A Multi-center Longitudinal Cohort Study of Familial Alzheimer's Disease in China
Conditions: Alzheimer Disease, Familial Alzheimer Disease (FAD)
Sponsor: Capital Medical University

 
1 
 
 
Study protocol for the Chinese familial 
Alzheimer’s disease network (CFAN) 
 
 
 
 
Leading site: Xuan Wu Hospital, Capital Medical University 
Principal investigator: Prof. Jianping Jia 
 
 
 
LYS [2019] No.110 
Version 1.4 
International Research Protocol Registration Number：SYXWJ002 
ClinicalTrials.gov ID: NCT03657732 
June 30, 2020 
 

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Contents 
1.
BACKGROUND AND SIGNIFICANCE ............................................................................................................................. 4 
2.
INTRODUCTION .................................................................................................................................................................. 5 
2.1 
Overview ......................................................................................................................................................................................... 5 
2.2 
Research sites ................................................................................................................................................................................ 6 
2.3 
Research period ............................................................................................................................................................................ 6 
2.4 
Sample size..................................................................................................................................................................................... 6 
3.
RESEARCH AIMS ................................................................................................................................................................. 6 
3.1     To set up a multi-center, nationwide FAD research network and database platform in China .................... ... 6 
3.2     To clarify the epidemiological characteristics of FAD in China. .................................................................................... 6 
3.3     To clarify the genetic characteristics of FAD in China. ..................................................................................................... 7 
3.4     To clarify the clinical characteristics and disease development laws of FAD in China. ......................................... 7 
3.5     To discover and verify the early diagnosis biomarkers of AD. ...................................................................................... 7 
3.6     To establish a genetic counseling model. ............................................................................................................................. 7 
4.
RESEARCH CONTENT ........................................................................................................................................................ 7 
4.1 
Cohorts ............................................................................................................................................................................................ 7 
4.2 
Epidemiological characteristics of FAD in China ............................................................................................................... 7 
4.3 
Genetic characteristics and mechanism of FAD in China ............................................................................................... 7 
4.4 
Clinical characteristics, disease development process and laws of FAD in China ................................................. 8 
4.5 
Biomarkers of FAD in China ..................................................................................................................................................... 8 
4.5.1 Body fluid markers ...................................................................................................................................................................... 8 
4.5.2 Image markers.............................................................................................................................................................................. 9 
4.6 
Research on early intervention and diagnosis and treatment of AD ......................................................................... 9 
5.
RESEARCH TECHNOLOGY ROUTE .................................................................................................................................. 9 
6.
RESEARCH PROCESS....................................................................................................................................................... 10 
6.1 
Participant population ..............................................................................................................................................................10 
6.2 
Inclusion criteria ..........................................................................................................................................................................11 
6.3 
Exclusion criteria .........................................................................................................................................................................11 
6.4 
Study discontinuation ...............................................................................................................................................................12 
6.5 
Baseline visit .................................................................................................................................................................................12 
6.6 
Follow-up in-person visits ......................................................................................................................................................13 
7.
ASSESSMENTS .................................................................................................................................................................. 14 
7.1 
Clinical evaluation ......................................................................................................................................................................14 
7.1.1 Demographic data  ..................................................................................................................................................................14 
7.1.2 Current medical history ...........................................................................................................................................................14 
7.1.3 Past history ..................................................................................................................................................................................15 
7.1.4 Medication situation.................................................................................................................................................................15 
7.1.5 Family history and family diagram drawing .....................................................................................................................15 
7.1.6 Physical examination ................................................................................................................................................................16 
7.2 
Psychometrics ..............................................................................................................................................................................16 
7.2.1 Mini Mental State Examination (MMSE) ............................................................................................................................16 
7.2.2 The Montreal Cognitive Assessment (MoCA) .................................................................................................................16 
7.2.3 Neuropsychiatric Inventory (NPI-Q)  ................................................................................................................................16 
7.2.4 Hamilton Anxiety Rating Scale (HAMA)  ..........................................................................................................................16 
7.2.5 Hamilton depression scale (HAMD) ....................................................................................................................................17 
7.2.6 Modified Hachinski ischemic scale (m-HIS)  ...................................................................................................................17 

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7.2.7 The world health organization university of California-Los Angeles auditory verbal learning Test (WHO-
UCLA AVLT) ............................................................................................................................................................................................17 
7.2.8 Rey–Osterrieth complex figure test  ..................................................................................................................................18 
7.2.9 Digit Span Test- Forward and Backward  ........................................................................................................................18 
7.2.10 Verbal Fluency Tests  ............................................................................................................................................................18 
7.2.11 Trail Making Test: Parts A and B  .....................................................................................................................................18 
7.2.12 Boston Naming Test (BNT) ..................................................................................................................................................19 
7.2.13 Activities of daily living (ADL)  ...........................................................................................................................................19 
7.2.14 Clinical Dementia Rating (CDR) .........................................................................................................................................19 
7.3 
Procedures for genetic studies ..............................................................................................................................................19 
7.3.1 Gene testing ................................................................................................................................................................................19 
7.3.2 Detection of pathogenic genes and risk genes ..............................................................................................................19 
7.3.3 Gene risk locus detection .......................................................................................................................................................20 
7.3.4 Body fluid testing ......................................................................................................................................................................20 
7.3.5 Blood specimens .......................................................................................................................................................................20 
7.3.6 Cerebrospinal fluid specimens .............................................................................................................................................21 
7.4 
Imaging ..........................................................................................................................................................................................21 
7.4.1 Magnetic resonance imaging (MRI) ....................................................................................................................................21 
7.4.2 Positron-emission tomography (PET) imaging ..............................................................................................................22 
7.4.3 Carotid ultrasound ....................................................................................................................................................................22 
8.
STATISTICAL ANALYSIS ................................................................................................................................................. 23 
9.
DATA MANAGEMENT .................................................................................................................................................... 23 
9.1 
Establishment of electronic database .................................................................................................................................23 
9.2 
Data entry .....................................................................................................................................................................................23 
9.3 
Data auditing ...............................................................................................................................................................................24 
9.4 
Data access permissions ..........................................................................................................................................................24 
9.5 
Data modification record ........................................................................................................................................................24 
10.
QUALITY CONTROL .................................................................................................................................................... 24 
10.1 
The writing of investigator’s case report form .................................................................................................................24 
10.2 
Investigator training ..................................................................................................................................................................25 
10.3 
Subject’s compliance ................................................................................................................................................................25 
11.
ETHICS ........................................................................................................................................................................... 25 
11.1 
Human subjects, ethical and regulatory considerations ..............................................................................................25 
11.2 
Research ethics boards (REB) .................................................................................................................................................26 
11.3 
Informed consent .......................................................................................................................................................................26 
11.4 
Informed consent for biomarkers, genetic material, and imaging data .................................................................26 
11.5 
Procedures to maintain confidentiality ...............................................................................................................................26 
11.5.1 Genetic research and storage of genetic material ......................................................................................................26 
11.5.2 Biomarker Samples and Research .....................................................................................................................................27 
12.
RESEARCH IMPLEMENTATION CONDITIONS AND RESEARCHERS ............................................................... 27 
12.1 
Research implementation conditions ..................................................................................................................................27 
12.2 
The capabilities of researchers ..............................................................................................................................................28 
13.
REFERENCES ................................................................................................................................................................. 29 
14.
APPENDIX ..................................................................................................................................................................... 34

 
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1. Background and significance 
Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by decline of 
episodic memory in the early stages and a loss of daily living ability in the late stages [1]. Currently, 
the number of patients with AD in China is 8.75 million [2]. This large patient population costs China 
US $167.74 billion2 per year [3], and thus has an immense social impact and heavy economic burden. 
AD has become one of the major diseases that seriously endanger the health of the elderly population 
in China. The early prevention and treatment of AD is an important social problem that needs to be 
solved urgently. 
AD can be categorized as sporadic AD (SAD) or familial AD (FAD) based on family history. FAD 
requires a patient with AD to have at least one first-degree relative diagnosed with AD or mild cognitive 
impairment (MCI) due to AD, and was reported to account for 12.50% to 25.00% of all AD cases [4,5]. 
FAD greatly contributes to AD research. First, it encompasses the physiological and pathological 
characteristics of all cognitive stages from preclinical to MCI to dementia. Second, it represents an 
ideal population, with a possible predictable age at onset (AAO), which is relatively young and has 
minimal complications (such as cerebrovascular disease), and facilitates exploration of the 
pathogenesis of AD. Third, it promotes the development of transgenic animal models with which anti-
dementia drugs are tested. 
FAD includes autosomal dominant AD (ADAD) [6], caused by mutations of genes including the 
amyloid precursor protein gene (APP), presenilin 1 gene (PSEN1), and presenilin 2 gene (PSEN2), 
which have been targeted by the Dominantly Inherited Alzheimer Network (https://dian.wustl.edu/); 
the E280A Antioquia cohort study[7]; and FAD cohorts, including those in France[8], England[9], 
Japan[10], South Korea[11], Finland[12], and so on. To date, 289 PSEN1, 48 PSEN2, and 58 APP 
mutations have been identified (https://www.alzforum.org/mutations), most of which were first 
reported in Caucasians. In Chinese, our team reported the first variant (NM_000021.3: c. 289G>T V97L 
in PSEN1) [13]. Several studies have since investigated the genetics of FAD: one study identified four 
variants in PSEN1 and one variant in APP, and the detection rate of variants in PSENs/APP was 18.75% 
[14].Another identified two variants in APP, eight variants in PSEN1, and three variants in PSEN2, and 
the detection rate of variants in PSENs/APP was 8.80% [15]. However, these cohorts were not 
multicentric and the sample sizes were relatively small; thus, the findings did not fully represent the 
mutation spectrum of FAD in China. 
As one of the early interventions of AD and dementia, non-pharmacologic treatment (NPT) has been 
studied more and more in recent years [16]. At present, the NPT research on dementia mainly focuses 
on improving the lifestyle, physical exercise [17], music [18], cognitive training, risk factor control and 

 
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so on. Physical exercise as a common NPT method can improve the cognitive function of MCI patients 
and slow down the progression of AD [19, 20]. Physical exercise may improve cognitive function 
through oxidative stress, inflammation, metabolism and other mechanisms [21], and affect the brain 
structure related to dementia, such as hippocampus/parahippocampal area, anterior cingulate gyrus and 
prefrontal cortex. Music therapy can improve some cognitive functions of mild AD patients, especially 
episodic memory, executive function and general cognition, and also has a positive impact on mental 
and psychological health [22]. Cognitive training can delay the onset of symptoms and improve the Aβ 
related memory deficit by preventing oxidative stress and changing the plasticity of white matter in the 
brain [23, 24]. In addition, functional task training [25], lifestyle intervention [26], Mediterranean diet 
(MeDi) [27], psychosocial intervention [28], and improving sleep quality [29] are also effective ways 
to improve cognitive function. At present, most of the NPT studies have a single sample, lack of 
quantitative and objective evaluation criteria, do not exclude other influencing factors (other comorbid 
diseases, gender, etc.). Furthermore, their neurobiological mechanism is not clear. It is necessary to 
explore the efficacy and potential neurobiological mechanism of NPT in AD and dementia through 
well-designed randomized controlled trials, and systematic and effective intervention programs. 
Therefore, Jia’s team relied on Xuanwu Hospital of Capital Medical University and many research 
institutes and hospitals aim to establish the Chinese Familial Alzheimer's disease network (CFAN). 
CFAN is a nationwide, multi-center, large-scale longitudinal observational research cohort. It will help 
to collect genetic information, clinical characteristics, cognition, neuroimaging, and biological 
specimen data of FAD to promote research progress on new mutations identification, pathogenesis 
mechanism and biomarkers. 
Recently, in our study, 3330 patients with AD or mild cognitive impairment in 514 pedigrees were 
enrolled from the CFAN. 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried 
PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP 
mutations. In the present study, 11missensemutations were first identified by the CFAN, including 10 
in PSEN1 and one in APP. The present study highlights that the FAD population in China needs 
extensive investigation, and a concerted effort is necessary to identify the crucial pathological genes 
underlying the pathogenesis of AD. 
 
2. Introduction 
2.1 Overview 
CFAN is the world’s second largest registry network started by Professor Jianping Jia in 2005. 
The sponsor of this project is Xuanwu Hospital of Capital Medical University. CFAN is a multicenter 
observational longitudinal cohort study. The main research population for CFAN are autosomal 

 
6 
dominant inherited AD and unknown gene mutation AD family. All CFAN participants will be assessed 
longitudinally with comprehensive clinical, cognitive, genetic, imaging, and biomarker examinations, 
and all data will be collected using a unified standard, and stored into a central database. The purpose 
of the establishment of CFAN is to advance the research progress of FAD new mutations, pathogenic 
mechanisms and biomarkers in the Chinese population. At the same time, CFAN has great clinical 
significance. Through gene screening of the family, asymptomatic gene carriers can be found earlier, 
early diagnosis and intervention can be performed, and the prognosis can be improved. Long-term 
follow-up of asymptomatic gene carriers is convenient to further reveal the evolution of AD disease, 
and to find a breakthrough for early diagnosis and intervention in the population of asymptomatic gene 
carriers. 
2.2 Research sites 
There is a total of 68 research centers participating in this project, involving 26 provinces and 
cities. For details, please refer to Appendix 16. 
2.3 Research period 
The research period of this project is from February 2005 to January 2038 or longer. 
2.4 Sample size 
There will be a total of 40,000 subjects participating in this project. The total number of subjects 
to be included in this hospital is 5,000, and other sites include 400-600 persons per sites. 
 
3. Research aims 
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. 
3.1 To set up a multi-center, nationwide FAD research network and database platform in China 
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. 
3.2 To clarify the epidemiological characteristics of FAD in China. 
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 

 
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occurrence and development of the disease. 
3.3 To clarify the genetic characteristics of FAD in China. 
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. 
3.4 To clarify the clinical characteristics and disease development laws of FAD in China. 
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. 
3.5 To discover and verify the early diagnosis biomarkers of AD. 
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. 
3.6 To establish a genetic counseling model. 
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. 
4. Research content 
4.1 Cohorts 
We recruit Pre-MCI, MCI and AD dementia patients and normal cognitive control people to 
establish horizontal and vertical research cohorts, including ADAD cohort and the unknown mutation 
carrier cohort. Establish a national FAD research network and electronic database platform to improve 
the clinical information database and biological sample database. 
4.2 Epidemiological characteristics of FAD in China 
Investigate the basic information of the cohort, including individual factors such as 
sociodemography, lifestyle, past medical history, vascular risk factors, occupational exposure, and 
external environmental factors such as socioeconomic level. Conduct a comprehensive FAD 
epidemiological survey in China to identify the impact of nationality, region, gender, age, living 
environment (rural/urban), education level, etc. on the occurrence and development of the disease. 
4.3 Genetic characteristics and mechanism of FAD in China 

8 
Based on the early recruitment and registration of FAD, the disease development laws of Chinese 
FAD families of different sizes will be analyzed. Each family must meet the characteristics of co-
segregation. Use the latest sequencing technology to find new genes and new mutation sites in the 
disease-causing genes (APP, PSEN1, PSEN2) that have been discovered. Explore differences in gene 
frequency from those reported in the West. Determine the frequency distribution of APOE genotypes 
and APOE alleles (APOEε4, APOEε3, and APOEε2), and explore the frequency and incidence of APOE 
genes in FAD population in China. All the above research will provide new evidence for risk assessment 
and intervention in the early stages of the disease. 
4.4 Clinical characteristics, disease development process and laws of FAD in China 
Clinical examination including medical history, past history, family history, physical examination 
and neurological examination will be performed. Neuropsychological assessment usually includes 
cognitive function assessment (memory assessment, attention/executive function assessment, language 
function assessment, visual space and structural ability, calculation), non-cognitive assessment (mental 
behavior change) and evaluation of daily functions (personal life ability, social ability, work ability), 
etc. It is evaluated by the following unified and standardized neuropsychological scales: Mini-Mental 
State Examination, MMSE; Rey-Osterrieth Complex Figure Test, ROCFT; Digit Span Backward, DSB; 
Digit Span Forward, DSF; Verbal Fluency Test, VFT; Trail Making Test A/B, TMT A/B; Boston 
Naming Test, BNT; Clinical Dementia Rating, CDR; Neuropsychiatric Inventory Questionaire, NPI-Q; 
Hamilton Anxiety Scale, HAMA; Hamilton Depression Scale, HAMD; Activities of Daily Living, ADL. 
In addition, Modified Hachinski Ischemic Scale (m-HIS) was used to distinguish AD from VaD. 
Through baseline and follow-up observation, we will analyze cognitive function, mental behavior 
symptoms and daily living ability of asymptomatic mutant gene carriers in FAD families. We will focus 
on the period from the asymptomatic to the development of symptoms, including subtle 
neuropsychological, clinical symptoms, changes in imaging, blood, cerebrospinal fluid, urine and 
saliva. 
4.5 Biomarkers of FAD in China 
We will conduct neuropsychological tests, clinical examinations, and imaging examinations on 
members of the FAD family, and conduct regular cerebrospinal fluid and blood sample collections. Use 
the international standardized electronic patient registration system to establish a large-scale and high-
quality clinical information database and biological sample database to provide a foundation and 
platform for the establishment of the AD diagnosis system and risk prediction model. We will also 
focus on the asymptomatic mutant gene carriers in FAD families and analyze the changes of various 
imaging and body fluid markers in normal cognitive, Pre-MCI, MCI, AD and other stages. 
4.5.1 Body fluid markers 

9 
Firstly, by collecting biological specimens of FAD family members, including blood, 
cerebrospinal fluid, urine and saliva etc., and referring biological sample banks of people in different 
clinical stages, the study can effectively identify highly sensitive and highly specific body fluid markers 
in different clinical stages of AD. Furthermore, longitudinal follow-up of people in different clinical 
stages of the family, detect AD potential and newly developed biomarkers in body fluids at baseline, 
and then combined with clinical neuropsychological evaluation, to establish a diagnosis system for AD 
clinical stages. Moreover, conduct regular follow-up and collection of body fluid samples in the 
included research cohort to monitor the dynamic changes of body fluid markers of patients as the 
disease 
progresses. 
Finally, 
combined 
with 
individual 
factors, 
clinical 
characteristics, 
neuropsychological assessment and body fluid markers, a comprehensive risk analysis of the entire 
disease process of AD occurrence and development was carried out, and body fluid marker prediction 
models in different stages of AD pathogenesis were established. 
4.5.2 Image markers 
We follow up the subjects with normal cognitive, Pre-MCI, MCI, AD stages in the FAD family, 
and test the hippocampus atrophy and cortical thickness of the subjects by MRI. We also detect eight 
observation brain regions by 18F-FDG PET (bilateral frontal lobe, bilateral temporal lobe, bilateral 
parietal lobe, bilateral hippocampus). We will obtain accurate registration image data of patients' brain 
structure, metabolic function, pathological protein molecule deposition at various stages of AD 
progression. We will determine the quantitative critical thresholds for the early diagnosis of AD by 18F-
FDG PET and 11C-PIB PET. Then we will obtain highly sensitive imaging markers for the early 
diagnosis of AD. 
4.6 Research on early intervention and diagnosis and treatment of AD 
Regularly follow up the non-onset members of the FAD family members, combined with the 
genetic characteristics of Chinese FAD, analyze the effects of lifestyle, physical exercise, nootropic 
drugs, cognitive training, etc. on the disease progression of FAD patients or asymptomatic mutant gene 
carriers. Investigate the effects of early non-pharmacological intervention on delaying the progression 
of the disease. Pay close attention to the cognitive situation of carriers of asymptomatic gene mutations. 
Once symptoms are found, intervene immediately to prevent disease progression. Early diagnosis of 
AD in the asymptomatic stage will provide a good time window for clinical intervention and treatment, 
and is expected to reverse and contain the development of dementia. 

