The Effect of Sequential Therapy on Alzheimer's Disease

Alzheimer's disease has a progressive clinical course, and traditional Chinese medicine theory describes changes in syndrome patterns across different stages of the disease. In the early stage, kidney deficiency is considered the predominant pattern. In the middle stage, phlegm, fire, and blood stasis may become more prominent, while the late stage is characterized by severe qi deficiency. Based on this stage-related evolution, a sequential traditional Chinese medicine approach was developed according to the "syndrome cascade hypothesis." Preliminary clinical observations have suggested potential benefits for cognitive function and overall clinical status, but evidence from prospective multicenter studies remains limited.

This prospective multicenter cohort study has three main objectives. First, it will describe the natural changes in cognitive function, activities of daily living, neuropsychiatric symptoms, and traditional Chinese medicine syndrome patterns across the early, middle, and late stages of Alzheimer's disease. It will also characterize the dynamic relationship between clinical symptoms and traditional Chinese medicine syndrome patterns during disease progression. Second, it will evaluate the clinical outcomes associated with stage-based sequential traditional Chinese medicine therapy, including short- and long-term clinical changes. Third, it will evaluate the safety of sequential traditional Chinese medicine therapy in real-world clinical use.

Treatment exposure will be recorded prospectively. Exposure assessment will consider cumulative medication use, medication adherence, treatment continuity, and treatment interruption. Information from medication dispensing and return records, medication diaries, and investigator follow-up records will be used to assess treatment exposure. The time from the beginning of treatment exposure to subsequent outcome assessment will also be recorded.

General demographic and baseline clinical characteristics will be summarized using descriptive statistics. Continuous outcomes will be analyzed using linear mixed-effects models to evaluate changes over time. The models will include time, exposure status, and the interaction between time and exposure status. Single-time-point comparisons may use independent-samples tests or analysis of covariance, as appropriate. Binary outcomes will be analyzed using logistic regression, with adjustment for potential confounding factors when appropriate.

Prespecified subgroup analyses will explore whether the associations with sequential therapy differ according to disease stage, age, sex, baseline cognitive function, concomitant use of Western medicines, and traditional Chinese medicine syndrome type. Interaction terms between subgroup factors and exposure status will be used to explore differences among subgroups. These subgroup analyses will be considered exploratory.

Missing data patterns will be assessed to determine whether data are missing completely at random, missing at random, or missing not at random. Multiple imputation will be used for missing primary outcomes and key covariates, with variables related to missingness included in the imputation model. Sensitivity analyses will be performed to examine the robustness of the findings under different assumptions and exposure definitions.