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Background: The management of Alzheimer’s disease is challenging due to its complexity. However, the currently approved and marketed treatments for this neurodegenerative disorder revolves around cholinesterase inhibitors and glutamate regulators or the combination of these agents. Despite the prompt assurance of many new drugs, several agents were unsuccessful, especially in phase II or III trials, not meeting efficacy endpoints. Objective: The execution of effective treatment approaches through further trials investigating a rational combination of agents is necessitude for Alzheimer’s disease. Method: For this review, more than 248 relevant scientific papers were considered from a variety of databases (Scopus, Web of Science, Google Scholar, Sciencedirect, and Pubmed) using the keywords Alzheimer’s disease, amyloid-β, combination therapies, cholinesterase inhibitors, dementia, glutamate regulators, AD hypothesis. Result and Discussion: The researcher's intent for either developing a disease-modifying therapeutic means for aiming in the early phases of dementia and/or optimizing the available symptomatic treatments principally committed to the more advanced stages of Alzheimer’s. Since Alzheimer possesses multifactorial pathogenesis, designing a multimodal therapeutic intervention for targeting different pathological processes of dementia may appear to be the most practical method to alter the course of disease progression. Conclusion: The combination approach may even allow for providing individual agents in lower doses, with reducible cost and side effects. Numerous studies on combination therapy predicted better clinical efficacy than monotherapy. The below literature review highlights the major clinical studies (both symptomatic and disease-modifying) conducted in the past decade on combination therapy to combat the cognitive disorder.