10 
Figure1. Research technology route of CFAN study 
6.
Research Process
6.1 Participant population
All participants enrolled in CFAN were adults, and at least two first-degree relatives had AD. All 
participants received clinical assessment and genetic testing at baseline. Based on whether carrying a 
pathogenic mutation of the PSEN1, PSEN2, or APP, the cohort was further divided into two subgroups: 
autosomal dominant AD and unknown gene mutation FAD (un-FAD).  
5. Research Technology Route

 
11 
Subjects come from three sources: 
1) FAD family in the memory clinic of Xuanwu Hospital.  
2) FAD family recruited from CFAN subsites, where recruitment was according to the study 
protocol. 
3) Online registration through the CFAN website (www.Chinacfan.org) and submission of basic 
demographic data and family information to CFAN. The CFAN administrator selects the family that 
meets inclusion criteria by reviewing the online registration materials, and recommends them to the 
CFAN subsite or Xuanwu Hospital memory clinic according to the geographical location. 
6.2 Inclusion criteria 
(1) Written informed consent obtained from the participant or a legal guardian prior to any study-
related procedures; 
(2) 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; 
(3) At least one family member with normal cognitive function (the age should be greater than the 
average age of onset of the family); 
(4) Pedigrees carrying FAD pathogenic genes (APP/PSEN1/PSEN2); 
(5) People in this family >18 years old can be recruited; 
(6) Participant is cognitively normal or demented but not reaching bedridden level; 
(7) Participants are able to provide two reliable informants who can provide clinical information; 
(8) Dementia is diagnosed according to the criteria described by the Diagnostic and Statistical 
Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-R [31]); 
(9) 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 [32]) or National Institute on Aging and the Alzheimer’s Association (NIA-AA) criteria [33]; 
(10) The diagnosis of MCI is made according to Petersen criteria [34] and the classiﬁcation is 
according to the method of Lopez et al [35]. 
6.3 Exclusion criteria  
(1) 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[36]), dementia with Lewy bodies (DLB[37]), 
and Parkinson’s dementia (PDD)； 
(2) MRI and laboratory tests do not support or rule out a diagnosis of AD； 
(3) Severe circulatory, respiratory, urinary, digestive, hematopoietic diseases (such as unstable 

 
12 
angina, uncontrollable asthma, active gastric bleeding) and cancer； 
(4) Participant has severe psychiatric illness or severe dementia that would interfere in completing 
initial and follow-up clinical assessments； 
(5) Participant has a history of alcoholism or drug abuse； 
(6) Pregnant or lactating women； 
(7) No reliable informant； 
(8) 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);  
(9) 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. 
6.4 Study discontinuation 
The primary reasons for study discontinuation are: 
(1) Protocol violation. The participant fails to meet inclusion criteria, or meets exclusion criteria.  
(2) Participant is unwilling or unable to participate.  
(3) Consent is withdrawn.  
(4) The study is terminated by the project director or the CFAN administration center.  
(5) Safety Risk. Any participant who develops safety risk at any time during the visit.  
(6) Death.  
(7) Others. 
6.5 Baseline visit  
The baseline study visit includes the following items: 
(1) Explain study contents and procedures to participant and sign the informed consent form. 
(2) Urine pregnancy test (for women of childbearing potential).  
(3) Check inclusion/exclusion criteria.  
(4) Blood, urine and saliva samples collection (biomarkers).  
(5) Genetic testing to examine risk gene APOE and known pathogenic genes PSEN1, PSEN2, and 
APP for all participants. 
(6) Collecting participant and informant demographics.  
(7) Collecting family history and draw family tree. 
(8) Previous medical, medication history and life style.  
(9) Physical exam and vital signs.  

 
13 
(10) Neurological Exam.  
(11) Neuropsychological test: Mini-Mental State Examination (MMSE), Montreal Cognitive 
Assessment (MoCA), Neuropsychiatric Inventory Questionaire (NPI-Q), Hamilton Anxiety Scale 
(HAMA), Hamilton Depression Scale (HAMD), Modified Hachinski Ischemic Scale (m-HIS), the 
world health organization university of California-Los Angeles auditory verbal learning Test (WHO-
UCLA AVLT), Rey-Osterrieth Complex Figure Test (ROCFT), Digit Span Forward (DSF), Digit Span 
Backward (DSB),Verbal Fluency Test (VFT),Trail Making Test (TMT) A/B, Boston Naming Test 
(BNT), Clinical Dementia Rating (CDR), Activities of Daily Living (ADL). 
(12) MRI includes the following: conventional scan T1 weighted image (T1WI), T2 weighted 
image (T2WI), T2 FLAIR and hippocampal scan coronary T1-FLAIR sequence. 
(13) 18F-FDG PET.  
(14) 11C-PIB PET. 
(15) Carotid ultrasound. 
(16) Lumbar puncture to examine cerebrospinal fluid (after MRI exams) and follow-up phone call 
(if participate in LP)  
(17) After informed consent, non-pharmaceutical interventions are carried out on non-onset gene 
mutation carriers in the family, including lifestyle changes, increased physical exercise and cognitive 
training, and nootropic drugs. 
6.6 Follow-up in-person visits 
The follow-up interval will be determined by the age of the individual in relation to the parent’s 
Average Age of Onset (AAO) or pedigree mean AAO. The affected parent’s AAO or pedigree mean 
AAO is used as the index for the frequency of assessments as follows in Table 1. In the years between 
in-person visits, telephone follow-up will be carried out every six months to inquire about cognitive 
change. If cognitive changes are reported by the participant and/or the informant during the telephone 
follow-up, the follow-up plan will be advanced and the participant will have a in-person clinical 
assessment. 
 
Follow-up study visit includes the following items: 
(1) Urine pregnancy test (for women of childbearing potential)  
(2) Blood, urine and saliva samples collection (biomarkers)  
(3) Family history update  
(4) Participant and informant demographics  
(5) Medical and concurrent medications history  
(6) Physical exam and vital signs  
(7) Neurological exam  

 
14 
(8) Neuropsychological test: Mini-Mental State Examination (MMSE), Montreal Cognitive 
Assessment (MoCA), Neuropsychiatric Inventory Questionaire (NPI-Q), Hamilton Anxiety Scale 
(HAMA), Hamilton Depression Scale (HAMD), Modified Hachinski Ischemic Scale (m-HIS), the 
world health organization university of California-Los Angeles auditory verbal learning Test (WHO-
UCLA AVLT), Rey-Osterrieth Complex Figure Test (ROCFT), Digit Span Forward (DSF), Digit Span 
Backward (DSB),Verbal Fluency Test (VFT),Trail Making Test (TMT) A/B, Boston Naming Test 
(BNT), Clinical Dementia Rating (CDR), Activities of Daily Living (ADL). 
(9) MRI includes the following: conventional scan T1 weighted image (T1WI), T2 weighted image 
(T2WI), T2 FLAIR and hippocampal scan coronary T1-FLAIR sequence. 
(10) 18F-FDG PET.  
(11) 11C-PIB PET.  
(12) Carotid ultrasound. 
(13) Lumbar puncture to examine cerebrospinal fluid. 
Table 1 Follow-up visit plan and frequency 
Index: 
In-person assessment interval 
Individual compared with 
parent’s AAO or pedigree 
mean AAO 
> 10y younger 
every 5 years 
10y – >3y younger 
every 3 years 
3y – 0y younger 
annual 
0y – <3y older 
annual 
> 3y older 
once, at 5 years older than parent’s AAO 
*Documented cognitive 
decline on telephone follow-
up, confirmed by an in- 
person clinical assessment 
every six months 
Telephone follow-up will occur as indicated in the schedule of events in order to maintain contact 
with the family, inquire about cognitive change, and update information about adverse effect. 
 
7. Assessments 
7.1 Clinical evaluation 
7.1.1 Demographic data (Appendix 1) 
 The demographic data should be filled in as completely as possible, including date of birth, age, 
family address, contact information, education level. 
7.1.2 Current medical history 

 
15 
 The detailed and objective current medical history must be filled out by the physicians. If case 
report form (CRF) cannot describe the symptoms and characteristics of the subject in detail, fill in the 
blanks. 
 Describe the specific manifestations of cognitive impairment, such as the specific manifestations 
of memory impairment (nearly/distant/ semantic forgetting); the specific manifestations of language 
barriers (difficulty in finding words, understanding, expressing, naming, writing, etc.); specific 
manifestations of disorientation (time, place, people, etc.); specific manifestations of personality and 
mental behavior (apathy, withdrawal, depression, agitation, wandering, abnormal sleep, antisocial 
behavior such as theft, etc.; the specific forms of hallucinations such as visual hallucinations, auditory 
hallucinations, etc.); manifestations of dyskinesia (such as ataxia, Parkinson-like dyskinesia, 
involuntary movements, etc.); implementation of dysfunction; spatial skills decline and other specific 
performance. 
Physicians should describe the extent of decline in each cognitive domain, whether cognitive 
impairment affects the patient's daily ability and social function, and how it behaves. 
7.1.3 Past history 
 According to the current internationally recognized diagnostic criteria, the previous illness of the 
subject is diagnosed or confirmed, and the presence or absence of the relevant disease, the time of 
diagnosis and the course of the disease are recorded in detail. Diseases with significant neurological 
sequelae, history of general anesthesia, and history of radiotherapy as well as chemotherapy need to be 
documented in detail. Try to let the subject or family provide the hospital's medical record/diagnostic 
certificate, etc., or the investigator will retrieve the patient's past medical records for inspection and 
confirmation.  
7.1.4 Medication situation 
 The subject's medication needs to be documented in detail, including the name of the medication 
for the treatment of cognitive impairment and other diseases, the frequency of administration, and the 
adherence of the medication. Try to have the subject present a medical record, drug package or 
prescription. 
7.1.5 Family history and family diagram drawing 
 For subjects with a family history, the investigator should investigate in detail the incidence of 
each member of the family, and generally investigate the three generations of relatives of the patient. 
For cognitive impairment and suspected cognitive impairment in the family, the disease should be 
recorded in detail (e.g. age of onset, first symptom, progression of disease, involvement of each 
cognitive domain, age of dementia, diagnosis and treatment, clinical consistency with the proband, etc.). 
Refer to operation manual for the rules of family diagram drawing. 

 
16 
7.1.6 Physical examination 
 Physical examinations include general medical examinations and neurological examinations 
performed by senior neurologists. 
7.2 Psychometrics 
7.2.1 Mini Mental State Examination (MMSE) [39] (Appendix 2) 
MMSE is simple and easy to use, widely used at home and abroad, and is the preferred scale for 
dementia screening. The scale includes the following seven aspects: time orientation, location 
orientation, immediate memory, attention and calculations, delayed memory, language, and visual 
space. There are 30 items. The total scores range from 0 to 30. Test scores are closely related to cultural 
level. 
7.2.2 The Montreal Cognitive Assessment (MoCA) [40] (Appendix 3) 
MoCA is designed as a rapid screening instrument for mild cognitive dysfunction. It was created 
in 1996 by Ziad Nasreddine in Montreal, Quebec. It assesses different cognitive domains: attention and 
concentration, executive functions, memory, language, visual constructional skills, conceptual thinking, 
calculations, and orientation. Time to complete the MoCA is approximately 10 minutes. The total score 
is 30; a score of 26 or above is considered normal. 
7.2.3 Neuropsychiatric Inventory (NPI-Q) [41] (Appendix 4) 
The NPI-Q is a well-validated, reliable, multi-item instrument to assess neuropsychiatric 
symptoms in AD based on an interview with an informant (caregiver). The interview is relatively brief 
(<15 minutes). It evaluates both the presence and severity of 12 neuropsychiatric features, including 
delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, 
aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. The 
questionnaire separately evaluates the frequency and severity of each abnormal psychiatric symptom 
and the degree of distress of the caregiver. The caregiver is asked to rate the frequency of the symptoms 
of that domain on a scale of 1 to 4 (1 = occasionally, less than once per week; 4 = very frequently, once 
or more per day or continuously) as well as their severity (1 = mild, 2 = moderate, 3 = severe). The 
total score for each domain is calculated by multiplying the frequency by the severity. A total score is 
calculated by adding all the domain scores together. Caregiver distress is rated by the caregiver on a 
six-point scale from 0 (no distress) to 5 (very severe or extreme distress). Finally, the total score of all 
the symptoms of the caregiver's distress is obtained separately.  
7.2.4 Hamilton Anxiety Rating Scale (HAMA) [42] (Appendix 5) 
The HAMA is a psychological questionnaire used by clinicians to rate the severity of a patient's 
anxiety. The scale [43] consists of 14 items designed to assess the severity of a patient’s anxiety. Each 
of the 14 items contains a number of symptoms, and each group of symptoms is rated on a scale of 0 

 
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to 4, with 4 being the most severe. All of these scores are used to compute an overarching score that 
indicates a person’s anxiety severity [44]. Upon the completion of the evaluation, the clinician compiles 
a total, composite score based upon the summation of each of the 14 individually rated items. This 
calculation will yield a comprehensive score in the range of 0 to 56. It has been predetermined that the 
results of the evaluation can be interpreted as follows: A score of 17 or less indicates mild anxiety 
severity. A score from 18 to 24 indicates mild to moderate anxiety severity. Lastly, a score of 25 to 30 
indicates a moderate to severe anxiety severity. 
7.2.5 Hamilton depression scale (HAMD) [45] (Appendix 6) 
The HAMD is a multiple item questionnaire used to provide an indication of depression. Max 
Hamilton originally published the scale in 1960 [45] and revised it in 1966 [46], 1967 [47], 1969[48], 
and 1980 [49]. The questionnaire is designed for adults and is used to rate the severity of their 
depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, 
anxiety, weight loss, and somatic symptoms. The original 1960 version contained 17 items (HDRS-17). 
Each item on the questionnaire is scored on a 3 or 5 points scale. The total score can be used to evaluate 
the severity of depression and treatment effect. The milder the symptoms, the lower the total score, and 
the severer the symptoms, the higher the total score. Assessment time is about 20 minutes.  
7.2.6 Modified Hachinski ischemic scale (m-HIS) [50] (Appendix 7) 
The m-HIS can be used to identify vascular dementia through clinical findings. The scale has 8 
items with a total score of 12 points. If there are step worse, telling physical symptoms, emotional loss, 
and history of hypertension, score 1 point each; if there are acute onset, history of stroke, focal 
symptoms of the nervous system, focal signs of the nervous system, score 2 points each. The total score 
ranges from 0 to 12. The higher the score, the greater the likelihood of vascular dementia; those with a 
score of 4 or less are AD; those with a score of 7 or more are vascular dementia. 
7.2.7 The world health organization university of California-Los Angeles auditory verbal 
learning Test (WHO-UCLA AVLT) [51] (Appendix 8) 
This test was originally developed by the World Health Organization to be used in international 
research. The WHO-UCLA AVLT includes immediate recall, delayed recall, and delayed recognition. 
The process is as follows: The tester reads 15 words while informing the subject that they need to 
immediately recall after listening. Learning and recalling 3 times, after about 30 minutes interval, 
delayed recall test of 15 words without prompting. Then the tester reads 30 words (including 15 learned 
words and 15 interference options). The subject is asked to judge whether it is a learned word, and the 
number of correct words is recorded. This is a recognition test. The scale examines the ability to enter, 
store, extract, pay attention, and vocabulary of memory, and the score increases with increasing 
educational level. 

