Abstract
OBJECTIVE: Offspring whose parents have Alzheimer disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele noncarriers. METHODS: We studied a cohort of 348 cognitively normal participants with or without family history of late onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging. RESULTS: A family history of late onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele noncarriers. INTERPRETATION: Unknown genetic factors, embodied in a family history of late onset AD, may affect DMN integrity prior to cognitive impairment.