Introduction: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer's disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aβ) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aβ accumulation. Methods: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aβ per cerebrospinal fluid (CSF) or amyloid positron emission tomography. Results: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P =.02), with significant weighting on linear regression toward CSF total tau (P =.03) and CSF phosphorylated tau at codon 181 (P =.03), but not CSF Aβ42. Discussion: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau.

Original languageEnglish
Pages (from-to)116-126
Number of pages11
JournalAlzheimer's and Dementia
Issue number1
StatePublished - Jan 2022


  • apolipoprotein E
  • functional connectivity
  • preclinical Alzheimer's disease
  • resting state
  • tau


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