 
18 
7.2.8 Rey–Osterrieth complex figure test [52] (Appendix 9) 
The Rey–Osterrieth complex figure test (ROCF) is a neuropsychological assessment in which 
examinees are asked to reproduce a complicated line drawing, first by copying it freehand (recognition), 
and then drawing from memory (recall). Many different cognitive abilities are needed for a correct 
performance, and the test therefore permits the evaluation of different functions, such as visuospatial 
abilities, memory, attention, planning, and working memory (executive functions). First proposed by 
Swiss psychologist André Rey in 1941[53] and further standardized by Paul-Alexandre Osterrieth in 
1944 [54], it is frequently used to further explain any secondary effect of brain injury in neurological 
patients, to test for the presence of dementia. 
7.2.9 Digit Span Test- Forward and Backward [55, 56] (Appendix 10) 
A digit-span task is used to measure working memory's number storage capacity. The tester reads 
a series of numbers of different lengths and asks the subject to immediately repeat in the forward or 
reverse direction. The digit span gradually increases from 3 to 10 in the forward test, and gradually 
increases from 2 to 8 in the reverse test. Each digit span includes two tests. The test was terminated 
when both of the two tests were performed incorrectly by the subject. The longest digit length that a 
subject can speak is its digit span. 
7.2.10 Verbal Fluency Tests [57] (Appendix 11) 
The test is mainly sensitive to frontal dysfunction and mild semantic memory impairment. 
Subjects are asked to speak as many words as possible within a given time (usually 1 minute), such as 
the name of an animal, fruit or vegetable. Record the correct number of words, repetitions, series and 
conversions. The correct number of words is usually used as a scoring indicator, but other factors such 
as concatenation and conversion can sometimes be used as scoring indicators. The number of series is 
the items listed consecutively in each sub-category, counting from the second item of each sub-category 
until the subject is converted to another sub-category, and the series of each sub-category are added to 
obtain the total series. The total number of series, mainly reflecting the semantic memory function. The 
number of conversions is the times the subject switches between subcategories, mainly reflecting the 
frontal lobe execution function. 
7.2.11 Trail Making Test: Parts A and B [58] (Appendix 12) 
Part A consists of 25 circles, numbered 1 through 25, and the tester instructs the participant to 
draw lines as fast as possible in increasing numerical order. Part B is also composed of 25 circles, but 
these circles are white circles (1-12) and black circles (1-13). Subjects need to alternately connect 
circles of different colors in numerical order. The completion performance of the subject is determined 
based on the number of correctly completed lines and the time required to complete. Although both the 
A test and the B test rely on visual motion and perceptual scanning skills, trail making test B requires 

 
19 
considerable cognitive flexibility to complete the black and white transition connection under time 
pressure. 
7.2.12 Boston Naming Test (BNT) [59] (Appendix 13) 
The BNT requires the participant to name objects depicted in outline drawings. In our modification 
of the full BNT, only 30 items are presented. The drawings are graded in difficulty, with the easiest 
drawings presented first. If a participant encounters difficulty in naming an object, a stimulus cue and/or 
a phonemic cue is provided. Record the correct number of independent initial naming, clue naming, 
and option naming. 
7.2.13 Activities of daily living (ADL) [60] (Appendix 14) 
The ADL scale can evaluate the daily activities of the subject comprehensively, accurately and 
quickly. It consists of the physical life self-care scale and the instrumental ADL. There are 14 items, 
including two parts: first, the physical life self-care scale has a total of 6 items, including toilet, eating, 
dressing, grooming, walking and bathing; second, instrumental ADL has a total of 8 items, including 
call, shop, prepare meals, do housework, laundry, use transportation, take medicine and financing 
abilities. The higher the subject scores, the worse the ability of daily living. 
7.2.14 Clinical Dementia Rating (CDR) [61] (Appendix 15) 
The CDR is a refinement of information that the doctor obtains through conversations with the 
patient and his/her family, and to assess the degree of impairment of the patient's cognitive function, 
and then to quickly assess the severity of the patient's condition. The assessment of cognitive domains 
consists of six items: memory, orientation, judgment and problem solving, work and social ability, 
family life and hobbies, and independent living ability. The judgment is in five levels, "normal CDR=0, 
suspected dementia CDR=0.5, mild dementia CDR=1, moderate dementia CDR=2, severe dementia 
CDR = 3". The CDR-SOB (CDR sum of box) total score is a simple sum of the scores of the six items. 
CDR sum of boxes adds up the 6 items, and the total score ranges from 0 to 18. As long as the score is 
greater than 0, the subject has at least one cognitive impairment. Generally, the change value of CDR 
sum of boxes can be used in clinical trials to obtain more accurate cognitive evaluation[62]. CDR is a 
widely used measure of the severity of dementia. 
7.3 Procedures for genetic studies 
7.3.1 Gene testing 
The goal of the genetic study of CFAN is the genetic information and useful biological materials 
(DNA, blood, cerebrospinal fluid, urine, saliva, etc.) provided by cognitive normal and dementia in the 
ADAD cohort and unknown gene mutation cohort. It is anticipated that collection of these data will 
facilitate clinical and basic science investigations of the pathogenesis of dementia. 
7.3.2 Detection of pathogenic genes and risk genes 

 
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After informed consent of the study subjects, we extract 3 ml of the peripheral venous blood of 
the participants. Peripheral blood genomic DNA is extracted using whole blood genomic DNA 
extraction kit. ApoE, PSEN1, PSEN2 and APP gene primer design are referenced. ApoE, PSEN1, 
PSEN2, and APP gene are screened by polymerase chain reaction (PCR). The PCR products above are 
subjected to Sanger sequencing. The sequencing results are analyzed by DNASTAR (vension7.1) 
software. The single nucleotide polymorphism gene mutation screening was performed with reference 
to the PubMed/GeneBank database. 
7.3.3 Gene risk locus detection 
We performed whole exon sequencing and whole genome sequencing on some families. Case-
control methods were used to discover, study and analyze risk-related risk sites, providing genetic basis 
for disease prevention and control.  
The peripheral blood DNA is extracted, and the genomic DNA is interrupted by ultrasound, and 
sequenced after the process of building a library, hybridization capture, and quality control. SNPs were 
annotated with CCDS, human genome database, and dbSNP information to determine the genes, 
coordinates, mRNA sites, amino acid changes, and SNP functions (missense mutations/nonsense 
mutations/variable cleavage sites) at which mutation sites occur, SIFT predicts that SNP affects protein 
function prediction and so on. 
7.3.4 Body fluid testing 
Detection of cerebrospinal fluid, blood, urine and saliva biomarkers in each group, including 
routine testing items such as blood, urine routine, biochemistry, electrolytes, coagulation function, 
cerebrospinal fluid routine, biochemical and other indicators. Also including special indicators 
cerebrospinal fluid and blood Aβ40, Aβ42, t-tau, p-tau and neurogranin. We conduct body fluid testing 
to study and explore early diagnostic markers of disease, and predictors of risk progression. 
7.3.5 Blood specimens 
Blood was taken on an empty stomach in the morning. Each subject received 8 ml of peripheral 
blood, 5 ml was injected into the purple head anticoagulation tube, and 3 ml was injected into the red 
head non-anticoagulated tube. The blood collection tube was marked with the name and number, and 
centrifuged within 2 hours. The purple head anticoagulation tube was centrifuged at 2000 rpm for 10 
minutes to aspirate the upper layer of plasma; the remaining specimens were retained in the 
anticoagulation tube. After the red head non-anticoagulation tube was centrifuged at 2000 rpm for 10 
minutes, the serum was aspirated and placed in two 1.5 ml centrifuge tubes, about 500 μl/tube, and the 
non-anticoagulant tube was discarded. The name and number of the specimen and the type of specimen 
(the serum is labeled Q and the plasma is J) are indicated on the centrifuge tube. The centrifuge tube 
was immediately stored at -80 ° C, and the anticoagulation tube was stored in a refrigerator at -20°C. 

 
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7.3.6 Cerebrospinal fluid specimens 
Lumbar puncture needs to be performed in the morning. To eliminate the impact of puncture 
bleeding on the quality of cerebrospinal fluid specimens, the first 1-2 ml of CSF should be discarded. 
10 ml of cerebrospinal fluid was collected, centrifuged within 2 hours after collection (2000 rpm / 10 
minutes of centrifugation), and the supernatant was aspirated and placed in 10 1.5 ml centrifuge tubes, 
1 ml/tube. Ten centrifuge tubes were immediately stored in a -80°C freezer. 
Approximately 1 ml each of CSF and plasma samples will be utilized for assessment of the various 
defined measures. CSF will be analyzed for Aβ1-40, Aβ1-42, tau and ptau181 measured via ELISA-based 
methods. Plasma will be analyzed for Aβ1-40, Aβx-40, Aβ1-42, and Aβx-42. The remaining aliquots will be 
banked at – 80℃. 
7.4 Imaging 
A model of how different AD biomarkers change during the development of the AD proposed that 
biomarkers became abnormal in the following order: 
(1) β-amyloid (indicating deposition of amyloid in plaques outside the cell, measured in CSF and 
by amyloid PET) 
(2) Tau (indicating the formation of tau fibrils with the neurons) 
(3) Glucose metabolism (measured on PET, indicating damage to neurons) 
(4) Structural MRI (indicating damage to brain structure) 
(5) Cognitive impairment 
At the time of each assessment, participants will undergo scanning with MRI and PET. The PET 
imaging will include both FDG and PIB scans to measure metabolism and Aβ deposition, respectively. 
Xuanwu Hospital and each sub-center have advanced imaging equipment, including cyclotron 
RDS111 (Siemens) and GE's PET/MR full body scanner. It has the license for the use of radioactive 
drugs by the National Food and Drug Administration (the fourth category) and has the qualification to 
prepare new drugs (tracer) for research and development. 
7.4.1 Magnetic resonance imaging (MRI) 
MRI is a medical imaging technique used in radiology to form pictures of the anatomy and the 
physiological processes of the body in both health and disease. MRI scanners use strong magnetic fields, 
magnetic field gradients, and radio waves to generate images of the organs in the body. MRI does not 
involve X-rays or the use of ionizing radiation. MRI is widely used in hospitals and clinics for medical 
diagnosis, staging of disease and follow-up without exposing the body to radiation. The contrast 
provided between grey and white matter makes MRI the best choice for many conditions of the central 
nervous system, including demyelinating diseases, dementia, cerebrovascular disease, infectious 
diseases, Alzheimer's disease and epilepsy. 

 
22 
All MRIs should be scheduled prior to the lumbar puncture procedure. All participants will be 
screened for standard MRI contraindications immediately before the MRI. Scanning will start with 
placement of stereotactic marker on participant’s right temple and proper orientation of head in coil. 
All participants will then undergo the following imaging: T1 weighted image (T1WI), T2 weighted 
image (T2WI), blood oxygenation level dependent (BOLD), Diffusion tensor imaging (DTI), arterial 
spin labeling (ASL), magnetic resonance angiography (MRA). 
7.4.2 Positron-emission tomography (PET) imaging 
7.4.2.1 11C-PIB PET imaging 
Amyloid tracer [N-methyl-11C]2-[4'-(methylamino) phenyl]-6-hydroxybenzothiazole (11C-PIB) 
is the mostly studied and relatively mature Phenothiazine Aβ imaging agent, which is a 11C-labeled 
derivative of Thioflavin-T. It can specifically bind to Aβ plaques in the brain of AD patients and is used 
for positioning and quantitative analysis of Aβ in brain. 11C-PIB PET can differentiate AD and normal 
patients in the early and middle stages of the disease, reflect the pathological changes of brain tissue, 
provide more objective data for early diagnosis. Further combined with clinical history, laboratory tests, 
neuropsychology scale and structural imaging results, it can help improve the accuracy of the diagnosis 
to guide early treatment. Image acquisition is completed by radiology department of each center, stored 
and transmitted in DICOM format, and then image processing is carried out to obtain whole brain and 
regional standard uptake value ratio (SUVR), and used as location and quantitative indicators of Aβ 
deposition. 
7.4.2.2 FDG-PET imaging 
FDG-PET can detect abnormal brain metabolism in patients with dementia, and should be 
performed within 1 month before or after neuropsychological examination (with no new vascular 
disease event). Fasting for at least 6 hours before examination, and fasting blood glucose was measured. 
Blood glucose levels should be <140 mg / dL (7.8 mmol/L). Image acquisition is completed by 
radiology department of each center, stored and transmitted in DICOM format, and then image 
processing is carried out to obtain whole brain and regional standard uptake value ratio (SUVR), and 
used as location and quantitative indicators of brain metabolic function.  
7.4.3 Carotid ultrasound 
Carotid ultrasound can clearly demonstrate the vascular intima-media thickness, the location and 
size of plaque, the degree of vascular stenosis, and analyze hemodynamics. It plays a key role in the 
assessment and diagnosis of vascular-related diseases caused by atherosclerosis. Carotid ultrasound 
examination should be performed within 1 month before or after neuropsychological examination (with 
no new vascular disease event). An experienced ultrasound physician is required to perform the 
operation according to "Guidelines for Carotid Ultrasound Examination". Longitudinal and transverse 

 
23 
section scanning are performed from frontal and lateral directions. Observe and record the peak systolic 
velocity (PSV), end diastolic velocity (EDV), intima-media thickness (IMT) and plaque (diameter, 
number, acoustic properties) of internal carotid artery, common carotid artery and carotid bifurcation. 
8. Statistical analysis 
Periodic review of the accumulating data will be made to safeguard the statistical quality of the 
data and to ascertain whether they conform to the expectations of the original statistical design. At the 
same time, the statistician will perform statistical quality control of FAD data, focusing on outlier and 
missing data detection and comparison among sites. Then, the statistician will participate in statistical 
data analyses, consultations and reporting using R software and other statistical software, such as SAS 
and SPSS for specialized statistical analyses. The sample size is calculated using the paired sample t 
test, and the statistical test level is set to 0.05. 
The normality and homogeneity of variance tests were performed on continuous variables. Data 
that passed these two tests were presented as mean ± standard deviation，then underwent t-testing for 
comparisons between two groups and one-way analysis of variance (ANOVA) testing for comparisons 
among three or more groups. After ANOVA analysis, a Dunnett’s multiple comparison test was used 
for post hoc testing. Data that did not pass the normality test were presented as quartiles, and underwent 
nonparametric testing, using the Kruskal-Wallis test and Dunn's multiple comparison test for 
comparisons among three or more groups. The significance of differences was assessed by the χ2 test 
for categorical variables. The correlation between variables were calculated using Pearson or Spearman 
method. 
 For the longitudinal repeated data, to explore the correlation between different markers and AD, 
a Bayesian linear mixed model was used to model each marker as a function of estimated years from 
expected symptom onset (EYO) and mutation status (carrier or noncarrier). The fixed effects included 
sex, age, follow-up time, mutation status, EYO, and their two-way interaction. 
 
9. Data management 
9.1 Establishment of electronic database 
The sponsor will (or entrusting other companies) establish a standard EDC in line with 
international management practices. During the collection of patient data, a paper version and scanned 
CRF should be generated when the electronic CRF is uploaded. 
9.2 Data entry 
The investigators or data management staffs will synchronically enter the data using double-entry 
method. Data entry will be implemented in two separate web-based systems. Image data and raw data 
will be uploaded and entered into the CFAN Central Archive (CCA). Coded participant identifiers will 

 
24 
be generated by Xuanwu consisting of a project code, a site number, and an individual number at the 
time of participant registration. If there are any questions during the data entry process, they will be 
answered by investigators. 
9.3 Data auditing 
All items of the data, including clinical, demographic, genetic and neuropsychologic data will be 
entered into CFAN data platform, and be checked by quality control committee. CFAN has rigorous 
quality system, and the requirement for the data is clear, correct and complete. Before generating the 
data base, through the way of integrating computer and manual quality control, examine and confirm 
the inclusion and exclusion criteria, make sure the losing or out of range data, recognize any repeated 
item, evaluate the consistency of follow up, and check the follow up status of the subjects. Any data 
problem found should be required to modify and verify by sub-centers.  
9.4 Data access permissions 
Data will be made accessible to CFAN personnel in a staged manner. Prior to the completion of 
quality control procedures, data will be held in a virtual “quarantine” and made accessible only to 
managerial staff and those responsible for completing Quality control (QC) procedures. After QC is 
complete, data will be released from quarantine and made accessible to approved users. All access to 
CFAN data, except that required for data entry, validation, and quality control at the Xuanwu, will be 
through the CCA. The CCA will be accessible via a secure password-protected web portal and web 
services. User accounts to the CCA will be approved by the Informatics Core leader, who will deliver 
regular updates to the CFAN. 
9.5 Data modification record 
The change trace in the database will be automatically recorded. The record content includes the 
data change name, the change reason, the original and modified data, the date of change, and the name 
of the modifier. Only a few people are authorized to change these records, and the modification history 
will be completely kept in the database. 
 
10. Quality control  
The sponsor and investigators should adopt standard operating procedures to ensure the 
implementation of clinical trial quality control and quality assurance systems. During the clinical trial, 
all observation results and findings should be verified to safeguard data reliability and ensure that all 
clinical trial conclusions are derived from the source data. Quality control must be implemented at each 
data processing stage to ensure that all data are reliable and processed correctly. 
10.1 
The writing of investigator’s case report form 
Case report form (CRF) refers to a type of document defined and designed according to the trial 

 
25 
protocol to record the data of each subject during the trial process. Investigator’s brochure and case 
report form are co-authored by principal investigator and sponsor. Requirements for data entry by 
investigators: 
(1) The investigators should ensure truthful, accurate, complete and timely entry of trial data 
into the CRF and upload to the EDC. 
(2) For all subjects who have filled out the informed consent form and are determined to be 
eligible for inclusion in this trial, all observed data should be recorded in the CRF in truthful and 
detailed manner without leaving blanks or missing items. 
(3) For all subjects who have filled out the informed consent form and are determined to be 
eligible for inclusion in this trial, all data in the CRF should be checked against the original medical 
records to ensure consistency. 
(4) When any correction is made in the CRF, only streaking and side notes are allowed, and 
the investigators should sign and date the changes. 
(5) The original laboratory test reports (or photocopies) and imaging reports (or photocopies) 
should be pasted to the laboratory report paste area in the study medical records. 
(6) All data that are significantly higher or lower or beyond the clinically acceptable range 
should be verified or reviewed and explained by the investigators as necessary. 
10.2 
Investigator training  
Before the clinical trial is initiated, the sponsor organizes and funds centralized training of 
investigators uniformly at each trial center to help investigators understand and familiarize with the 
trial protocol, investigator's brochure, case report form and various scales. 
Clinical evaluation is conducted by respectively independent evaluators, including physicians, 
nurses and caregivers. The compilation, implementation, score assessment and result interpretation of 
all neuropsychological tests are standardized and unified; in addition, centralized training of the 
evaluators is provided to achieve consistence standards in scale grading. The testing environment and 
sequence also need to be consistent to reduce the impact of human or environmental factors. 
10.3 
Subject’s compliance  
(1) Signing informed consent forms;  
(2) The investigators should conscientiously implement the informed consent so that the subjects 
can fully understand the trial requirements and cooperate with the trial. The sponsor provides trial drugs 
free of charge and cover the laboratory examination costs. 
 
