Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau

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 Aβ 42 . Discussion Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau.