Alzheimer’s disease (AD) is the most common form of dementia, and its prevalence is rapidly increasing with the aging population. Among the growing number of genetic risk factors, apolipoprotein E (ApoE) is the most prevalent and strongest risk factor, accounting for nearly three-quarters of AD cases. ApoE is a key protein involved in lipids and cholesterol metabolism in the central nervous system. There are three subtypes of ApoE: ApoE2, ApoE3, and ApoE4, among which ApoE4 is a high-risk factor for the incidence of AD. ApoE4 not only affects lipid efflux and distribution in glial cells, but also affects the lipid metabolism in neurons, resulting in the imbalance of lipid homeostasis. ApoE plays a role in the processing of amyloid precursor protein (APP), which is associated with the early production of amyloid β-(Aβ) protein and plaque deposition. ApoE4 also reduces the solubility of Tau protein, which contributes to promoting the aberrant phosphorylation and the aggregation of Tau, and resulting in neurofibrillary tangles (NFTs). Moreover, brain regions expressing ApoE4 are more susceptible to Tau diffusion. Furthermore, ApoE4 has been demonstrated to activate the NF-κB inflammatory pathway, convert microglia and astrocytes into the pro-inflammatory phenotypes, secrete pro-inflammatory factors and oxidative mediators, and induce neuroinflammation. Altogether, ApoE participates in AD neuropathology through multiple pathways such as Aβ plaque, Tau pathology, neuroinflammation, neuroplasticity and blood-brain barrier, which all jointly promotes the progression of the disease. It has been demonstrated that anti-ApoE4 antibodies can reduce the formation of Aβ plaques and neuroinflammation. The repurposing of metformin, rapamycin, enoxaparin, DHA, and tamoxifen have been shown to reduce the expression of ApoE4 protein and ameliorate AD pathology. Gene therapies utilising antisense oligonucleotides (ASO) and double-stranded interfering small RNA (siRNA) has been proved to be effective technologies to reduce ApoE4 expression and mitigate AD pathology. Adeno-associated virus (AAV)-mediated ApoE2 has been demonstrated to neutralize the negative effects of ApoE4 by expressing ApoE2 in the ventricular membrane. Traditional Chinese medicine resveratrol and waterside delivered by ApoE-modified liposome nanodrug delivery system can improve the BBB penetration of drugs and provid a new method for the treatment of AD. In addition, targeting the interaction of ApoE with low-density lipoprotein receptor (LDLR) and low density lipoprotein-related protein 1 (LRP1) receptors can indirectly regulate the expression level of ApoE, which provids a new perspective for the treatment of AD. This article aims to elucidate the roles of ApoE and its isoforms in the pathogenesis of AD and summarize the potential therapeutic strategies against ApoE with the hope of providing novel insights for the ApoE-based therapies combat AD.