11. Ethics 
11.1 
Human subjects, ethical and regulatory considerations 

 
26 
This study will be conducted according to Good Clinical Practice guidelines. Written informed 
consent for the study must be obtained from all participants and/or authorized representatives and the 
study partners before protocol-specific procedures are carried out. 
11.2 
Research ethics boards (REB) 
Before the study is initiated, the protocol shall be reviewed and approved by the ethics committee 
prior to implementation. Verification of REB unconditional approval of the protocol and the written 
informed consent statement with written information to be given to the participants and/or their 
authorized representatives. This approval must refer to the study by exact protocol title and number, 
identify documents reviewed, and state the date of review. During the study period, any modifications 
of the protocol shall be approved by the ethics committee prior to implementation. 
11.3 
Informed consent  
The principles of informed consent in the current edition of the Declaration of Helsinki and will 
be implemented before protocol procedures are carried out. Information should be given in both oral 
and written form and deemed appropriate by the REB.  
Participants, their relatives, guardians or authorized representatives and study partners must be 
given ample opportunity to inquire about details of the study. The consent form generated by the 
investigator must be approved, along with the protocol. Consent forms must be in a language fully 
comprehensible to the prospective participants and/or their authorized representatives. Informed 
consent will be documented by the use of a written consent form approved by the REB and signed by 
the participant and/or an authorized representative. The written consent document will embody the 
elements of informed consent as described in the Declaration of Helsinki and will also comply with 
local regulations. Consent must be documented by the dated signature of the participant and/or 
authorized representative. In either case the signature confirms that the consent is based on information 
that has been understood. Informed consent signed by each participant must be kept on file by the 
investigator for possible review by regulatory authorities and/or monitors. 
11.4 
Informed consent for biomarkers, genetic material, and imaging data 
The informed consent will not only cover consent for the trial itself, but for the genetic research, 
biomarker studies, biological sample storage and imaging scans as well. The consent for storage will 
include consent to access stored data, biological samples, and imaging data for secondary analyses. The 
informed consent will specify that the CFAN will receive and store all research data. Consent forms 
will specify that DNA and biomarker samples are for research purposes only; the research tests are not 
diagnostic in nature and participants will not be informed of their test results.  
11.5 
Procedures to maintain confidentiality 
11.5.1 Genetic research and storage of genetic material 

 
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Each sample will contain the following information: sample ID#(to preserve confidentiality), date 
of collection and processing, total initial volume collected, sample type (plasma, serum, CSF), volume, 
aliquot number, freezer, shelf, rack, box, location in the box. DNA and RNA will be prepared at the 
central laboratory for AD. The only information that will be maintained in this database is an Individual 
number (to preserve confidentiality), DNA/RNA number (barcode #), type of sample received, date 
drawn, date received, initial volume collected for each tube type, time of draw, year of birth and gender. 
The samples banked in a locked freezer dedicated to the CFAN study at the central laboratory of 
neurodegenerative diseases, Xuanwu hospital of capital medical university. The samples are without a 
link to identity of the participant from whom the sample came. All samples are bar coded and identified 
by a bar code. 
11.5.2 Biomarker Samples and Research 
Biomarker fluid samples will be labeled by bar coding samples. Samples will be stored by bar 
code number and no other identifying information will be provided. 
 
12. Research implementation conditions and researchers 
12.1 
Research implementation conditions 
The research team relies on Xuanwu Hospital of Capital Medical University. The research team 
recruited appropriate patients by enrolling in the memory clinic and neurodegenerative and cognitive 
disorders. Memory Clinic has long been devoted to providing standardized diagnosis and treatment for 
cognitive impairment caused by various causes and dementia patients of various subtypes, and 
providing counseling and help to caregivers. The memory clinic has been insisting on systematically 
collecting clinical data and neuropsychological evaluation results of various types of elderly cognitive 
impairment and dementia patients, and conducting free APOE genetic testing to strive for early 
detection, early diagnosis and diagnosis of cognitive impairment diseases. For early treatment, the 
memory clinic is suitable for patients including memory loss and other cognitive decline patients, such 
as language ability, orientation, computing power, thinking and judgment ability, etc., including some 
cognitive impairments accompanied by emotional, psychological or sleep problems Of patients. 
Neurodegenerative and cognitive impairment diseases are divided into 4 main groups, 56 beds. This 
will help us to actively carry out the research and development and research of clinical new 
technologies for early diagnosis of neurodegenerative diseases and cognitive disorders, further improve 
the screening scale for neurodegenerative diseases and cognitive disorders, develop genetic early 
diagnosis technology and early diagnosis markers of cerebrospinal fluid To study the sensitivity and 
specificity of early diagnostic techniques in imaging. 
At present, the laboratory has a nerve tissue section room, a microscope room, a histochemical 

 
28 
staining room, a molecular biology laboratory, and a tissue cell culture room. The operating room and 
clean animal rooms (rats, mice) are rented from the laboratory of Capital Medical University. It can 
independently complete many experiments such as molecular biology, cytology, experimental zoology 
and so on. 
12.2 
The capabilities of researchers 
Jianping Jia has been devoted to AD research for more than 20 years. (1) An AD family carrying 
a presenilin 1 gene mutation (PS1 V97L) in China was reported for the first time, which opened the 
first of FAD research in China. It also reported for the first time 53 genetic mutation sites in Chinese, 
and based on this, 7 transgenic mouse models were constructed. Studies have found that Aβ oligomers 
and APP (precursor of Aβ protein) palmitoylation are affected by related gene mutations, which are two 
important ways to cause AD. In animal models, preliminary verification has shown that these two ways 
can be prevented or cut by Chinese medicine monomers such as honokiol. (2) They reported first that 
there are 31 million patients with mild cognitive impairment and 10 million dementia patients in China. 
The prevalence rates are 20.8% and 5.14%, respectively; the annual cost of dementia in China is more 
than 1.100 billion-yuan, accounting for 1/4 of the total cost of dementia in the world. These data provide 
an important basis for China to formulate a national prevention and control strategy for dementia. (3) 
Optimize AD clinical trials and continuously introduce new drug researches. He has chaired 8 domestic 
and 6 international multi-center clinical trials. It is proved that the new drug butylphthalide and the 
Chinese medicine Selotonone have significant effects on vascular dementia, breaking the dilemma of 
no available vascular dementia drugs in the world. The safety and effectiveness of donepezil in Chinese 
patients with severe AD have been verified, and new treatment options have been provided for patients. 
In collaboration with British experts, the world's first clinical trial of new anti-tau dementia drugs has 
brought new hope for AD treatment. (4) It was confirmed that Aβ, T-tau, and P-tau in peripheral blood 
exosomes can effectively reflect pathological changes in the brain and have clinical diagnostic value 
equivalent to cerebrospinal fluid. (5) Design and develop peripheral blood Aβ protein detectors for 
early diagnosis of AD patients. At present, preliminary distinction can be made between AD and normal 
controls. (6) Presided over the development of two editions of "Guidelines for the Diagnosis and 
Treatment of Dementia and Cognitive Impairment in China" (published by Human Health Press), and 
a series of 17 articles on diagnosis and treatment guidelines, which provided guidance documents for 
standardizing clinical practice of dementia in China. (7) Editor-in-chief of the textbooks compiled by 
many colleges and universities of China's medical colleges. He has been the editor-in-chief of the 6th, 
7th, and 8th editions of Neurology. In addition, he edited the standardized training materials for national 
residents and training materials for specialists in neurology, and made special contributions to the 
cultivation of medical talents in China. 

 
29 
This study brings together more than 150 experts in 68 well-known hospitals in China who have 
established memory clinics in the field of AD and cognitive impairment. The purpose of this study is 
to condense the national AD clinical centers and establish the largest cohort of FAD in China. 
The doctors participating in the study in our hospital have medical qualifications and rich clinical 
experience, and are competent for the safety protection and medical diagnosis and treatment of the 
subjects. Qualified or trained researchers are responsible for obtaining informed consent and receiving 
consultations on safety issues at any time. 
 
13. References 
[1] Holtzman, D.M., J.C. Morris, and A.M. Goate. Alzheimer's disease: the challenge of the second 
century. Sci Transl Med. 2011, 3(77): p. 77sr1. 
[2] Chan, K.Y., et al., Epidemiology of Alzheimer's disease and other forms of dementia in China, 1990-
2010: a systematic review and analysis. Lancet. 2013, 381(9882): 2016-23. 
[3] Jia, J., et al., The cost of Alzheimer's disease in China and re-estimation of costs worldwide. 
Alzheimers Dement. 2018, 14(4): 483-491. 
[4 ]Cruchaga, C., et al., Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset 
Alzheimer's disease families. PLoS One. 2012, 7(2): e31039. 
[5] Cacace, R., K. Sleegers, and C. Van Broeckhoven, Molecular genetics of early-onset Alzheimer's 
disease revisited. Alzheimers Dement. 2016, 12(6): 733-48. 
[6] Tanzi, R.E., A brief history of Alzheimer's disease gene discovery. J Alzheimers Dis. 2013, 33 Suppl 
1: S5-13. 
[7] Aguirre-Acevedo, D.C., et al., Diagnostic accuracy of CERAD total score in a Colombian cohort 
with mild cognitive impairment and Alzheimer's disease affected by E280A mutation on presenilin-1 
gene. Int Psychogeriatr. 2016, 28(3): 503-10. 
[8] Lanoiselee, H.M., et al., APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A 
genetic screening study of familial and sporadic cases. PLoS Med. 2017, 14(3): e1002270. 
[9] Weston, P.S.J., et al., Accelerated long-term forgetting in presymptomatic autosomal dominant 
Alzheimer's disease: a cross-sectional study. Lancet Neurol. 2018, 17(2): 123-132. 
[10] Ikeuchi, T., et al., Mutational analysis in early-onset familial dementia in the Japanese population. 
The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008, 26(1): 43-9. 
[11] Park, H.K., et al., Cognitive profiles and neuropsychiatric symptoms in Korean early-onset 
Alzheimer's disease patients: a CREDOS study. J Alzheimers Dis. 2015, 44(2): 661-73. 
[12] Kruger, J., et al., Molecular genetic analysis of the APP, PSEN1, and PSEN2 genes in Finnish 
patients with early-onset Alzheimer disease and frontotemporal lobar degeneration. Alzheimer Dis 

 
30 
Assoc Disord. 2012, 26(3): 272-6. 
[13] Jia, J., et al., One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer's 
disease. J Alzheimers Dis. 2005, 7(2): 119-24; discussion 173-80. 
[14] Jiao, B., et al., Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. 
Neurobiol Aging. 2014, 35(8): 1957 e1-6. 
[15] Gao, Y., et al., Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's 
disease. Neurobiol Aging. 2019, 77: 154-157. 
[16] Zucchella C, Sinforiani E, Tamburin S, Federico A, Mantovani E, Bernini S, et al. The 
Multidisciplinary Approach to Alzheimer's Disease and Dementia. A Narrative Review of Non-
Pharmacological Treatment. Front Neurol. 2018, 9:1058.  
[17] Anderson-Hanley C, Barcelos NM, Zimmerman EA, Gillen RW, Dunnam M, Cohen BD, et al. 
The Aerobic and Cognitive Exercise Study (ACES) for Community-Dwelling Older Adults With or At-
Risk for Mild Cognitive Impairment (MCI): Neuropsychological, Neurobiological and Neuroimaging 
Outcomes of a Randomized Clinical Trial. Front Aging Neurosci. 2018, 10:76.  
[18] Leggieri M, Thaut MH, Fornazzari L, Schweizer TA, Barfett J, Munoz DG, et al. Music 
Intervention Approaches for Alzheimer's Disease: A Review of the Literature. Front Neurosci. 2019, 
13:132.  
[19] Serebrovska ZO, Serebrovska TV, Kholin VA, Tumanovska LV, Shysh AM, Pashevin DA, et al. 
Intermittent Hypoxia-Hyperoxia Training Improves Cognitive Function and Decreases Circulating 
Biomarkers of Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Pilot Study. Int J 
Mol Sci. 2019, 20(21).  
[20] Haeger A, Costa AS, Schulz JB, Reetz K. Cerebral changes improved by physical activity during 
cognitive decline: A systematic review on MRI studies. Neuroimage Clin. 2019, 23:101933. 
[21] McGurran H, Glenn JM, Madero EN, Bott NT. Prevention and Treatment of Alzheimer's Disease: 
Biological Mechanisms of Exercise. Journal of Alzheimer's disease. 2019, 69(2):311-38.  
[22] Garcia-Casares N, Moreno-Leiva RM, Garcia-Arnes JA. Music therapy as a non-pharmacological 
treatment in Alzheimer's disease. A systematic review. Rev Neurol. 2017, 65(12):529-38.  
[23] Pongan E, Tillmann B, Leveque Y, Trombert B, Getenet JC, Auguste N, et al. Can Musical or 
Painting Interventions Improve Chronic Pain, Mood, Quality of Life, and Cognition in Patients with 
Mild Alzheimer's Disease? Evidence from a Randomized Controlled Trial. Journal of Alzheimer's 
disease. 2017, 60(2):663-77.  
[24] Rossi Dare L, Garcia A, Alves N, Ventura Dias D, de Souza MA, Mello-Carpes PB. Physical and 
cognitive training are able to prevent recognition memory deficits related to amyloid beta neurotoxicity. 
Behav Brain Res. 2019, 365:190-7.  

 
31 
[25] Pedroso RV, Ayan C, Fraga FJ, da Silva TMV, Cancela JM, Santos-Galduroz RF. Effects of 
Functional-Task Training on Older Adults With Alzheimer's Disease. J Aging Phys Act. 2018, 26(1):97-
105.  
[26] McMaster M, Kim S, Clare L, Torres SJ, D'Este C, Anstey KJ. Body, Brain, Life for Cognitive 
Decline (BBL-CD): protocol for a multidomain dementia risk reduction randomized controlled trial for 
subjective cognitive decline and mild cognitive impairment. Clin Interv Aging. 2018, 13:2397-406.  
[27] Rubia Orti JE, Garcia-Pardo MP, Drehmer E, Sancho Cantus D, Julian Rochina M, Aguilar MA, 
et al. Improvement of Main Cognitive Functions in Patients with Alzheimer's Disease after Treatment 
with Coconut Oil Enriched Mediterranean Diet: A Pilot Study. Journal of Alzheimer's disease. 2018, 
65(2):577-87.  
[28] Duan Y, Lu L, Chen J, Wu C, Liang J, Zheng Y, et al. Psychosocial interventions for Alzheimer's 
disease cognitive symptoms: a Bayesian network meta-analysis. BMC Geriatr. 2018, 18(1):175.  
[29] Minakawa EN, Wada K, Nagai Y. Sleep Disturbance as a Potential Modifiable Risk Factor for 
Alzheimer's Disease. Int J Mol Sci. 2019, 20(4). 
[30] Jia, L., et al., PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial 
Alzheimer's disease. Alzheimers Dement, 2020. 16(1): 178-191. 
[31] Association AP. Diagnostic and Statistical Manual of Mental Disorders. 4th text revision ed. 
Washington, DC: American Psychiatric Association. 2000:553-557. 
[32] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of 
Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department 
of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984, 34:939–44. 
[33] McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The 
diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on 
Aging and the Alzheimer’s Assocation Workgroup. Alzheimers Dement. 2011, 7:263–9. 
[34] Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004, 256:183–94. 
[35] Petersen R C. Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine. 2010, 
256(3):183-194. 
[36] Lopez OL, Jagust WJ, Dulberg C, Becker JT, DeKosky ST, Fitzpatrick A, et al. Risk factors for 
mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol. 
2003, 60:1394–9. 
[37] McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and 
pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal 
Dementia and Pick’s Disease. Arch Neurol. 2001, 58(11):1803–9. 
[38] McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, 

 
32 
Lippa C, Perry EK, et al. Diagnosis and management of dementia with Lewy bodies: third report of the 
DLB Consortium. Neurology. 2005, 65(12):1863–72.  
[39] Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatr Res. 1975, 12(3): 189-198. 
[40] Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief 
screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005, 53(4):695-699.[41] Cummings 
J L. The Neuropsychiatric Inventory: Assessing psychopathology in dementia patients. Neurology. 
1997, 48 (5 Suppl 6): S10. 
[42] Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959, 32:50–55. 
[43] Maier W, Buller R, Philipp M, et al. The Hamilton Anxiety Scale: reliability, validity and 
sensitivity to change in anxiety and depressive disorders. J Affect Disord. 1988, 14(1):61–68. 
[44] Vaccarino AL, Evans KR, Sills TL, Kalali AH. Symptoms of anxiety in depression: assessment of 
item performance of the Hamilton Anxiety Rating Scale in patients with depression. Depress Anxiety. 
2008, 25(12):1006-1013. 
[45] Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960, 23:56-62. 
[46] Hamilton M. Assessment of change in psychiatric state by means of rating scales. Proc R Soc Med. 
1966, 59 Suppl:10-13. 
[47] Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 
1967, 6(4):278-296. 
[48] Hamilton M. Standardised assessment and recording of depressive symptoms. Psychiatr Neurol 
Neurochir. 1969, 72(2):201-205. 
[49] Hamilton M. Rating depressive patients. J Clin Psychiatry. 1980, 41(12 Pt 2):21-24. 
[50] Hachinski V, Oveisgharan S, Romney A K, et al. Optimizing the Hachinski Ischemic Scale. Arch 
Neurol. 2012, 69(2):169-175. 
[51] Maj M, Satz P, Janssen R, et al. WHO Neuropsychiatric AIDS study, cross-sectional phase II. 
Neuropsychological and neurological findings. Arch Gen Psychiatry. 1994, 51(1):51-61. 
[52] Shin MS, Park SY, Park SR, et al. Clinical and empirical applications of the Rey-Osterrieth 
Complex Figure Test. Nat Protoc. 2006, 1(2):892-899. 
[53] Rey, A. L'examen psychologique dans les cas d'encephalopathie traumatique. Arch. Psychol. 1941, 
28: 286-340. 
[54] Osterrieth, P.A. Le test de copie d'une figure complexe. Arch. Psychol. 1944, 30: 206-356. 
[55] Jones G, Macken B. Questioning short-term memory and its measurement: Why digit span 
measures long-term associative learning. Cognition. 2015, 144:1-13. 
[56] Wechsler D. Manual, Wechsler Adult Intelligence Scale-Revised. The Psychological Corporation. 

 
33 
1981. 
[57] Diesfeldt HF. [Category-related verbal fluency in a psychogeriatric practice]. Tijdschr Gerontol 
Geriatr. 1983, 14(2):49-59. 
[58] Armitage S G. An analysis of certain psychological tests used for the evaluation of brain injury. 
Psychological Monographs. 1946, 60(1):1-48. 
[59] Goodglass H, Kaplan E. Boston Diagnostic Aphasia Examination Booklet Philadelphia: Lea& 
Febiger. 1983. 
[60] Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical 
trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 
1997, 11 Suppl 2: S33-39. 
[61] Hughes CP, Berg L, Danziger WL, et al. A new clinical scale for the staging of dementia. Br J 
Psychiatry.1982, 140: 566-572. 
[62] Berg, L, Miller, J P, Baty, J, et al. Mild senile dementia of the Alzheimer type 4 Evaluation of 
intervention. Ann Neurol. 1992, 31: 242-249. 
 

