The Chinese Familial Alzheimer's Network

Study Overview
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Brief Summary
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This research will establish and continuously improve the FAD research network in conjunction with multi-center institutions nationwide. By collecting information on the family's demography, genetics, neuropsychology, neuroimaging, biomarkers and other information, we can understand the current FAD population in China, clarify the genetic characteristics, pathogenesis, disease characteristics and diagnosis and treatment status of AD in China; which will lay the foundation for ameliorating clinical diagnosis and treatment, establishing a Chinese FAD clinical database and an international cooperative research platform. To set up a multi-center, nationwide FAD research network and database platform in China To clarify the epidemiological characteristics of FAD in China. To clarify the genetic characteristics of FAD in China. To clarify the clinical characteristics and disease development laws of FAD. To discover and verify the early diagnosis biomarkers of AD. To establish a genetic counseling model.

Detailed Description
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The network and database include ADAD cohort of the known mutations of PSEN1, PSEN2 and APP (mutation carriers and noncarriers; pre-symptomatic and symptomatic) and unknown mutations cohort. Conduct a comprehensive FAD epidemiological survey in China to clarify the impact of different nationalities, regions, gender, age, living environment (rural/urban), education level, etc. on the occurrence and development of the disease. This project is to discover new FAD mutation sites，pathogenic genes, to protective genes, to explore the pathogenic and protective mechanism, to analyze the disease development laws of families with different sizes of FAD in China, and to clarify the frequency distribution of mutant genes in the Chinese FAD population. The project will collect and regularly follow-up the samples (blood, urine and saliva etc.) and data (neuropsychology, imaging etc.) in the cohort. Emphasis is placed on the occurrence and development of asymptomatic mutant gene carriers from asymptomatic to symptomatic periods. In the FAD family cohort, we will screen high-sensitivity and high-specificity body fluid markers suitable for Chinese people, verify in the SAD cohort, and establish a prediction model of body fluid markers for AD occurrence and disease progression; use structural MRI, dual tracer 18F-FDG PET and 11C-PIB PET multimodal imaging technology, dynamically monitor the dynamic evolution of imaging biomarkers such as brain structure, glucose metabolism and Aβ deposition at various stages of AD progression. We will combine with the genetic characteristics of Chinese FAD to analyze the impact of lifestyle, physical exercise, nootropic drugs, cognitive training, etc. on the disease progression of FAD patients or asymptomatic mutant gene carriers, to establish a genetic counseling model.

Official Title
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A Multi-center Longitudinal Cohort Study of Familial Alzheimer's Disease in China

Conditions
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Alzheimer Disease, Familial Alzheimer Disease (FAD)

