Apolipoprotein E is the most well-established genetic risk factor for Alzheimer’s disease. However, the associations of apolipoprotein E with tau pathology and cognition remain controversial. The research checks the hypothesis that the relationships between apolipoprotein E alleles and cerebrospinal fluid tau and cognition differ in persons with and without significant amyloid-\beta deposition. We divided 1119 subjects into cognitively normal (n = 275), mild cognitive impairment (n = 629), and Alzheimer’s disease (n = 215), and these subjects were from the Alzheimer’s Disease Neuroimaging Initiative database. Linear regression models were used to compare the relationships of apolipoprotein E alleles with cerebrospinal fluid tau and cognition in persons with significant amyloid-\beta deposition relative to individuals without significant amyloid-\beta deposition. The associations of apolipoprotein E \epsilon4 and \epsilon3 with total tau (T-tau), phosphorylated tau (P-tau), and Alzheimer’s disease assessment scale was significantly substantial among participants with significant amyloid-\beta deposition. Stratified analyses showed that apolipoprotein E \epsilon4 related to increased concentrations of T-tau, P-tau, and Alzheimer’s disease assessment scale and apolipoprotein E \epsilon3 associated with decreased concentrations of T-tau, P-tau, and Alzheimer’s disease assessment scale in mild cognitive impairment participants with significant amyloid-\beta deposition, but not in Alzheimer’s disease. Our study shows that the presence of apolipoprotein E \epsilon4 and \epsilon3 alleles is related to tau pathology and cognitive impairment in the presence of amyloid-\beta in mild cognitive impairment, but not in Alzheimer’s disease. This work indirectly provides additional evidence that apolipoprotein E and amyloid-\beta may not have a role in modulating clinical Alzheimer’s disease, and apolipoprotein E \epsilon3 may be supposed to be protective to mild cognitive impairment.