34 
 
14. Appendix 
Appendix 1 Participants information 
Basic 
A1 Number 
Province Number—Hospital Number—Participant 
Number：______--_______--_______ 
A2 ID number 
 
A3 Gender 
□1 male 
□2 female 
A4 Age 
_____ years 
 
A5 Ethnicity 
□1 Han，□2 Zhuang，□3 Hui，□4 Miao，□5 Tibetan，
□6 Uyghur，□7 Other    
 
A6 Education 
□ ＜1 year         □ 1-6 years        □ ＞6 years 
A7 Residence 
□1 Urban      □2 Rural 
A8 Home address 
Urban  A8.1.1       Province、municipality directly 
under the central government  A8.1.2      city A8.1.3     
district（county） A8.1.4              Street（Road、
Vallage） A8.1.5_______ Community A8.1.6      
Building A8.1.7________ Unit A8.1.8________ House 
number  A8.1.9 Post Code           
A9 Contact number 
A9.1 Telephone（district 
number）               
A9.2 
Mobile____________ 
－                    
A10 Handedness 
□1 Dextromanulity   □2 Left handedness    □3 With both 
hands 
A11 Occupation 
A11.1 Record occupational 
before retirement        
□1 Agricultural, forestry, 
animal husbandry, fishery 
□7 Soldier 
□8 Media, cultural and sports 
personnel 
□9 Student 

35 
 
and water conservancy 
industry production 
personnel 
□2 Production and 
transportation equipment 
operators and related 
personnel 
□3 Business and service 
personnel 
□4 Officals 
□5 Administritive staff 
□6 Professionals 
□10 No Job 
□11 House working 
□12 Religious personnel 
□13 Others 
A12 Marrital status 
□1 Married 
□2 Widowed 
□3 Divorced 
□4 Separated 
□5 Single 
□6 Live together 
A13 Living condition 
□1 Living alone 
□2 Living with spouse 
□3 Living with children 
□4 Living with nanny 
□5 Living with spouse and 
children 
□6 Living in nursing home or 
gerocormium 
□7Living with relatives or 
friends 
A14 Hight（cm） 
__ __ __  
A15 Body weight（kg） 
__ __ __   
A16 Waistline（cm） 
__ __ 

36 
 
A17 Blood pression
（mmHg） 
A17.1 Systolic__ __ __mmHg 
A17.2 Diastolic__ __ __mmHg 
A18 Resting heart rate
（Beat/ Minute） 
__ __ __  
A19 Normal vision 
□0 No  □1 Yes 
A20 Normal hearing 
□0 No  □1 Yes 
 
 
 

37 
 
Appendix 2 mini-mental state examination (MMSE)[39] 
Activity 
                                                               Score 
 
 
ORIENTATION – one point for each answer 
  Ask: “What is the: (year)(season)(date)(day)(month)?”                         _______ 
  Ask: “Where are we: (state)(county)(town)(hospital)(floor)?”                    _______ 
 
 
REGISTRATION – score 1,2,3 points according to how many are repeated  
  Name three objects: Give the patient one second to say each. 
  Ask the patient to: repeat all three after you have said them.  
  Repeat them until the patient learns all three.                                 _______ 
 
ATTENTION AND CALCULATION – one point for each correct subtraction  
  Ask the patient to: begin from 100 and count backwards by 7. 
  Stop after 5 answers. (93, 86, 79, 72, 65)                                    _______ 
 
 
RECALL – one point for each correct answer 
  Ask the patient to: name the three objects from above.                          _______ 
 
 
LANGUAGE 
Ask the patient to: identify and name a pencil and a watch. (2 points)                _______ 
Ask the patient to: repeat the phrase “No ifs, ands, or buts.” (1 point)                _______ 
Ask the patient to: “Take a paper in your right hand, fold it in half, 
 and put it on the floor “ (1 point for each task completed properly)                 _______ 
Ask the patient to: read and obey the following: “Close your eyes.” (1 point)          _______ 
Ask the patient to: write a sentence. (1 point)                                   _______ 
Ask the patient to: copy a complex diagram of two interlocking pentagons. (1 point)    _______ 
 
 
 
                                                   
 
 
 
                                            TOTAL (0-30):  _______ 
 
 

38 
Appendix 3 Montreal Cognitive Assessment (MoCA) [40] 
Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses 
different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual 
thinking, calculations, and orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 30 
points; a score of 26 or above is considered normal. 
contents 
Administration and Scoring Instructions 
score 
1 
Alternating Trail 
Making 
Administration: The examiner instructs the subject: "Please draw a line, going from a number to a 
letter in ascending order. Begin here [point to (1)] and draw a line from 1 then to A then to 2 and 
so on. End here [point to (E)]." 
Scoring: Allocate one point if the subject successfully draws the following pattern: 1 −A- 2- B- 3- 
C- 4- D- 5- E, without drawing any lines that cross. Any error that is not immediately self-
corrected earns a score of 0.
1 score□
2 
Visuoconstructional 
Skills (Cube) 
Administration: The examiner gives the following instructions, pointing to the cube: “Copy this 
drawing as accurately as you can, in the space below”. 
Scoring: One point is allocated for a correctly executed drawing. 
• Drawing must be three-dimensional
• All lines are drawn
• No line is added
• Lines are relatively parallel and their length is similar (rectangular prisms are accepted)
A point is not assigned if any of the above-criteria are not met.
2 score□

39 
 
3 
Visuoconstructional 
Skills (Clock) 
Administration: Indicate the right third of the space and give the following instructions: “Draw a 
clock. Put in all the numbers and set the time to 10 past 11”. 
Scoring: One point is allocated for each of the following three criteria: 
• Contour (1 pt.): the clock face must be a circle with only minor distortion acceptable (e.g., slight 
imperfection on closing the circle); 
• Numbers (1 pt.): all clock numbers must be present with no additional numbers; numbers must be 
in the correct order and placed in the approximate quadrants on the clock face; Roman numerals 
are acceptable; numbers can be placed outside the circle contour; 
• Hands (1 pt.): there must be two hands jointly indicating the correct time; the hour hand must be 
clearly shorter than the minute hand; hands must be centered within the clock face with their 
junction close to the clock center. 
A point is not assigned for a given element if any of the above-criteria are not met.  
At the same time, the score is given by the 15-point method (see table below), not counting the 
total score. 
 
Contents 
Yes 
No 
score 
1 
Shape similar to the clock 
1 
0 
 
2 
Round circumference 
1 
0 
 
3 
Diameter >2.5 cm (if the first painting is small, encourage it to 
draw larger) 
1 
0 
 
4 
All the numbers are inside the circle 
1 
0 
 
5 
First locate 12,6,3,9 
1 
0 
 
6 
The numbers are arranged at regular intervals (symmetrically 
arranged on a 12-6 axis). If it is so, skip the 7th question 
2 
0 
 
7 
If there is a spatial alignment error, it can be corrected (with 
traces of alteration) 
1 
0 
 
8 
Only Arabic numerals 
1 
0 
 
9 
Only the Arabic numerals 1-12 appear 
1 
0 
 
10 
1-12 appears in sequence, no omission or misalignment 
1 
0 
 
11 
Only 2 pointers 
1 
0 
 
12 
The pointer is like an arrow 
1 
0 
 
13 
The hour hand is between 11 and 12 
1 
0 
 
14 
The minute hand is longer than the hour hand 
1 
0 
 
15 
There is no problem under the column 
1 
0 
 
 
1)The minute hand points to 10 o'clock 
 
 
 
 
2)Write the words 11:10 
 
 
 
 
3)Extra pointer or circle 
 
 
 
 
4)Any letters, words or diagrams appear 
 
 
 
 
5)Any extra lines appear below the circle 
 
 
 
3 score □——3-point method 
3.1 score□□——15-point method 
4 
Naming 
Administration: Beginning on the left, point to each figure and say: “Tell me the 
name of this animal”. 
Scoring: One point each is given for the following responses: (1) lion (2) giraffe 
4 score□ 

40 
 
(3) camel or dromedary. 
 
5 
Memory 
Administration: The examiner reads a list of 5 words at a rate of one per second, giving the 
following instructions: “This is a memory test. I am going to read a list of words that you will have 
to remember now and later on. Listen carefully. When I am through, tell me as many words as you 
can remember. It doesn’t matter in what order you say them”. Mark a check in the allocated space 
for each word the subject produces on this first trial. When the subject indicates that (s) he has 
finished (has recalled all words), or can recall no more words, read the list a second time with the 
following instructions: “I am going to read the same list for a second time. Try to remember and 
tell me as many words as you can, including words you said the first time.” Put a check in the 
allocated space for each word the subject recalls after the second trial. 
At the end of the second trial, inform the subject that (s)he will be asked to recall these words 
Again by saying, “I will ask you to recall those words again at the end of the test.” 
Scoring: No points are given for Trials One and Two. 
 
Face 
Velvet 
School 
Daisy 
Red 
First 
 
 
 
 
 
Second 
 
 
 
 
 
6 
Forward Digit Span 
Give the following instruction: “I am going to say some numbers and when I am 
through, repeat them to me exactly as I said them”. Read the five number sequence 
at a rate of one digit per second. 
Scoring: Allocate one point for each sequence correctly repeated. 
21854 [  ] 
6 score□ 
7 
Backward Digit Span 
Administration: Give the following instruction: “Now I am going to say some more 
numbers, but when I am through you must repeat them to me in the backwards 
order.” Read the three number sequence at a rate of one digit per second. 
Scoring: Allocate one point for each sequence correctly repeated, (N.B.: the correct 
response for the backwards trial is 2-4-7). 
742 [  ] 
7 score□ 
8 
Vigilance 
Administration: The examiner reads the list of numbers at a rate of one per second, 
after giving the following instruction: “I am going to read a sequence of numbers. 
Every time I say the number 1, knock the table once. If I say a different letter, do 
not knock the table”. 
Scoring: Give one point if there is zero to one errors (an error is a knock on a 
wrong number or a failure to knock on number 1). 
52139411806215194511141905112 [  ] 
8 score□ 

41 
 
9 
Serial 7s 
(Refer to the MMSE 
result score) 
Administration: The examiner gives the following instruction: “Now, I will ask 
you to count by subtracting seven from 100, and then, keep subtracting seven from 
your answer until I tell you to stop.” Give this instruction twice if necessary. 
Scoring: This item is scored out of 3 points. Give no (0) points for no correct 
subtractions, 1 point for one correction subtraction, 2 points for two-to-three 
correct subtractions, and 3 points if the participant successfully makes four or five 
correct subtractions. Count each correct subtraction of 7 beginning at 100. Each 
subtraction is evaluated independently; that is, if the participant responds with an 
incorrect number but continues to correctly subtract 7 from it, give a point for each 
correct subtraction. For example, a participant may respond “92 – 85 – 78 – 71 – 
64” where the “92” is incorrect, but all subsequent numbers are subtracted 
correctly. This is one error and the item would be given a score of 3. 
[  ]93   [  ]86   [  ]79   [  ]72   [  ]65 
9 score□ 
10 
Sentence repetition 
Administration: The examiner gives the following instructions: “I am going to read 
you a sentence. Repeat it after me, exactly as I say it [pause]: I only know that John 
is the one to help today.” Following the response, say: “Now I am going to read 
you another sentence. 
Repeat it after me, exactly as I say it [pause]: The cat always hid under the couch 
when dogs were in the room.” 
Scoring: Allocate 1 point for each sentence correctly repeated. Repetition must be 
exact. Be alert for errors that are omissions (e.g., omitting "only", "always") and 
substitutions/additions (e.g., "John is the one who helped today;" substituting 
"hides" for "hid", altering plurals, etc.). 
I only know that John is the one to help today. [  ] 
The cat always hid under the couch when dogs were in the room. [  ] 
10score□ 
11 
Verbal fluency 
Administration: "Please tell as many animals as you can, as soon as possible. The 
time is 1 minute, are you ready? Start." Stop after one minute. 
Scoring: If the subject names ≥11 within 1 minute, score 1 point. At the same 
time, record the examiner's answer as much as possible. Deified animals such as 
dragons, phoenixes, and unicorns are also correct. 
please record ： 
2.11.1(0-15 s)                                                      
2.11.2(16-30 s)                                                        
2.11.3(31-45 s)                                                  
2.11.4(46-60 s)                                          
[  ]        ( N≥11 words) 
11score□ 
12 
Abstraction 
Administration: The examiner asks the subject to explain what each pair of words 
has in common, starting with the example: “Tell me how an orange and a banana 
are alike”. If the subject answers in a concrete manner, then say only one additional 
time: “Tell me another way in which those items are alike”. If the subject does not 
give the appropriate response (fruit), say, “Yes, and they are also both fruit.” Do 
not give any additional instructions or clarification. After the practice trial, say: 
“Now, tell me how a train and a bicycle are alike”. Following the response, 
administer the second trial, saying: “Now tell me how a ruler and a watch are 
alike”. 
Do not give any additional instructions or prompts. 
Scoring: Only the last two item pairs are scored. Give 1 point to each item pair 
12score□ 

42 
 
correctly answered. The following responses are acceptable:  
[  ] Train-bicycle： Means of transportation, means of travelling, you take trips 
in both; 
[  ] Ruler-watch ： Measuring instruments, used to measure. 
The following responses are not acceptable: Train-bicycle = they have wheels; 
Ruler-watch = they have numbers. 
13 
Delayed recall 
Administration: The examiner gives the following instruction: “I read some words 
to you earlier, which I asked you to remember. Tell me as many of those words as 
you can remember.” Make a check mark ( √ ) for each of the words correctly 
recalled spontaneously without any cues, in the allocated space. 
Scoring: Allocate 1 point for each word recalled freely without any cues. 
Following the delayed free recall trial, prompt the subject with the semantic 
category cue provided below for any word not recalled. Make a check mark ( √ ) 
in the allocated space if the subject remembered the word with the help of a 
category or multiple-choice cue. Prompt all non-recalled words in this manner. If 
the subject does not recall the word after the category cue, give him/her a multiple 
choice trial, using the following example instruction, “Which of the following 
words do you think it was, NOSE, FACE, or HAND?”  
Use the following category and/or multiple-choice cues for each word, when 
appropriate: 
 
Face 
Velvet 
School 
Daisy 
Red 
No prompt 
 
 
 
 
 
category 
cue 
part of 
the body 
type of 
fabric 
type of 
building 
type of 
flower 
a colour 
 
 
 
 
 
multiple 
choice 
nose, 
face, 
hand 
denim, 
cotton, 
velvet 
church, 
school, 
hospital 
rose, 
daisy,  
tulip 
red, blue, 
green 
 
 
 
 
 
Scoring: No points are allocated for words recalled with a cue. A cue is used for 
clinical information purposes only and can give the test interpreter additional 
information about the type of memory disorder. For memory deficits due to 
retrieval failures, performance can be improved with a cue. For memory deficits 
due to encoding failures, performance does not improve with a cue. 
13score□ 
14 
Orientation 
Administration: The examiner gives the following instructions: “Tell me the date 
today”. If the subject does not give a complete answer, then prompt accordingly by 
saying: “Tell me the [year, month, exact date, and day of the week].” Then say: 
“Now, tell me the name of this place, and which city it is in.” 
Scoring: Give one point for each item correctly answered. The subject must tell the 
exact date and the exact place (name of hospital, clinic, office). No points are 
allocated if subject makes an error of one day for the day and date. 
[  ] Date [  ] Month [  ] Year [  ] Day [  ] Place [  ] City 
14score□ 
15 
Total score 
 
15score□
□ 
TOTAL SCORE: Sum all sub scores listed on the right-hand side. Add one point for an individual who has 12 years or fewer of formal 
education, for a possible maximum of 30 points. 
A final total score of 26 and above is considered normal.