Participation Criteria
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Eligibility Criteria
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Familial Alzheimer's disease group Inclusion criteria: Written informed consent obtained from the participant or a legal guardian prior to any study-related procedures; At least two first-degree relatives in a family have AD (clinically or by testing)，and at least 3 out of 2 generations are patients; At least one family member with normal cognitive function (the age should be greater than the average age of onset of the family); Pedigrees carrying FAD pathogenic genes (APP/PSEN1/PSEN2); People in this family >18 years old can be recruited; Participant is cognitively normal or demented but not reaching bedridden level; Participants are able to provide two reliable informants who can provide clinical information; Dementia is diagnosed according to the criteria described by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-R ); The diagnosis of AD is made using the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA ) or National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria ; The diagnosis of MCI is made according to Petersen criteria and the classiﬁcation is according to the method of Lopez et al. Exclusion criteria: Dementia caused by other factors such as depression, other psychiatric illnesses, thyroid dysfunction, encephalitis, multiple sclerosis, brain trauma, brain tumor, syphilis, acquired immunodeficiency syndrome (AIDS), Creutzfeldt-Jakob disease and other types of dementias such as vascular dementia (VaD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and Parkinson's dementia (PDD)； MRI and laboratory tests do not support or rule out a diagnosis of AD； Severe circulatory, respiratory, urinary, digestive, hematopoietic diseases (such as unstable angina, uncontrollable asthma, active gastric bleeding) and cancer； Participant has severe psychiatric illness or severe dementia that would interfere in completing initial and follow-up clinical assessments； Participant has a history of alcoholism or drug abuse； Pregnant or lactating women； No reliable informant； Lumbar puncture exclusion criteria：coagulation disorders or platelet counts < 100,000 cells/μL, lumbar surgery within the last 6 months prior to lumbar puncture that interferes with anatomy of the inter-vertebral spaces, History of chronic or repeated CSF leakage following previous LP(s); MRI Exclusion Criteria: electronic and magnetic metal implants such as pacemakers, artificial heart valve, metal prosthesis, metal joint, etc.; metallic foreign body in the eye; aneurysm clips in the brain. Normal control group Inclusion criteria: Aged 18 (inclusive) or above; Normal MMSE and MoCA evaluations. MMSE>19 points for illiteracy, >24 points for those educated less than 7 years, >27 points for those educated equal to or more than 7 years. MoCA>13 points for illiteracy, >19 points for those educated less than 7 years, >24 points for those educated equal to or more than 7 years. Exclusion criteria: Subjects with abnormal MMSE or MoCA scores; Subjects with a history of cerebral infarction, traumatic brain injury or related manifestations in MRI; Other neurological diseases that can cause brain dysfunction (such as depression, brain tumor, Parkinson's disease, metabolic encephalopathy, encephalitis, multiple sclerosis, epilepsy, brain trauma, normal intracranial pressure hydrocephalus, etc.); Other systemic diseases that can cause cognitive impairment (such as liver, renal and thyroid insufficiency, severe anemia, folic acid or vitamin B12 deficiency, syphilis, HIV infection, alcohol and drug abuse, etc.); Mental and neurodevelopmental retardation; Suffering from a disease that cannot be combined with a cognitive examination; Contraindications to MRI; Refuse to draw blood; Refuse to sign the informed consent at baseline.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Familial Alzheimer's disease group<br>Familial Alzheimer's disease with the known mutation presenilin1 (PSEN1), presenilin2 (PSEN2) and amyloid precursor protein (APP) including mutation carriers and noncarriers, presymptomatic and symptomatic. | |
| Normal control group<br>Normal cognitive control people | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The prevalence of gene mutations in familial Alzheimer's disease in China. | Gene analysis of known mutations (PSEN1, PSEN2 and APP), apolipoprotein E (APOE) genotype and unknown mutations in familial Alzheimer's disease patients. | An Average of 1 year | 
| The development patterns of genetic, biofluid, imaging, and neuropsychological markers of FAD. | The development patterns of genetic, biofluid, imaging, and neuropsychological markers of FAD. The dynamic changes of biochemical, pathological, structural and functional markers with disease progression. | An Average of 3 to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of neuropsychological function in pedigree members at different stage of cognitive impairment in familial Alzheimer's disease in China. | Changes of neuropsychological function measured by neuropsychological assessment battery. | An Average of 1 year | 
| Changes of brain structure in pedigree members at different stage of cognitive impairment in familial Alzheimer's disease in China. | Changes of structure of the whole brain, hippocampus other brain structures measured by MRI. | An Average of 1 year | 
| Changes of brain glucose metabolism in pedigree members at different stage of cognitive impairment in familial Alzheimer's disease in China. | Changes of glucose metabolism of the whole brain, hippocampus and other brain structures as measured by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). | An Average of 1 year | 
| Changes of brain amyloid deposition in pedigree members at different stage of cognitive impairment in familial Alzheimer's disease in China. | Changes of amyloid deposition of the whole brain, hippocampus and other brain structures as measured by amyloid PET. | An Average of 1 year | 
| Changes of brain tau deposition in pedigree members at different stage of cognitive impairment in familial Alzheimer's disease in China. | Changes of tau deposition of the whole brain, hippocampus and other brain structures as measured by tau PET. | An Average of 1 year | 
| Changes of humoral biomarkers in pedigree members at different stage of cognitive impairment in familial Alzheimer's disease in China. | Humoral biomarkers are included Aβ42, Aβ40, phosphated tau and total tau in plasma, cerebrospinal fluid, saliva, and urine. | Each biomarker with time frame of average 1 year | 
| The effective non-pharmacologic treatment(NPT) intervention | The effective non-pharmacologic treatment(NPT) intervention- including lifestyle(diet and sleep habits, smoking, drinking and social networking), health products, exercise habits, cognitive training, risk factor control- on APOE ε4 carriers, MCI and dementia patients using questionnaire. | An Average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease