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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:ObjectivesTo confirm associations of apolipoprotein E (ApoE) ε4 carrier status, sex, and time-dependent cognitive status with mortality risk and to investigate these joint effects of these associations in a cohort of community-dwelling U.S. adults.DesignProspective cohort study.SettingThe Baltimore Longitudinal Study of Aging (BLSA).ParticipantsOf 3,047 BLSA participants aged 17 to 98 at first visit (60.1% male), 1,704 with complete ApoE genotype data were included, of whom 1,461 aged 50 and older with one or more visits were eligible.MeasurementsTime to death from all, cardiovascular, and noncardiovascular causes.ResultsProbability of survival was lower for ApoE ε4 carriers, particularly those who were older. A Cox proportional hazards model for all-cause mortality yielded a hazard ratio (HR) for ApoE ε4 carrier versus noncarriers of 1.31 (95% confidence interval (CI) = 1.02-1.68). This association was also found for cardiovascular mortality. Time-dependent all-cause dementia (HR = 1.73, 95% CI = 1.33-2.26) and mild cognitive impairment (HR = 1.95, 95% CI = 1.42-2.67) increased all-cause mortality risk, associations that were also detected for noncardiovascular mortality. When individuals were free of cognitive impairment, a dose-response relationship with ε4 alleles was found for all-cause mortality (HR = 1.40, 95% CI = 0.94-2.07 for 1 ε4; HR = 2.61, 95% CI = 1.12-6.07 for 2 ε4). After onset of Alzheimer's disease (AD), carrying only one ε4 allele resulted in an approximately 77% greater all-cause mortality risk than in noncarriers. ApoE ε4 carrier status increased all-cause mortality risk in men and interacted with time-dependent AD to increase the risk of this outcome (relative excess risk due to interaction = 2.15, 95% CI = 1.22-3.07).ConclusionApoE ε4 carrier status was found to increase all-cause and cardiovascular mortality risks and interacted with sex and time-dependent AD status to affect all-cause mortality.

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.

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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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