43 
 
Appendix 4 Neuropsychiatric Inventory (NPI-Q) [41] 
Scoring levels with example definitions for the NPI-Q 
Frequency of occurrence (1~4) 
1. 
Occasionally: less than once per week 
2. 
Often: about once per week 
3. 
Frequently: several times per week but less than every day 
4. 
Very frequently: once or more per day 
Severity of behavior (1~3) 
1. 
Mild: mildly distressing to the patient and not a major problem 
2. 
Moderate: distressing to the patient but easily overcome by reassurance 
3. 
Marked: distressing to the patient and difficult to redirect or deal with 
Distress to you (0~5) 
0. 
Not at all 
1. 
Minimally: rarely distressing and easily tolerated 
2. 
Mildly: occasionally distressing, but not a significant problem 
3. 
Moderately: somewhat distressing and problematic, but usually tolerable 
4. 
Severely: very distressing and difficult to cope with 
5. 
Very severely or extremely: markedly distressing and extremely difficult to cope with 
The score for each item is calculated by multiplying the frequency by the intensity; and the total score for the NPI is calculated by 
adding the scores of all symptoms. 
Thus, scores may range from 0 to a maximum of 144, where the higher the score, the more severe the psychopathology. 
                                 Summary table for NPI-Q scores. 
Symptom 
FrequencySeverity
Total 
(frequency × 
severity)  
Distress 
to you 
1. 
Delirium  
Does the patient have a false idea, such as thinking that 
someone else has stolen his/her things? Do you suspect that 
someone is harming him? 
2. 
Hallucinations  
Does the patient have hallucinations such as visual 
hallucinations or auditory hallucinations? See or hear 
something or sound that doesn't exist? Talking to someone 
who doesn't actually exist? 
3. 
Agitation/aggression  Does the patient often refuse help from others? 
Unmanageable? Stubborn? Shouting at others? Snoring 
others? 
4. 
Depression/dysphoria  Does the patient show grief or express a depression? 
5. 
Anxiety  
Is it uncomfortable after the patient is separated from the 
caregiver? Does the patient have mental stress such as 
shortness of breath, sigh, can't relax or feel nervous? 
6. 
Joy/euphoria  
Is the patient too happy and feeling too good? Feeling 
humorous and laughing at things that others are not interesting 
about? Joy that doesn't match the situation? 
7. 
Apathy  
Did the patient lose interest in activities that were previously 
of interest? Indifferent to other people's activities and plans? 
8. 
Disinhibition  
Does the patient lose self-control, such as talking to strangers 
like an acquaintance? Or talk regardless of the feelings of 
others? 
9. 
Irritability/lability 
Does the patient show impatience or crazy behavior? Can't 
bear the delay? Can't wait patiently for the planned activities? 
10. Abnormal motor 
behaviour 
Does the patient repeat nonsense activities, such as turning 
around a house, playing with buttons, bandaging with a rope, 
etc.? Or other repetitive activities? 
11. Sleep disorders 
Does the patient wake others up at night? Get up early in the 
morning? Frequent snoring during the day? 
12. Eating disorders  
Does the patient's weight decrease or increase? Do you like 
the taste of food changes? 
13. Total score 

44 
 
Appendix 5 Hamilton Anxiety scale (HAMA) [42] 
 
Asymptomatic 0  
Minor 1 
Moderate 2 
Heavier 3 
Serious 4 
1. Anxious mood 
□0  
□1 
□2 
□3 
□4 
2. nervous 
□0  
□1 
□2 
□3 
□4 
3. afraid 
□0  
□1 
□2 
□3 
□4 
4. insomnia 
□0  
□1 
□2 
□3 
□4 
5. memory, attention disorder 
□0  
□1 
□2 
□3 
□4 
6. depression mood 
□0  
□1 
□2 
□3 
□4 
7. somatic anxiety: the muscular system 
□0  
□1 
□2 
□3 
□4 
8. somatic anxiety: sensory system 
□0  
□1 
□2 
□3 
□4 
9. cardiovascular system symptoms 
□0  
□1 
□2 
□3 
□4 
10. respiratory symptoms 
□0  
□1 
□2 
□3 
□4 
11. gastrointestinal symptoms 
□0  
□1 
□2 
□3 
□4 
12. reproductive system symptoms 
□0  
□1 
□2 
□3 
□4 
13. autonomic nervous system symptoms □0  
□1 
□2 
□3 
□4 
14. performance at the time of the talks 
□0  
□1 
□2 
□3 
□4 
15. Total points  
Score 
 
 
 
 

45 
 
Appendix 6 Hamilton depression scale (HAMD) [45] 
Item 
0 
1 
2 
3 
4 
score 
1. Depressed Mood 
 
No 
Only tell when 
asked 
Spontaneously 
expressed in 
conversation 
The patient express 
this emotion from 
expressions, 
gestures, sounds or 
crying without 
words. 
The patient's speech 
and non-verbal 
expressions 
(expressions, 
movements) are 
almost completely 
expressed as such 
emotions. 
|____| 
2. Guilt 
No 
Blame yourself 
and feel that you 
have been 
hurting others 
Think that you 
have committed a 
crime, or think 
twice about past 
mistakes and 
mistakes 
Think that the 
current illness is a 
punishment for 
yourself, or that 
there is a crime of 
sin 
Evil wants to be 
accused or 
threatening 
|____| 
3. Suicide 
 
No 
He feels that 
living is 
meaningless. 
Wishes he were 
dead, Often think 
of things related to 
death 
Negative 
concept(Suicidal 
ideas) 
 
Serious suicidal 
behavior 
|____| 
4. Difficulty in 
falling asleep 
 
No 
Sometimes it is 
difficult to fall 
asleep, and still 
can't sleep for 
half an hour after 
going to bed. 
Difficulty in falling 
asleep every night 
/ 
/ 
|____| 
5. Sleep is not deep 
No 
Shallow sleep, 
nightmare 
Woke up in the 
middle of the night 
(before 12 o'clock) 
(not including the 
toilet) 
/ 
/ 
|____| 
6. Wake up early 
No 
Wake up early, 
wake up 1 hour 
earlier than 
usual, but can 
fall asleep again. 
Can't fall asleep 
after waking up 
early. 
/ 
/ 
|____| 
7. Work and Interests 
 
Normal 
Only tell when 
asked 
Spontaneously, 
directly or 
indirectly, lose 
interest in 
activities, work, or 
learning, such as 
being slouched, 
hesitant, unable to 
persist or force 
himself to work or 
activity 
Reduced activity 
time or reduced 
effectiveness, 
inpatients who 
participate in ward 
labor or 
entertainment for 
less than 3 hours a 
day. 
Stop working 
because of the 
current illness, the 
residents can not 
complete the daily 
affairs of the ward 
without participating 
in any activities or 
without the help of 
others. 
|____| 
8. 
Retardation: 
Slowness of thought, 
speech, and activity 
Apathy, Stupor 
No 
Slight retardation 
at interview 
Obvious 
retardation at 
interview 
Interview difficult 
Complete stupor 
|____| 
9. Agitation 
No 
feel a little 
uneasy when 
checking 
Obviously uneasy 
or small 
movements 
Can't sit still, stand 
up in the inspection 
Pick up hands, bite 
fingers, pull hair, bite 
lips 
|____| 
10. Mental anxiety 
No 
Only tell when 
asked 
Spontaneously 
expressed in 
conversation 
Expressions and 
words reveal 
obvious worries 
Fears 
 
|____| 

46 
 
11. Somatic anxiety: 
dry mouth, bloating, 
diarrhea, snoring, 
abdominal cramps, 
palpitations, 
headaches, excessive 
ventilation and sighs, 
as well as frequent 
urination and 
sweating. 
No 
Mild 
Moderate, with a 
positive appeal 
symptom 
Severe, the above 
symptoms are 
serious, affecting 
life, need to be 
treated 
Seriously affecting 
life and activities 
|____| 
12. 
Gastrointestinal 
symptoms 
 
Normal 
Loss of appetite, 
but eat without 
the 
encouragement 
of others 
Eating 
requires 
someone to urge or 
request 
, or need to apply 
laxatives or 
digestives 
/ 
/ 
|____| 
13. Systemic 
symptoms 
Normal 
Four limbs, 
heavy back and 
neck, back pain, 
headache, 
muscle pain, 
general 
weakness 
Significant 
symptoms 
/ 
/ 
|____| 
14. Sexual 
symptoms: loss of 
libido, menstrual 
disorders, etc. 
Normal 
Mild 
Severe 
Not sure or not 
suitable for the test, 
not included in the 
total score 
 
|____| 
15. Hypochondriasis 
No 
Self-absorption 
(bodily) 
Preoccupation with 
health 
Querulous attitude 
Hypochondriacal 
delusions 
|____| 
16. Loss of Weight 
 
No 
Weight loss of 1 
kg or more in a 
week 
Weight loss of 
more than 2 kg in a 
week 
 
 
|____| 
17. Self-awareness 
Yes 
I know that I am 
sick, but I am 
poor at food, 
environment, 
work, etc. 
Completely deny 
that there is a 
disease 
 
 
|____| 
18 Total score 
(Note: scores ≤ 17 can be selected) 
| 
|____| 
 
 
 
 

4 7  
 
A p pe n di x  7 m o difie d  H ac hi ns ki  isc he mic sc ale( m-HI S)  [ 5 0] 
 
Feat ure  
Yes  
N o  
1   
A br u pt  o nset  
2  
0  
2   
Ste p wise  d eteri orati o n  
1  
0  
3  
S o matic  c o m plai nt 
1  
0  
4  
E m oti o n al  i n c o nti n e n ce 
1  
0  
5  
Hist or y  or  prese n ce  of  h y p er te nsi o n 
1  
0  
6  
Hist or y  of  str o k es 
2  
0  
7   
F o cal  n e ur ol o gical  s y m pt o ms 
2  
0  
8              
F o cal  n e ur ol o gical  si g ns 
2  
0  
9  
T otal  (atte nti o n：sc ore ≥4 ca n  be  c h ose n) 
| _ _ _ _|.| _ _ _ _| 

48 
 
Appendix 8 WHO-UCLA Verbal Learning Test [51] 
Administration: I will give you some words of the object below. After I finish reading, please tell me the words you remember. You 
can say what you remember, not in order. Then I will give you a few more times. Please tell me every word you remember, including 
the words you have said before, and see how much you can remember at the end, ok? 
The examiner clearly reads out at the speed of 1 second per word, records with Arabic numerals 1, 2, 3, etc., and records the number of 
insertions and the number of repetitions. Insertion of the same item twice or more is counted as one insertion, and each repetition is 
counted as one repetition, but the repetition of the inserted item is not counted as a repetition. Recall time every 2 minutes. 
If the test has been carried out in the past 3 months, the date of the record check (year/month/day) / / 0000/00/00 = not determined 
project 
1.1 first pass  
2.1 second pass  
3.1 third pass 
arm 
 
 
 
cat 
 
 
 
ax 
 
 
 
bed 
 
 
 
aircraft 
 
 
 
ear 
 
 
 
dog 
 
 
 
hammer 
 
 
 
chair 
 
 
 
car 
 
 
 
eye 
 
 
 
horse 
 
 
 
knife 
 
 
 
bell 
 
 
 
bicycle 
 
 
 
 
The correct number 
1.2       
2.2       
3.2       
Insert word record 
1.3        
2.3        
3.3        
Number of insertions 
1.4       
2.4       
3.4       
Repeat number 
1.5       
2.5       
3.5       
Memory strategy 
□1Yes □2No □1Yes □2No □1Yes □2No 
 
4 the correct number 
3 times correct total recall 
          (Abnormal reference value≤18) 
5 insert number 
3 times the total number of inserts 
            
6 repeat number 
Repeated recalls in 3 times 
            
7 Memory Strategy (According to 
object classification memory) 
□1Yes 
□2No 
Delayed Recall 
Administration: "Remember the words I have just read to you several times? Please remember as much as possible" (2 minutes of recall 
time. Record with 1, 2, 3 and other Arabic numerals, and record the number of insertions And the number of repetitions. The insertion 
of the same item multiple times is counted as one insertion, and each repetition is counted as one repetition, but the repetition of the 
inserted item is not counted as a repetition.)". 
7.2 
Correct number of recalls (reference value ≤ 6) 
Correct number of recalls (reference value ≤ 6) 
7.3 
Insert word record 
7.4 
Number of insertions 
Number of insertions 

49 
 
7.5 
Repeat number 
Repeat number 
7.6 
Memory strategy (memory according to object classification) □1 Yes □0 No 
 
Cued Recall 
Administration: The 15 words you have learned before can be divided into 5 categories. I will give you some tips below. Please 
continue to try to recall the words you have memorized. Record the picture "√". 
Item category 
8.1Record 
Body class 
□ arm 
□ ears 
□ eyes 
Animal 
□ cat 
□ dog 
□ horse 
Tools 
□ Axe 
□ hammer 
□knife 
Furniture 
□ bed 
□ chair 
□ clock 
Vehicle type 
□Airplane 
□ car 
□Bicycle 
Recognition 
Administration: I will read 30 words below, among which I have just let you remember, some are added, please tell me which ones I let 
you remember and which ones are added. (Non-shadows are remembered - target words; shadows are interference items). For all 
words, just answer "yes" in the cell that is "yes" at the back, as long as the answer to "no" is snoring in the cell "No". 
 
Yes 
No 
 
Yes 
No 
mirror 
 
 
lips 
 
 
hammer 
 
 
tree 
 
 
knife 
 
 
arm 
 
 
candle 
 
 
nose 
 
 
motorcycle 
 
 
sun 
 
 
ax 
 
 
truck 
 
 
bell 
 
 
eye 
 
 
chair 
 
 
fish 
 
 
aircraft 
 
 
ear 
 
 
tortoise 
 
 
bicycle 
 
 
horse 
 
 
snake 
 
 
thigh 
 
 
Bench 
 
 
dog 
 
 
bus 
 
 
table 
 
 
bed 
 
 
Cat 
 
 
car 
 
 
 
8.2 
Measurable number 
       
9.1 
The number of non-shadowed "yes" 
       
9.2 
The number of "yes" in the shadow 
       
9.3 
9.1 minus 9.2 
       

50 
 
Appendix 9 Rey-Osterrieth Complex Figure Test [52] 
 
Administration: Please draw an identical picture according to the picture. 
Scoring: Consider each of the 18 units separately (the highest score is 36 points). Appraise accuracy of each unit and relative position 
within the whole of the design. For each unit count as follows: 
Correct 
Placed properly 
2 points 
Placed poorly 
1 points 
Distorted or 
incomplete but 
recognizable 
Placed properly 
1 points 
Placed poorly 
0.5 points 
Absent or not 
recognizable 
 
0 points 
1. 
Cross upper left corner, outside of rectangle 
□2   □1   □0.5   □0 
2. 
Large rectangle 
□2   □1   □0.5   □0 
3. 
Diagonal cross  
□2   □1   □0.5   □0 
4. 
Horizontal midline of (2) 
□2   □1   □0.5   □0 
5. 
Vertical midline 
□2   □1   □0.5   □0 

51 
 
6. 
Small rectangle, within (2) to the left 
□2   □1   □0.5   □0 
7. 
Small segment above (6) 
□2   □1   □0.5   □0 
8. 
Four parallel lines within (2), upper left 
□2   □1   □0.5   □0 
9. 
Triangle above (2), upper right  
□2   □1   □0.5   □0 
10. 
Small vertical line within (2), below (9) 
□2   □1   □0.5   □0 
11. 
Circle with three dots, within (2) 
□2   □1   □0.5   □0 
12. 
Five parallel lines within (2) and crossing (3), 
lower right 
□2   □1   □0.5   □0 
13. 
Sides of triangle attached to (2) on right 
□2   □1   □0.5   □0 
14. 
Diamond attached to (13) 
□2   □1   □0.5   □0 
15. 
Vertical line within triangle (13), parallel to the 
right side of (2) 
□2   □1   □0.5   □0 
16. 
Horizontal line within (13), continuing (4) to the 
right 
□2   □1   □0.5   □0 
17. 
Cross attached to (5), below (2) 
□2   □1   □0.5   □0 
18. 
Square attached to (2), lower left 
□2   □1   □0.5   □0 
19. Total Score□
□ 
 
Recall 
Administration: Do you remember the picture I asked you to draw? Please remember and draw the picture as much as possible. If you 
can only recall some of the graphics, but can't determine their location, feel free to draw. 

52 
 
Correct 
Placed properly 
2 points 
Placed poorly 
1 points 
Distorted or 
incomplete but 
recognizable 
Placed properly 
1 points 
Placed poorly 
0.5 points 
Absent or not 
recognizable 
 
0 points 
1. 
Cross upper left corner, outside of rectangle 
□2   □1   □0.5   □0 
2. 
Large rectangle 
□2   □1   □0.5   □0 
3. 
Diagonal cross  
□2   □1   □0.5   □0 
4. 
Horizontal midline of (2) 
□2   □1   □0.5   □0 
5. 
Vertical midline 
□2   □1   □0.5   □0 
6. 
Small rectangle, within (2) to the left 
□2   □1   □0.5   □0 
7. 
Small segment above (6) 
□2   □1   □0.5   □0 
8. 
Four parallel lines within (2), upper left 
□2   □1   □0.5   □0 
9. 
Triangle above (2), upper right  
□2   □1   □0.5   □0 
10. 
Small vertical line within (2), below (9) 
□2   □1   □0.5   □0 
11. 
Circle with three dots, within (2) 
□2   □1   □0.5   □0 
12. 
Five parallel lines within (2) and crossing (3), 
lower right 
□2   □1   □0.5   □0 
13. 
Sides of triangle attached to (2) on right 
□2   □1   □0.5   □0 

53 
 
14. 
Diamond attached to (13) 
□2   □1   □0.5   □0 
15. 
Vertical line within triangle (13), parallel to the 
right side of (2) 
□2   □1   □0.5   □0 
16. 
Horizontal line within (13), continuing (4) to the 
right 
□2   □1   □0.5   □0 
17. 
Cross attached to (5), below (2) 
□2   □1   □0.5   □0 
18. 
Square attached to (2), lower left 
□2   □1   □0.5   □0 
19. Total Score□
□ 
 
 
 

54 
 
Appendix 10 Digit Span Test (DST) [55] 
Digit Span Forward 
Administration: "Now we have to do a simple test, please pay attention to listen to me to read some numbers, I repeat it after I finish 
reading." Read a string of numbers at a rate of one digit per second. Test 1 is done first, and the number string of the same serial 
number in test 2 is repeated. 
Scoring method: When both tests of the same length fail, and the test completes the highest score, the test ends. The highest score for 
success before the end of the record is the length of the digital breadth (any test in both tests of the same item is correct). 
 
 
Test 1 
 
Test 2 
3 
5-8-2 
3 
6-9-4 
4 
6-4-3-9 
4 
7-2-8-6 
5 
4-2-7-3-1 
5 
7-5-8-3-6 
6 
6-1-9-4-7-3 
6 
3-9-2-4-8-7 
7 
5-9-1-7-4-2-8 
7 
4-1-7-9-3-8-6 
8 
5-8-1-9-2-6-4-7 
8 
3-8-2-9-5-1-7-4 
9 
2-7-5-8-6-2-5-8-4 
9 
7-1-3-9-4-2-5-6-8 
10 
5-2-7-4-9-1-3-7-4-6 
10 
4-7-2-5-9-1-6-2-5-3 
Digit Span Forward length                
 
Digit Span Backward 
Administration: "I will say some numbers below, please listen carefully. After I finish reading, you repeat it again. I said 7-1-9, what 
should you say?" If the answer is correct, he said: "Here. and also". So from the second 3 digits of the test 1, if the answer is wrong or 
do not understand the practice, tell the correct answer should be 9-1-7, and another example, said: "Remember, to back." Another 
example is 3-4-8. If this success, it starts with 3 digits. If it fails again, it will return to the 2-digit test 1; if the subject passes the 
example, but the 3 digits are tested twice If it fails, it will return to 2 digits and the test will end. 
Scoring method: When both tests fail, and the test completes the highest score, the test ends. The highest score for success is the length 
of the inverse digital breadth (any test in both tests of the same item can be successful). 
 
