AbstractBackgroundHearing loss was recently identified as a modifiable risk factor for dementia. However, investigations have yet to evaluate whether hearing loss may interact with other risk factors of dementia, such as female sex and APOE4 allele. The goal of this study was to explore the associations between hearing loss, female sex, and APOE4 on functional connectivity.MethodResting‐state fMRI functional connectivity in 1,000 participants (61.98±7.41 years, 50% female, 50% APOE4 carriers) from the UK Biobank was computed between bilateral planum temporale ROIs (auditory seed regions) and the 1) default mode (DMN), 2) frontoparietal (FPN), and 3) cingulo‐opercular (CON) network ROIs (target regions). Hearing was measured with a speech in noise reception task, which was used to split participants into better performing ear groups (better left ear (56%): ‐5.97±1.50dB; better right ear (44%): ‐6.07±.1.55dB), in which higher scores indicate poorer hearing. ANCOVA models with FDR corrections were used to examine associations of functional connectivity and left and right ear hearing measures, controlling for age. Interactions with sex and APOE4 status were examined, followed by stratified models for sex and APOE4.ResultLeft ear hearing was poorer in females compared to males; this sex difference was also observed within APOE4 carriers. Right ear hearing did not differ between groups. Main effects of sex on functional connectivity showed that females generally have lower connectivity than males; no main effects of APOE4 were observed. Stratified analyses showed that female APOE4 carriers with poorer left ear hearing showed lower functional connectivity between left planum temporale and ROIs of the DMN and CON. Similar results were found for functional connectivity from right planum temporale. No significant associations were found for female noncarriers, male carriers and noncarriers, nor for right ear hearing.ConclusionHearing loss is associated with lower functional connectivity in females who are APOE4 carriers. Lower functional connectivity was observed between auditory processing areas and networks associated with episodic memory, working memory, and attention. These results support that a possible mechanistic underpinning for why hearing loss increases risk for dementia may be due to altered connectivity to higher‐order cognitive networks, particularly for females who are APOE4 carriers.