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NCT Number: NCT07768579

The Effect of Sequential Therapy on Alzheimer's Disease

The goal of this observational study is to learn how Alzheimer's disease changes over time in people at different stages of the disease. It will look at changes in memory and thinking, daily activities, behavior, and traditional Chinese medicine symptom patterns. It will also learn about the outcomes and safety of sequential traditional Chinese medicine treatment based on the stage of Alzheimer's disease. The main questions this study aims to answer are:

* How do memory and thinking, daily activities, behavior, and traditional Chinese medicine symptom patterns naturally change over time in participants with early-, middle-, and late-stage Alzheimer's disease? * How do symptoms and traditional Chinese medicine symptom patterns change together as Alzheimer's disease progresses? * Do participants receiving stage-based sequential traditional Chinese medicine treatment have different changes in memory and thinking, daily activities, behavior, and overall disease status? * What medical problems or side effects occur during sequential traditional Chinese medicine treatment?

About 600 participants aged 55 to 85 years will take part in this study. Participants will be followed for 12 months.

Participants will:

* Visit the study center at the start of the study and at 3, 6, 9, and 12 months. * Complete assessments of memory and thinking, daily activities, behavior, overall disease status, and traditional Chinese medicine symptoms. * Have blood tests and other study examinations. * Have their treatment use and medical problems recorded during follow-up.

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Key information

Conditions

Mild Cognitive Impairment Due to Alzheimer Disease Alzheimer Disease Brain Diseases Central Nervous System Diseases Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies

Age range

55 year–85 year

Sex eligibility

All sexes

Study type

Observational

Primary location

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age 55 to 85 years, regardless of sex.
  • Memory decline reported by the participant or family member for at least 6 months.
  • Meets the diagnostic criteria for the target disease and is clinically diagnosed with mild cognitive impairment due to Alzheimer's disease or mild, moderate, or severe Alzheimer's dementia.
  • Able to complete clinical scale assessments and blood sampling.
  • Able to undergo brain magnetic resonance imaging (MRI) or amyloid-beta positron emission tomography (Aβ-PET) examinations using the tracers specified in the study protocol.
  • Written informed consent provided by the participant or a legally authorized representative.
  • Able to complete study follow-up.
  • Participants with a known allergy to components of the exposure medications will be assigned to the non-exposed group.

Exclusion criteria

  • Cerebrovascular disease, traumatic brain injury, thyroid dysfunction, vitamin deficiency, or other diseases sufficient to cause cognitive impairment.
  • Malignant tumors unrelated to the target disease, hematological diseases, severe psychiatric disorders, depression, or anxiety disorders.
  • Severe dysfunction of major organs, including the heart, brain, liver, or kidneys.
  • Infectious diseases, including HIV or HBV infection.
  • Pregnancy, breastfeeding, or plans for pregnancy in the near future.
  • Gastrointestinal diseases that may affect drug absorption.
  • Use of medications affecting cognitive function within 4 weeks before enrollment.
  • Recent participation in or current participation in another trial.

Treatment and study plan

Primary outcomes

  1. Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB)

    Time frame: Baseline to Month 12

    The Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) is used to assess overall cognitive and functional impairment. The total score ranges from 0 to 18, with higher scores indicating greater disease severity and a worse outcome. The outcome is the change in CDR-SB score from baseline to Month 12.

  2. Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog11)

    Time frame: Baseline to Month 12

    The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is used to assess cognitive impairment in participants with early- and middle-stage Alzheimer's disease. The standard 11-item ADAS-Cog total score ranges from 0 to 70, with higher scores indicating greater cognitive impairment and a worse outcome. The outcome is the change in ADAS-Cog score from baseline to Month 12.

  3. Change From Baseline in Severe Impairment Battery (SIB)

    Time frame: Baseline to Month 12

    The Severe Impairment Battery (SIB) is used to assess cognitive function in participants with late-stage Alzheimer's disease. The total score ranges from 0 to 100, with higher scores indicating better cognitive function and a better outcome. The outcome is the change in SIB score from baseline to Month 12.

Secondary outcomes

  1. Change From Baseline in Mini-Mental State Examination (MMSE)

    Time frame: Baseline to Month 12

    The Mini-Mental State Examination (MMSE) is used to assess cognitive function. The total score ranges from 0 to 30, with higher scores indicating better cognitive function and a better outcome. The outcome is the change in MMSE score from baseline to Month 12.

  2. Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)

    Time frame: Baseline to Month 12

    The Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) is used to assess performance of activities of daily living. The total score ranges from 0 to 78, with higher scores indicating greater independence in daily functioning and a better outcome. The outcome is the change in ADCS-ADL score from baseline to Month 12.

  3. Change From Baseline in Neuropsychiatric Inventory (NPI)

    Time frame: Baseline to Month 12

    The Neuropsychiatric Inventory (NPI) is used to assess neuropsychiatric symptoms. The 12-domain total score ranges from 0 to 144, with higher scores indicating more severe neuropsychiatric symptoms and a worse outcome. The outcome is the change in NPI score from baseline to Month 12.

