In recent years, it has been found that complex pathological manifestations of Alzheimer's disease (AD) cannot be fully explained by β-amyloid (Aβ) cascade hypothesis, and researchers question this hypothesis resulting from the poor effect of targeted Aβ drugs. Probabilistic apolipoprotein E (APOE) hypothesis affirms the Aβ pathogenesis but also emphasizes the important role of APOE gene in diagnosis, treatment and progression of AD. In AD diagnosis, subjects should be firstly grouped according to presence or absence of APOE ε4 allele, and then classified according to Aβ deposition/tau neurofibrillary tangles/neurodegeneration. This article reviews the recent advance in the pathogenesis, diagnosis and treatment of 3 types of AD variants (autosomal dominant AD, sporadic AD related to APOE ε4, and sporadic AD unrelated to APOE ε4), with a view to understand the importance of APOE ε4 allele in AD from a new perspective.