Test 1 
 
Test 2 
2 
2-4 
2 
5-8 
3 
6-2-9 
3 
4-1-5 
4 
3-2-7-9 
4 
4-9-6-8 
5 
1-5-2-8-6 
5 
6-1-8-4-3 
6 
5-3-9-4-1-8 
6 
7-2-4-8-5-6 
7 
8-1-2-9-3-6-5 
7 
4-7-3-9-1-2-8 
8 
9-4-3-7-6-2-5-8 
8 
7-2-8-1-9-6-5-3 
Digit Span Backward length              

55 
 
Appendix 11 Verbal Fluency Test (VFT) [57] 
Animal Fluency 
Administration: "Please tell as many animals as you know as soon as possible. The time is 1 minute. Are you ready? Start." Stop after 
one minute. 
Scoring method: Record the name of the animal that was spoken within one minute of the subject. Mythical animals such as dragons, 
phoenixes, and unicorns are also correct. The names spoken by the subjects can be grouped by animal species (reference: mammals, 
birds, fish, insects, etc.), in tandem to the names of the animals listed in each subcategory, from the second of each subcategory. The 
animals start counting until they switch to another sub-category, and the sub-categories of each sub-category add the total number of 
series in this test. The number of conversions, that is, the number of times to switch between groups. Please note that duplicate, 
incorrect names, nicknames are not counted in the correct number, but are counted in the concatenation and conversion numbers. 
 
 
 
 
 
 
 
Vegetable fluency 
Administration: "Please tell as many fruits as you can, as soon as possible. The time is 1 minute. Are you ready? Start." Stop after one 
minute. 
Grading method: Record the name of the fruit spoken by the subject within one minute. The recording method is the same as above. 
 
 
 
 
 
 
Category Switching 
Administration: "Please tell as many animals and fruits as you can as fast as possible. The time is 1 minute. Are you ready? Start." Stop 
after one minute. 
Grading method: Record the number of item names spoken by the subject within one minute. The recording method is the same as 
above. Tandem is the name of the item listed consecutively in each sub-category, counting from the second item in each sub-category 
until it is converted to another sub-category, and the sub-series of each sub-category is added to obtain the total number of series in this 
test. . The number of conversions, that is, the number of times to switch between groups. Please note that duplicate, incorrect names, 
nicknames are not counted in the correct number, but are counted in the concatenation and conversion numbers. 
1. article_______________________________ 
2. the correct number _ _ 
3. the number of repetitions _ _ 
4. the number of errors _ _ 
5. the total number of series _ _ 
6. the number of conversions ＿ ＿ 
1. animal_______________________________ 
2. the correct number _ _ 
3. the number of repetitions _ _ 
4. the number of errors ＿ ＿ 
1. goods_______________________________ 
2. the correct number _ _ 
3. the number of repetitions _ _ 
4. the number of errors _ _ 

56 
 
Appendix 12 Trail Making Test (TMT) [58] 
Part A 
Practice test 
Administration: The following are some circles with numbers in the circle. I would like to ask you to connect in the order of 1-2-3... 
with a pen. Note: Do not leave the pen tip away from the paper and the line drawn must pass through the graphic. If I am wrong, I will 
point out that you need to go back and paint again. Let us give it a try now. The sooner you paint, the better. Are you ready? Start! 
Note: The following is a practice test, not scored. Correct every time you make a mistake, and tell the correct connection method, while 
actively encouraging. 
 
 
 

57 
 
Actual test 
Administration: There is a similar circle diagram here, please connect it again as above. Please note that the faster you draw, the better. 
Do not leave the pen tip and the lines drawn must pass through the graphic. Start here (pointing to the starting point) until here 
(pointing to the end). Ready? Start. (time) 
 
 
 
 
 
1.1 All digital completion time     (0-150) seconds (if 150 seconds is not completed, record 150) 
1.2 Number of errors      (0-25; 88=Not applicable) 
1.3 Correct number       (0-25; 88=Not applicable) 
End 
Begin 

58 
 
Part B 
Administration: The following are 1-13 white circle numbers and 1-12 black circle numbers. They are also scattered. Please connect 
them in order, i.e. white circle 1 - black circle 1 - white circle 2 - black circle 2... Note: Do not leave the pen tip away from the paper 
and the line drawn must pass through the graphic. If I am wrong, I will point out that you need to go back and paint again. Let us give it 
a try now. The sooner you paint, the better. Are you ready? Start! 
Practice test 
 
 
End  
Begin  

59 
 
Actual test 
 
 
2.1 All digital completion time       (0-300) seconds (if 300 seconds is not completed, record 300) 
2.2 Number Sequence Error Number       (0-25; 88=Not applicable) 
2.3 Correct number of lines       (0-24; 88=Not applicable) 
Begin  
End  

60 
 
Appendix 13 Boston Naming Test (BNT) [59] 
Administration: "I will show you some pictures now, please tell me what these pictures are." 
If the tester fails to answer the answer, he is prompted: For example, "This is (plant), is there another name?" 
If you still can't answer, then three answers are given in order to let the tester choose. Remember to record every answer of the testier, 
whether correct or not (only calculate the score of spontaneous naming: correct = 1, answer = 0). 
Picture 
Answer 
(yes = 1; 
wrong = 
0) 
If wrong, 
specific 
record 
If the answer 
is wrong, 
prompt 
Answer 
(yes = 1; 
wrong = 0) 
If wrong, 
specific 
record 
If the prompt still answers the error, please 
select (circle the specific choice) 
1 
2. Tree 
 
plant 
  
Peach blossom Tree 
Fireworks 
2 
3. Pen 
 
Used for 
writing 
  
straw 
Original ball 
pen 
pen 
3 
6. Scissors 
 
tool 
  
Scissors 
clamp 
Spoon 
4 
8. Flowers 
 
plant 
  
Vegetables 
straw hat 
flower 
5 
9. Saw 
 
Woodworkin
g equipment 
  
Machine gun 
Saw 
Knife 
6 
12. Broom 
 
Used for 
cleaning 
  
Mop 
Writing 
brush 
Broom 
7 
*14. 
Mushroom 
 
food 
  
Mushroom 
Cauliflower umbrella 
8 
15. Hangers 
 
Inside the 
wardrobe 
  
roof 
hanger 
hook 
9 
16. Wheelchair  
Patient use 
  
Executive 
chair 
trolley 
wheelchair 
10 
17. Camel 
 
animal 
  
camel 
mountain 
Cattle 
11 
21 racquet 
 
Sporting 
goods 
  
Ping pong 
paddle 
racquet 
mirror 
12 
22. Snail 
 
animal 
  
snails  
Squid 
scallop 
13 
24. Seahorse 
 
Marine life 
  
hook 
abalone 
Seahorse 
14 
25. Darts 
 
Used to 
throw 
  
Target 
Darts 
rocket 
15 
30. Harmonica  
Musical 
instrument 
  
Harmonica 
Air 
conditioner 
box 
16 
31. Rhinoceros  
animal 
  
Canned knife 
hippo 
rhinoceros 
17 
33. Igloo 
 
Used to live 
  
Ice house 
Grass house grave 
18 
36. Cactus 
 
plant 
  
Iron tree 
cactus 
cross 
19 
37 escalator 
 
Use up and 
down 
  
Sliced bread  
Slide 
escalator 
20 
38. Harp 
 
Musical 
instrument 
  
harp 
floor lamp 
piano 
21 
42. Stethoscope  
Doctor 
  
Earphone 
Stethoscope sphygmomano
meter 
22 
43. Pyramid 
 
In Egypt 
  
Zongzi 
Sphinx 
pyramid 
23 
46. Funnel 
 
Pour water 
  
Funnel 
Ice cream 
cones 
Pump 
24 
47. Accordion 
 
Musical 
instrument 
  
Harmonica 
accordion 
Blinds 
25 
50. Compass 
 
painting 
  
Cotton pliers 
ruler 
Compasses 
26 
52. Tripod 
 
For 
photography 
  
tripod  
Mechanical 
arm 
easel 
27 
54. tongs 
 
Appliance 
  
Spatula 
tongs 
canoe 
28 
57. Flower 
shed/ trellis 
 
Park has 
  
Flower shed/ 
trellis 
trash can  
network 
29 
59. Protractor 
 
stationery 
  
Pound scale 
Triangle ruler Protractor 
30 
60. Abacus 
 
Counting 
  
Calculator 
Abacus 
Curtain 
Total 
31 
32 
 
33 
 
 
 

61 
 
Appendix 14 Activities of daily living (ADL) [60] 
Ask the insider to rate the following functions of the patient based on the information provided (assessed according to the level of 
intelligence). 
Rating 
Instrumental Daily Living Ability Scale (LADH) Scoring Project 
1 
Ability to use the phone 
 
□1、take the initiative to operate the phone - check the number, dial, etc. 
 
□2、can dial a few familiar numbers 
 
□3、can answer the phone but not dial the phone 
 
□4、cannot use the telephone 
2 
Shopping 
 
□1、independently handle all shopping needs 
 
□2、a small amount of shopping independently 
 
□3、need to accompany on any purchase 
 
□4、completely unable to shopping 
3 
Cooking 
 
□1、independently plan, prepare and make the right amount of meal 
 
□2、if the raw materials can be prepared to prepare enough meal 
 
□3、heating, serving or cooking, or cooking but not keeping the right amount 
 
□4、Need to prepare the meal and do it well 
4 
Hosting housework 
 
□1、independently host housework or occasionally need help (such as heavy work needs family 
help) 
 
□2、do daily light physical housework such as washing dishes, making beds 
 
□3、do daily light physical housework but cannot maintain an acceptable level of cleanliness 
 
□4、all housework needs help 
 
□5、do not participate in any housework 
5 
Washing 
 
□1、can complete a personal bath 
 
□2、wash small pieces of clothing - wash socks, etc.  

62 
 
 
□3、all washing must be done by others 
6 
Transportation 
 
□1、independent public transport or driving a car 
 
□2、travel by taxi, but no bus 
 
□3、take the bus when accompanied by others 
 
□4、can only travel by taxi or car with the help of others 
 
□5、no travel at all 
7 
Responsibility for the medical care 
 
□1、can take medicine seriously according to the correct time and dose 
 
□2、if you prepare for each dose, you can take medicine 
 
□3、you can't prepare your own medicine 
8 
Financial ability 
 
□1、independently handle finance (budget, write checks, pay rent, bills, go to the bank), collect and 
maintain income channels 
 
□2、manage daily shopping, but need help in banking affairs and big shopping, etc. 
 
□3、can't handle finance 
9 IADL total score               
Rating 
Somatic Self-care Ability Scale (PSUS) Scoring Project 
10 
Bowel and bladder function at the toilet, 
 
□1、in the bathroom can be completely self-care, no incontinence 
 
□2、need to be reminded of self-cleaning, or need help, or a small number of accidents (at least once 
a week) 
 
□3、dirty or wet during sleep, more than once a week 
 
□4、dirty or wet when awake, more than once a week 
 
□5、incontinence 
11 
Eating 
 
□1、no need to help when eating 
 
□2、eating a small amount of time to eat and/or need to prepare special food, or need help after 
cleaning after meals 
 
□3、need moderate help for meal, and it is not neat 

63 
 
 
□4、all meals need a lot of help 
 
□5、can't eat at all, and resist feeding by others 
12 
Dressing 
 
□1、wear clothes, undress, and choose clothes from your wardrobe 
 
□2、wearing clothes and undressing, need a small amount of help 
 
□3、need moderate help in dressing and choosing clothes 
 
□4、need more help in wearing clothes, but with the help of others 
 
□5、can't wear clothes at all, and it is against the help of others 
13 
Carding (tidy, hair, nails, hands, face, clothes) 
 
□1、always dressed neatly, properly decorated, no need to help 
 
□2、can properly decorate themselves, occasionally need a small amount of help, such as repairing 
beard 
 
□3、need moderate or reasonable help or guidance in combing 
 
□4、all combing matters need help, but can be kept neat after others help 
 
□5、actively oppose the efforts of others to help sort out 
14 
Walking 
 
□1、walk to the venue or urban area 
 
□2、Walk in the residential area or walk near a street 
 
□3、walking needs help (choose 1) a() cane, b() walker, c() wheelchair 
 
    □1-In and out without help 
 
    □2-In and out need help 
 
□4、don’t need to sit in a chair or a wheelchair, but you can’t push it yourself without help 
 
□5、more than half of the time bedridden 
15 
Bathing 
 
□1、take a bath (bath, shower, bath), no need to help 
 
□2、need help when getting in and out of the tub 
 
□3、only wash your face and hands, cannot wash other parts of the body 

64 
 
 
□4、cannot take a bath, but with others to bathe him 
 
□5、cannot take a bath, and resist efforts to keep him clean 
16 BADL total score         
17 ADL total score (IADL+BADL)             
The total score below 16 is completely normal, and greater than 16 points have different degrees of functional decline, up to 64 points. 
The single item is divided into 1 normal, 2 to 4 is divided into functional decline, where there are 2 or more than ≥ 3 points, or the 
total score is ≥ 22 points, there are obvious obstacles to function.

65 
 
Appendix 15 Clinical Dementia Rating (CDR) [61] 
This is a semi-structured interview. Please ask all of these questions. Ask any additional questions necessary to 
determine the subject’s CDR. Please note information from the additional questions. 
Memory Questions for Informant: 
1. 
Does he/she have a problem with his/her memory or thinking? 
 
1a. If yes, is this a consistent problem (as opposed to inconsistent)? 
□Yes 
□Yes 
□No 
□No 
2. 
 Can he/she recall recent events? 
□Yes 
□No 
3. 
Can he/she remember a short list of items (shopping)? 
□Usually 
□Sometimes 
□Rarely 
4. 
Has there been some decline in memory during the past year? 
□Usually 
□Sometimes 
□Rarely 
5. 
Is his/her memory impaired to such a degree that it would have 
interfered with his/her activities of daily life a few years ago (or 
pre-retirement activities)? (collateral sources opinion) 
□Yes 
□No 
6. 
Does he/she completely forget a major event (e.g., trip, party, 
family wedding) within a few weeks of the event? 
□Usually 
□Sometimes 
□Rarely 
7. 
Does he/she forget pertinent details of the major event? 
□Usually
□Sometimes
□Rarely
8. 
Does he/she completely forget important information of the distant 
past (e.g., birthdate, wedding date, and place of employment)? 
□Usually 
□Sometimes 
□Rarely 
9. 
Tell me about some recent event in his/her life that he/she should remember. (For later testing, obtain details such as location 
of the event, time of day, participants, how long the event was, when it ended and how the subject or other participants got 
there). 
Within 1 week:  
 
 
 
 
Within 1 month: 
 
 
 
 
10. When was he/she born? 
 
11. Where was he/she born? 
 
12. What was the last school he/she attended? 
     Name                                                                                              
     Place                                                                                               
     Grade                                                                                              
13. What was his/her main occupation/job (or spouse’s job if subject was not employed)? 
14. What was his/her last major job (or spouse’s job if subject was not employed)? 
15. When did he/she (or spouse) retire and why? 

66 
 
Orientation Questions for Informant: 
 
How often does he/she know of the exact： 
1. Date of the Month? 
□Usually 
□Sometimes 
□Rarely 
□Don’t know 
2. Month? 
□Usually 
□Sometimes 
□Rarely 
□Don’t know 
3. 
Year? 
 
 
 
□Usually 
□Sometimes 
□Rarely 
□Don’t know 
4. 
Day of the Week? 
 
 
□Usually 
□Sometimes 
□Rarely 
□Don’t know 
5. Does he/she have difficulty with time relationships (when events happened in relation to each other)? 
□Usually 
□Sometimes 
□Rarely 
□Don’t know 
6. Can he/she find his/her way about familiar streets? 
□Usually 
□Sometimes 
□Rarely 
□Don’t know 
7. How often does he/she know how to get from one place to another outside his/her neighborhood? 
□Usually 
□Sometimes 
□Rarely 
□Don’t know 
8. How often can he/she find his/her way about indoors? 
□Usually 
□Sometimes 
□Rarely 
□Don’t know 

67 
 
Judgment and Problem Solving Questions for Informant: 
1. 
In general, if you had to rate his/her abilities to solve problems at the present time, would you consider them: As good as they 
have ever been 
□Good, but not as good as before 
 
□Fair 
 
□Poor 
 
□No ability at all 
 
2. 
Rate his/her ability to cope with small sums of money (e.g., make change, leave a small tip):  
         □No loss 
 
□Some loss 
 
□Severe loss 
 
3. Rate his/her ability to handle complicated financial or business transactions (e.g., balance check-book, pay bills): 
 
□No loss 
 
□Some loss 
 
□Severe loss 
 
4. Can he/she handle a household emergency (e.g., plumbing leak, small fire)? 
 
□As well as before 
 
□Worse than before because of trouble thinking 
 
□Worse than before, another reason (why) 
  
 
 
 
 
 
5. Can he/she understand situations or explanations? 
 

68 
 
□Usually 
 □Sometimes 
 □Rarely 
 □ Don’t know 
 
6. Does he/she behave* appropriately [i.e., in his/her usual (premorbid) manner] in social situations and interactions with 
other people? 
 
□Usually 
 □Sometimes 
 □Rarely 
  □Don’t know 
 
*This item rates behavior, not appearance. 

69 
 
Community Affairs Questions for Informant: Occupational 
1. Is the subject still working?                                                     □Yes  □No □N/A 
If not applicable, proceed to item 4  
If yes, proceed to item 3 
If no, proceed to item 2 
2. 
Did memory or thinking problems contribute to the subject’s decision 
to retire?  (Question 4 is next) 
 □Yes  □No □D/K 
3. 
Does the subject have significant difficulty in his/her job because of problems with memory or 
thinking? 
           □Rarely or Never 
□Sometimes 
□Usually 
□Don’t know 
Social 
4. 
Did he/she ever drive a car? 
 □Yes  □No 
 
5. 
Does the subject drive a car now? 
 □Yes  □No 
 
6. 
If no, is this because of memory or thinking problems? 
 □Yes  □No 
 
7. 
If he/she is still driving, are there problems or risks because of poor thinking? 
 □Yes  □No 
 
8. 
Is he/she able to independently shop for needs? 
□Rarely or Never 
□Sometimes 
□Usually 
□Don’t know 
(Needs to be 
accompanied on any 
shopping trip) 
(Shops for limited 
number of items; 
buys duplicate items 
or forgets needed 
items) 
 
 
9. Is he/she able to independently carry out activities outside the home? 
□Rarely or Never 
□Sometimes 
□Usually 
□Don’t know 
(Generally unable to 
perform activities 
without help) 
(Limited and/or 
routine, e.g.,  
superficial  
participation in  
church or meetings; 
trips to beauty parlor) 
(Meaningful 
participation in 
activities, e.g., 
voting) 
10.Is he/she taken to social functions outside a family home? 
□Yes □No 
If no, why not?    
 
 
 
11. Would a casual observer of the subject’s behavior think the subject was ill? 
□Yes 
□No  
12. If in nursing home, does he/she participate well in social functions (thinking)? 
□Yes 
□No 
IMPORTANT: 
Is there enough information available to rate the subject’s level of impairment in community affairs? 