  4. Change From Baseline in Blood Aβ42/Aβ40 Ratio

    Time frame: Baseline to Month 12

    The blood amyloid beta 42 to amyloid beta 40 (Aβ42/Aβ40) ratio will be measured at baseline and Month 12. The Aβ42/Aβ40 ratio is a dimensionless value. The outcome is the change in the Aβ42/Aβ40 ratio from baseline to Month 12.

  5. Change From Baseline in Blood Phosphorylated Tau 181 (P-Tau181)

    Time frame: Baseline to Month 12

    Blood phosphorylated tau 181 (P-Tau181) will be measured in picograms per milliliter (pg/mL) at baseline and Month 12. The outcome is the change in P-Tau181 concentration from baseline to Month 12.

  6. Change From Baseline in Blood Phosphorylated Tau 217 (P-Tau217)

    Time frame: Baseline to Month 12

    Blood phosphorylated tau 217 (P-Tau217) will be measured in picograms per milliliter (pg/mL) at baseline and Month 12. The outcome is the change in P-Tau217 concentration from baseline to Month 12.

  7. Change From Baseline in Blood Neurofilament Light Chain (NfL)

    Time frame: Baseline to Month 12

    Blood neurofilament light chain (NfL) will be measured in picograms per milliliter (pg/mL) at baseline and Month 12. The outcome is the change in NfL concentration from baseline to Month 12.

  8. Change From Baseline in Blood Glial Fibrillary Acidic Protein (GFAP)

    Time frame: Baseline to Month 12

    Blood glial fibrillary acidic protein (GFAP) will be measured in picograms per milliliter (pg/mL) at baseline and Month 12. The outcome is the change in GFAP concentration from baseline to Month 12.

Other outcomes

  1. Incidence of Adverse Events

    Time frame: Up to 12 months

    The number and proportion of participants experiencing adverse events during traditional Chinese medicine use and follow-up. Adverse events include any unfavorable medical events occurring during treatment or follow-up, including symptoms, signs, or laboratory abnormalities, regardless of whether they are considered related to treatment.

  2. Incidence of Serious Adverse Events

    Time frame: Up to 12 months

    The number and proportion of participants experiencing serious adverse events during the study follow-up period.

  3. Change From Baseline in Kidney Deficiency Score Assessed by the Revised Pattern Elements Scale in Alzheimer's Disease （PES-AD）

    Time frame: Baseline and Months 3, 6, 9, and 12

    Kidney deficiency is assessed using the kidney deficiency subscale of the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD). The score ranges from 0 to 21, with higher scores indicating a greater degree of kidney deficiency and therefore a worse pattern outcome. A score of 7 or higher indicates the presence of the kidney deficiency pattern element. The outcome is the change from baseline in the kidney deficiency score at each follow-up assessment.

  4. Change From Baseline in Phlegm Obstruction Score Assessed by the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD)

    Time frame: Baseline and Months 3, 6, 9, and 12

    Phlegm obstruction is assessed using the phlegm obstruction subscale of the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD). The score ranges from 0 to 20, with higher scores indicating a greater degree of phlegm obstruction and therefore a worse pattern outcome. A score of 7 or higher indicates the presence of the phlegm obstruction pattern element. The outcome is the change from baseline in the phlegm obstruction score at each follow-up assessment.

  5. Change From Baseline in Fire Disturbance Score Assessed by the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD)

    Time frame: Baseline and Months 3, 6, 9, and 12

    Fire disturbance is assessed using the fire disturbance subscale of the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD). The score ranges from 0 to 20, with higher scores indicating a greater degree of fire disturbance and therefore a worse pattern outcome. A score of 7 or higher indicates the presence of the fire disturbance pattern element. The outcome is the change from baseline in the fire disturbance score at each follow-up assessment.

  6. Change From Baseline in Blood Stasis Score Assessed by the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD)

    Time frame: Baseline and Months 3, 6, 9, and 12

    Blood stasis is assessed using the blood stasis subscale of the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD). The score ranges from 0 to 20, with higher scores indicating a greater degree of blood stasis and therefore a worse pattern outcome. A score of 7 or higher indicates the presence of the blood stasis pattern element. The outcome is the change from baseline in the blood stasis score at each follow-up assessment.

  7. Change From Baseline in Yang Deficiency Score Assessed by the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD)

    Time frame: Baseline and Months 3, 6, 9, and 12

    Yang deficiency is assessed using the Yang deficiency subscale of the Revised Pattern Elements Scale in Alzheimer's Disease (PES-AD). The score ranges from 0 to 21, with higher scores indicating a greater degree of Yang deficiency and therefore a worse pattern outcome. A score of 7 or higher indicates the presence of the Yang deficiency pattern element. The outcome is the change from baseline in the Yang deficiency score at each follow-up assessment.

Study contacts

Contact information is provided by the study sponsor or research team.

JinZhou Tian

CONTACT

[email protected]

+86 10 84011920

Jing Shi

CONTACT

[email protected]

Sponsors and collaborators

Lead sponsor

Dongzhimen Hospital, Beijing

Other

Registry information

Official study title

The Effect of Sequential Therapy on Alzheimer's Disease: A Prospective Cohort Study

Important dates

Study start
2026
Primary completion
2028
Study completion
2028
First posted
Aug 17, 2026
Registry last updated
Aug 19, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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