AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative dementia syndrome, which is characterized by irreversibly progressive cognitive decline, neuropsychiatric symptoms, and impaired function of independent daily living. The majority of AD occurs in individuals aged over 65 years and is termed late‐onset AD. The apolipoprotein E (APOE) ε4 allele is the highest individual risk factor. Despite lifelong influences of APOE ε4, not all APOE ε4 carriers develop cognitive decline, some APOE ε4 carriers appear to be better than others in maintaining structural and functional properties of their brains while aging. Although previous studies showed that the AD patients with higher levels of cognitive reserve had more advanced Alzheimer’s type pathology in the comparable clinical severity, the underlying mechanism is unclear. Thus, the association between the individual’s cognitive reserve and the aging‐related brain pathologies need further investigation.MethodThis study recruited dementia free homozygous APOE ε4 allele carriers and all participants’ cognitive statuses were evaluated by neuropsychological tests. Cognitive reserve was evaluated by Cognitive Reserve Index questionnaire (CRIq). In neuroimage study, we collected brain MRI images and analyzed the severity of hippocampal atrophy and white matter hyperintensities (WMH). The relationship between different kinds of cognitive reserve and age‐related neuroimaging findings were analyzed.ResultIn total, 39 participants carrying two APOE ε4 alleles were analyzed, with an average age of 61.5 years, an education level of 13.1 years, and an average MMSE of 26.4 points. Correlation analysis showed significant associations between CRI and neuropsychological tests, especially in short‐term memory, visuospatial function, and language function tests. In neuroimaging analysis, CRI‐education was associated with hippocampal atrophy, which suggested more education might help to prevent the hippocampal atrophy. The correlation between WMH severity of brain MRI and the CRI was not statistically significant.ConclusionCognitive reserve is associated with the cognitive function in dementia free homozygous APOE ε4 allele carriers and education might prevent hippocampal atrophy.