 allele is associated with poorer performance in verbal episodic memory and task switching, and a reduction in GM volume in healthy young adults, suggesting that the effects of ApoE ε4 upon cognition and brain morphology exist long before the possible occurrence of AD.

Dataset Information

Apolipoprotein E ?4 allele effects on longitudinal cognitive trajectories are sex and age dependent.

Publications

Apolipoprotein E ε4 allele effects on longitudinal cognitive trajectories are sex and age dependent.

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