The APOE ε4 allele is a genetic risk factor for late-onset Alzheimer's disease and is associated with brain changes in middle-aged and elderly individuals. This study investigated the effects of the APOE ε4 allele in 18 young healthy carriers (20–35 years) and 18 noncarriers. Using resting-state and task-based fMRI, the study found increased coactivation in the default mode network (DMN) in ε4 carriers during rest, and greater hippocampal activation during a memory encoding task compared to noncarriers. These differences were not explained by memory performance, brain morphology, or resting cerebral blood flow. The results suggest that the APOE ε4 allele influences brain function decades before any clinical or neurophysiological signs of neurodegeneration. The study highlights that the ε4 allele affects brain activity in the DMN and hippocampus, even in young adults without cognitive impairment. These findings indicate that the APOE ε4 allele plays a fundamental role in brain function, particularly in the memory system, long before any clinical symptoms of neurodegenerative diseases appear. The study used a multimodal MRI protocol to examine structural and functional neurophysiological characteristics, and found that BOLD fMRI is the most sensitive measure of genotypic differences in this age range. The results suggest that the APOE ε4 allele may confer systematic vulnerability in the memory system in carriers. The study also found increased activation in the cerebellum and anterior midbrain in ε4 carriers during memory tasks, which may be secondary to effects in the hippocampus. The study concludes that the APOE ε4 allele influences brain function in young adults, and that BOLD fMRI is the most sensitive measure of these differences. The findings have implications for understanding the early effects of the APOE ε4 allele on brain function and may inform future research on the genetic basis of neurodegenerative diseases.The APOE ε4 allele is a genetic risk factor for late-onset Alzheimer's disease and is associated with brain changes in middle-aged and elderly individuals. This study investigated the effects of the APOE ε4 allele in 18 young healthy carriers (20–35 years) and 18 noncarriers. Using resting-state and task-based fMRI, the study found increased coactivation in the default mode network (DMN) in ε4 carriers during rest, and greater hippocampal activation during a memory encoding task compared to noncarriers. These differences were not explained by memory performance, brain morphology, or resting cerebral blood flow. The results suggest that the APOE ε4 allele influences brain function decades before any clinical or neurophysiological signs of neurodegeneration. The study highlights that the ε4 allele affects brain activity in the DMN and hippocampus, even in young adults without cognitive impairment. These findings indicate that the APOE ε4 allele plays a fundamental role in brain function, particularly in the memory system, long before any clinical symptoms of neurodegenerative diseases appear. The study used a multimodal MRI protocol to examine structural and functional neurophysiological characteristics, and found that BOLD fMRI is the most sensitive measure of genotypic differences in this age range. The results suggest that the APOE ε4 allele may confer systematic vulnerability in the memory system in carriers. The study also found increased activation in the cerebellum and anterior midbrain in ε4 carriers during memory tasks, which may be secondary to effects in the hippocampus. The study concludes that the APOE ε4 allele influences brain function in young adults, and that BOLD fMRI is the most sensitive measure of these differences. The findings have implications for understanding the early effects of the APOE ε4 allele on brain function and may inform future research on the genetic basis of neurodegenerative diseases.