Ephrin type-A receptor 1 (EPHA1) (11771145) was documented to be one of the most strongly associated locus with Alzheimer's disease (AD) in a recent meta-analysis of five genome wide association studies. However, its contribution to the pathogenesis of AD remains unclear to date. Here, we addressed the role of EPHA1 in AD by investigating the influence of EPHA1 on cerebrospinal fluid and neuroimaging biomarkers in three clinical stages from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We did not detect significant association of EPHA1 with amyloid-β deposition or tau protein. However, the A-allele in the mild cognitive impairment group remarkably prevented hippocampal atrophy (partial correlation coefficient 2.812, 95% CI 0.651 to 4.973) at two-year follow-up. Additionally, AD subjects with the A-allele displayed less atrophy and greater cerebral metabolic rate for glucose (CMRgl) in the right lateral occipitotemporal gyrus (volume: partial correlation coefficient 540.10, 95% CI 247.26 to 832.95; CMRgl: partial correlation coefficient 0.056, 95% CI 0.024 to 0.087) and inferior temporal gyrus (volume: partial correlation coefficient 327.98, 95% CI 11.65 to 644.31; CMRgl: partial correlation coefficient 0.055, 95% CI 0.019 to 0.091) at baseline. This study suggests EPHA1 (rs11771145) interferes with the pathological alteration of the hippocampus and the lateral occipitotemporal and inferior temporal gyri throughout the AD process, leading to a lower risk of AD. However, the limited sample size and follow-up as well as the diversity across ethnicities precluded explanation of these findings.