Alzheimer's disease (AD) exerts a heavy burden on China. Substantial factors are found associated with high expenditure of AD in high-income countries. To date, few studies have been conducted in China. This study aimed to analyze the associated factors of the total annual costs of AD in China. Data were drawn from a multi-center, cross-sectional, socioeconomic study on the costs of AD conducted in China from October 2015 to March 2016. Generalized linear model (GLM) using gamma distribution with a log-link function was employed to examine the associated factors of the total cost. Univariate analysis showed that the demographic and clinical characteristics of AD patients and their caregivers had a substantial impact on the total cost. In GLM analysis, age, monthly household income, AD severity, number of comorbidities, and treatment with memantine were associated with higher expenditure, while the use of a nursing home/care facility was associated with lower expenditure. The mean annual costs for patients with severe dementia were almost twice as high as those for patients with mild dementia (US$ 25,601 versus US$ 13,387, p?<?0.001). The mean total cost of AD patients with at least five comorbidities (US$ 38,348) was almost three times than those with no comorbidities (US$ 13,744). In China, AD severity and comorbidities were the most critical factors impacting the total cost. Optimizing care patterns, delaying disease progression, and managing comorbidities comprehensively could decrease the heavy burden of AD.