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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurol. | doi: 10.3389/fneur.2019.00900

Sex moderates amyloid and apolipoprotein E4 effects on default mode network connectivity at rest

 Jessica Z. Kirkland Caldwell1*,  Xiaowei Zhuang1, MacKenzie Leavitt1, Sarah Banks2, Jeffrey Cummings1, 3 and  Dietmar Cordes1
  • 1Lou Ruvo Center for Brain Health, Cleveland Clinic, United States
  • 2University of California, San Diego, United States
  • 3School of Allied Health Sciences, University of Nevada, Las Vegas, United States

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), a network of brain regions showing progressive dysfunction in AD. Separate work suggests connectivity of left prefrontal cortex (PFC) correlates with 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 Ɛ4 (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 memory on the Rey Auditory Verbal Learning Test (RAVLT), and with preliminary analyses within NC and eMCI groups. 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 ε4 allele and A+ showed greater aDMN/pDMN connectivity than their E4- counterparts. No significant results were observed in men. Subgroup analyses suggested the aDMN/pDMN finding was true for 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.

Keywords: Aging, degenerative disease, functional MRI (fMRI), Memory, Positron emission 

Received: 07 May 2019; Accepted: 02 Aug 2019.

Edited by:

Nicoletta Cera, University of Porto, Portugal

Reviewed by:

Gabriel Gonzalez-Escamilla, University Medical Centre, Johannes Gutenberg University Mainz, Germany
Nicola Filippini, University of Oxford, United Kingdom  

Copyright: © 2019 Kirkland Caldwell, Zhuang, Leavitt, Banks, Cummings and Cordes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jessica Z. Kirkland Caldwell, Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, United States,