70 
 
□Yes     □No 
 If not, please probe further. 
Community Affairs: Such as going to church, visiting with friends or family, political activities, professional organizations 
such as bar association, other professional groups, social clubs, service organizations, educational programs. 
               
 
*Please add notes if needed to clarify subject’s level of functioning in this area. 

71 
 
Home and Hobbies Questions for Informant: 
 
1a. What changes have occurred in his/her abilities to perform household chores?     
 
 
 
1b. What can he/she still do well? 
 
 
2a. What changes have occurred in his/her abilities to perform hobbies? 
 
 
2b. What can he/she still do well? 
 
 
3. If in nursing home, what can he/she no longer do well (H and H)? 
 
 
4. Everyday Activities (Blessed):  
                                          □No loss     □severe      □loss 
• 
Ability to perform household tasks            0             0.5          1 
Please describe:     
 
 
5 
Is he/she able to perform household chores at the level of: (Pick one Informant does not need to be asked directly). 
 
□No meaningful function. 
(Performs simple activities, such as making a bed, only with much supervision) 
 
□Functions in limited activities only. 
(With some supervision, washes dishes with acceptable cleanliness; sets table) 
 
□Functions independently in some activities. 
(Operates appliances, such as a vacuum cleaner; prepares simple meals) 
 
□Functions in usual activities but not at usual level.  
 
□Normal function in usual activities. 
      IMPORTANT: 
Is there enough information available to rate the subject’s level of impairment in HOME & HOBBIES? 
 
□Yes 
   □No 
 
      If not, please probe further. 
 
Homemaking Tasks: Such as cooking, laundry, cleaning, grocery shopping, taking out garbage, yard work, simple care 
maintenance, and basic home repair. 
 
Hobbies: Sewing, painting, handicrafts, reading, entertaining, photography, gardening, going to theater or symphony, 
woodworking, participation in sports. 
 

72 
 
Personal Care Questions for Informant: 
 
*What is your estimate of his/her mental ability in the following areas? 
*A box-score of 1 can be considered if the subject’s personal care is impaired from a previous level, even if they do not receive prompting. 
 
Memory Questions for Subject: 
1. Do you have problems with memory or thinking? 
□ Yes 
□ No 
2. A few moments ago your (spouse, etc.) told me a few recent experiences you had. Will you tell me something about those?  
(Prompt for details, if needed such as location of the event, time of day, participants, how long the event was, when it ended and 
how the subject or other participants got there). 
Within 1 week 
                   
                                             1.0 – Largely correct 
                   
                                              0.5 – Partly correct 
                   
                                          0.0 – Largely incorrect 
Within 1 month 
                   
                                             1.0 – Largely correct 
                   
                                              0.5 – Partly correct 
                   
                                          0.0 – Largely incorrect 
3. I will give you a name and address to remember for a few minutes. Repeat this name and address after me: (Repeat until the phrase 
is correctly repeated or to a maximum of three trials). 
 
Elements 
1 
2 
3 
4 
5 
John 
Brown, 
42 
Market Street, 
Chicago 
John 
Brown, 
42 
Market Street, 
Chicago 
John 
Brown, 
42 
Market Street, 
Chicago 
 
(Underline elements repeated correctly in each trial). 
4. When were you born?  
                                     
 
5. Where were you born? 
  
 
6. What was the last school you attended? 
Name 
 
Place 
 
Grade 
                                                                               
 
A. Dressing (Blessed) 
Unaided 
Occasionally 
misplaced buttons, 
etc. 
Wrong 
sequence 
commonly 
forgotten 
items 
Unable to dress 
0 
1 
2 
3 
 
B. 
Washing, grooming 
Unaided 
Needs 
Prompting 
Sometimes 
needs help 
Always or nearly 
always needs 
0 
1 
2 
3 
 
C. 
Eating habits 
Cleanly 
proper utensils 
Messily; 
spoon 
Simple 
solids 
Has to be fed 
completely 
0 
1 
2 
3 
 
D. Sphincter control 
(Blessed) 
Normal complete 
control 
Occasionally 
wets bed 
 
Frequently 
wets bed 
Doubly 
incontinent 
 
0 
1 
2 
3 

73 
 
7. What was your main occupation job (or spouse if not employed)?    
 
8. What was your last major job (or spouse if not employed)? 
  
 
9. When did you (or spouse) retire and why? 
 
 
 
10. Repeat the name and address I asked you to remember: 
 
Elements 
1 
2 
3 
4 
5 
John 
Brown, 
42 
Market Street, 
Chicago 
(Underline elements repeated correctly). 
Orientation Questions for Subject: 
 
Record the subject’s answer verbatim for each question 
 
1. What is the date today? 
□Correct 
□Incorrect 
 
 
 
2. What day of the week is it? 
□Correct 
□Incorrect 
 
 
 
3. What is the month? 
□Correct 
□Incorrect 
 
 
 
4. What is the year? 
□Correct 
□Incorrect 
 
 
 
5. What is the name of this place? 
□Correct 
□Incorrect 
 
 
 
6. What town or city are we in? 
□Correct 
□Incorrect 
 
 
 
7. What time is it? 
□Correct 
□Incorrect 
 
 
 
8. Does the subject know who the informant is (in your judgment)? 
□Correct 
□Incorrect 
 
 

74 
 
Judgment and Problem-Solving Questions for Subject: 
Instructions: If initial response by subject does not merit a grade 0, press the matter to identify the subject’s best understanding of the 
problem. Circle nearest response. 
Similarities: 
Example: “How are a pencil and pen alike? (Writing instruments) How are these things alike?” Subject’s Response 
1. turnip……cauliflower 
 
(0 = vegetables) 
(1 = edible foods, living things, can be cooked, etc.) 
(2 = answers not pertinent; differences; buy them) 
2. desk……bookcase 
                    (0 = furniture, office furniture; both hold books) 
                    (1 = wooden, legs) 
                    (2 = not pertinent, differences) 
Differences: 
Example: “What is the difference between sugar and vinegar? (sweet vs sour) What is the difference between these things?” 
3. lie……mistake_______________ 
                   (0 = one deliberate, one unintentional) 
                   (1 = one bad the other good – or explains only one) 
(2 
= anything else, similarities) 
 
4. river……canal_______________________ 
                   (0 = natural - artificial) 
                   (2 = anything else) 
Calculations: 
5. How many nickels in a dollar? 
        □Correct 
   □Incorrect 
 
6. How many quarters in $6.75? 
        □Correct 
   □Incorrect 
 
7. Subtract 3 from 20 and keep subtracting 3 from each new number all the way down. 
□Correct        □Incorrect 
Judgment: 
 
8. Upon arriving in a strange city, how would you locate a friend that you wished to see? 
 
                   (0 = try the telephone book, go to the courthouse for a directory; call a mutual friend)  
                   (1 = call the police, call operator (usually will not give address) 
(2 = no clear response) 
9. Subject’s assessment of disability and station in life and understanding of why he/she is present at the 
examination (may have covered, but rate here): 
 
□Good Insight 
□Partial Insight 
□Little Insight 

75 
 
Global CDR 
Use all the information you get to make the most appropriate judgment. Evaluate the six functional domains separately, fill in the scores 
in the corresponding “_”, and note that the scores are scored only when the decline in ability is caused by cognitive impairment. If the 
severity of the dysfunction is between two levels, it is assessed in principle at a severe level. Finally, the scores of the six functional 
domains are combined and the CDR overall score (global CDR) is summarized according to the following principles: 
1. Memory (M) is the main item and the other 5 items are secondary items; 
2. When M=0.5, CDR≠0, can only be =0.5 or 1; 
3. CDR=M (memory score): 
1) When at least 3 secondary items are the same as the memory score; 
2) When there are only 1 or 2 minor item scores = M, no more than 2 minor item scores are on either side of M; 
3) When the 3 minor items score on one side of the memory score and the other 2 minor item scores on the other side of the memory 
score; 
4) When at least 3 minor items are 0, if M=0.5, then CDR=0.5; 
5) When only one minor item is ≥ 0.5, if M = 0, CDR = 0. 
4. CDR≠M (memory score) 
1) When 3 or more secondary item scores are greater or less than M, CDR = most secondary item scores; 
2) When M=0.5, at least 3 minor items are ≥1, CDR=1; 
3) When M=0, 2 or more minor items ≥0.5, CDR=0.5; 
4) When M ≥ 1, CDR ≠ 0, at this time if most other minor items = 0, CDR = 0.5. 
5. The principle of proximity: when the above principles are not met, the score of the closest secondary item of CDR=M (eg: M and the 
score of a secondary item = 3, the score of 2 secondary items = 2, 2 The score of the secondary item is 1, CDR = 2). 
 
CDR domain total score (sum of boxes) 
Refers to the arithmetic sum of the scores of all six functional domains. 
 
CDR supplement 
According to the test situation, it is not included in the total score. 
 
Impairment 
None 0 
Questionable 0.5 
Mild 1 
Moderate 2 
Severe 3 
Memory 
        
No memory loss or 
Consistent slight 
Moderate memory loss; 
Severe memory loss; only 
Severe memory 
inconsistent 
forgetfulness 
forgetfulness; partial 
recollection of events; 
more marked for recent 
events; defect interferes 
highly learned material 
retained; new material 
only fragments 
remain 
"benign" forgetfulness 
with everyday activities 
rapidly lost 
Orientation 
         
Fully oriented 
Fully 
oriented 
except for slight 
difficulty with time 
relationships 
Moderate difficulty 
with time 
relationships; 
oriented for place at 
examination; may 
have geographic 
disorientation 
elsewhere 
Severe difficulty with 
time relationships; 
usually disoriented to 
time, often to place 
Oriented to person 
only 

76 
 
Judgment 
&Proble
m 
Solving 
         
Solves everyday 
problems 
& handles business 
& financial affairs 
well; 
judgment good in 
relation 
to past performance 
Slight 
impairment in 
solving 
problems, 
similarities, 
and differences 
Moderate 
difficulty in 
handling 
problems, 
similarities, and 
differences; 
social judgment 
usually 
maintained 
Severely impaired in 
handling problems, 
similarities, and 
differences; social 
judgment usually 
impaired 
Unable to make 
judgments or 
solve problems 
Community 
Affairs 
         
Independent 
function at usual 
level in job, 
shopping, 
volunteer and 
social groups 
Slight impairment in 
these activities 
Unable to function 
independently at these 
activities although 
may still be engaged 
in some; appears 
normal to casual 
inspection 
No pretense of independent function outside home 
Appears well enough 
to be taken to 
functions outside a 
family home 
Appears too ill to 
be taken to 
functions outside 
a family home 
Home and 
Hobbies 
         
Life at home, 
hobbies, and 
intellectual 
interests well 
maintained 
Life at home, 
hobbies, and 
intellectual interests 
slightly impaired 
Mild but definite 
impairment of 
function at home; 
more difficult chores 
abandoned; more 
complicated hobbies 
and interests 
abandoned 
Only simple chores 
preserved; very 
restricted interests, 
poorly maintained 
No significant 
function in 
home 
Personal 
Care 
          
Fully capable of self-care 
Needs prompting 
Requires assistance in 
dressing, hygiene, 
keeping of personal 
effects 
Requires much 
help with 
personal care; 
frequent 
incontinence 
               CDR sum of boxes 
              global CDR 
 
Score only as decline from previous usual level due to cognitive loss, not impairment due to other factors. 
 
 
 

77 
 
Appendix 16 Study glossary 
Abbreviations  
Abbreviated Term 
ADL 
Activity of daily living 
AA 
Alzheimer's association 
AD 
Alzheimer's disease 
APP 
Amyloid precursor protein gene  
APOE 
Apolipoprotein E 
ADAD 
Autosomal dominant Alzheimer’s disease 
AAO 
Average age at onset 
BOLD  
Blood oxygen level dependent 
BNT 
Boston naming test 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CDR 
Clinical dementia rating 
CCDS 
Consensus coding sequence 
CFAN 
The chinese familial alzheimer’s disease network 
COAST 
The cognition and aging study 
DLB 
Dementia with lewy bodies 
DSM-IV-R 
Diagnostic and Statistical Manual of Mental Disorders-IV-R 
DWI  
Diffusion weighted imaging 
DSB 
Digit span backward 
DSF 
Digit span forward 
DST 
Digit span test 
DIAN 
Dominantly inherited alzheimer network  
EOAD 
Early onset of Alzheimer's disease 
EDV 
End diastolic velocity 
EYO 
Estimated years to symptom onset 
FAD 
Familial Alzheimer's disease 
FDG 
[18F]Fluorodeoxy glucose 
FLAIR 
Fluid attenuated inversion recovery 
FTD 
Frontotemporal dementia 
GWAS 
Genome-wide association studies 
HAMA 
Hamilton anxiety scale 
HAMD 
Hamilton depression scale 
IHHT 
Intermittent hypoxic-hyperoxic training 
IMT 
Intima-media thickness 
LMMs 
Linear mixed models 
MRA 
Magnetic resonance angiography 
MRI 
Magnetic resonance imaging 
MCMC 
Markov chain Monte Carlo 
MTA 
Medial temporal lobe atrophy 
MeDi 
Mediterranean diet 
mRNA 
Messenger ribonucleic acid 
MCI 
Mild cognitive impairment 
MMSE 
Mini-mental state examination 

78 
 
M-HIS 
Modified hachinski ischemic scale 
MoCA 
Montreal cognitive assessment 
NINCDS-
ADRDA 
National institute of neurological and communicative disorders and stroke-AD and 
related disorders association criteria 
NIA 
National institute on aging 
NIA-AA 
National institute on aging-Alzheimer’s association 
NPI-Q 
Neuropsychiatric inventory questionaire 
NPT 
Non-pharmacological treatment 
PDD 
Parkinson's disease dementia 
PSV 
Peak systolic velocity 
PIB 
Pittsburgh compound B 
PCR 
Polymerase chain reaction 
PET 
Positron emission tomography  
PSEN1  
Presenilin 1  
PSEN2  
Presenilin 2 gene 
ROCFT 
Rey-Osterrieth complex figure test 
SNP 
Single nucleotide polymorphism 
SAD 
Sporadic Alzheimer's disease 
SUVR 
Standardized uptake value ratio 
T1WI 
T1weighted image 
T2WI 
T2weighted image 
TMT 
Trail making test 
WHO-UCLA 
AVLT 
The world health organization university of California-Los Angeles auditory verbal 
learning test 
VaD 
Vascular dementia 
VFT 
Verbal fluency test 
 
 
 

79 
 
Appendix 17 Participating unit and participant number 
A total of 8 digits: the number of each unit (3) + the number of the participant (5), with a horizontal bar in the middle. For example, 
the number of eighth participant in Xuanwu Hospital is 001-00008. The number of each participating unit is shown in the table below. 
NO. 
Unit name 
NO. 
Unit name 
001  
Xuanwu Hospital, Capital Medical University 
035 
Jiangxi Provincial People's Hospital 
002  
Beijing Tian Tan Hospital, Capital Medical 
University 
036  
Anshanshi Changda the Hospital 
003  
Beijing Chao-Yang Hospital, Capital Medical 
University 
037  
Affiliated Zhongshan Hospital of Dalian 
University 
004  
Fu Xing Hospital, Capital Medical University 
038  
The First Hospital of China medical 
University 
005  
Peking Union Medical College Hospital 
039  
Baotou Central Hospital  
006  
Peking University First Hospital 
040  
General Hospital of Ningxia Medical 
University  
007  
Peking University Third Hospital 
041  
People’s Hospital of Ningxia Hui 
Autonomous Region 
008  
Chinese PLA General Hospital 
042  
The Affiliated Hospital of Qingdao 
University 
009  
China-Japan Friendship Hospital 
043  
78th Hospital of the People's Liberation 
Army 
010  
Beijing Geriatric Hospital 
044  
Qilu Hospital of Shandong University 
011 
Dalian Municipal Hospital Affiliated of Dalian 
Medical University 
045  
Qilu Hospital of Shandong University 
(Qingdao) 
012  
Fujian Medical University Union Hospital 
046  
Shangdong Provincial Hospital 
013  
Guangzhou Brain Hospital 
047  
QingDao Municipal Hospital 
014  
Sun Yat-Sen Memorial Hospital, Sun Yat-Sen 
University 
048  
First Hospital of Shanxi Medical 
University 
015  
The first Affiliated Hospital of Guangxi Medical 
University 
049  
Tangdu Hospital, Fourth Military 
Medical University 
016  
The Affiliated Hospital of Guizhou Medical 
University 
050  
The first Affiliated Hospital of Xi’ an 
Jiao Tong University 
017 
HanDan Central Hospital 
051  
Rui Jin Hospital Shanghai Jiao Tong 
University School of Medicine 
018 
Heibei General Hospital 
052 
Renji Hospital Shanghai Jiao Tong 
University School of Medicine 
019 
Shijiazhuang First Hospital 
053 
Shanghai Changzheng Hospital 
020 
Tangshan Workers Hospital 
054 
Affiliated Hospital of North Sichuan 
Medical University 
021 
Hennan Provincial People’s Hospital 
055 
Tianjin Huanhu Hospital 
022 
KaiFeng Central Hospital 
056 
General Hospita of Tianjin Medical 
University 
023 
People's Hospital of Zhengzhou 
057 
Xinjiang Autonomous Region Chinese 
Medicine Hospital 
024 
The First Affiliated Hospital of Harbin Medical 
University 
058 
Ningbo City Medical Treatment Center 
Lihuili Hospital 
025 
Tongji Hospital, Huazhong University of Science 
and Technology 
059 
The First Affiliated Hospital of 
Wenzhou Medical University 
026 
People's Hospital Affiliated Hubei University of 
Medicine 
060 
The First Affiliated Hospital, Zhejiang 
University 
027 
Zhongnan Hospital of Wuhan University 
061 
Shao Yifu Hospital, Zhejiang University 
of Medicine 

80 
 
028 
The Third Xiangya Hospital of Central South 
University 
062 
Zhejiang Provincial People's Hospital 
029 
Xiangya Hospital, Central South University 
063 
Daping Hospital of the Third Military 
Medical University 
030 
The First Hospital of Jilin University 
064 
The Second Affiliated Hospital of 
Chongqing Medical University 
031 
China-Japan Friendship Hospital of Jilin 
University 
065 
The First Hospital Affiliated Anhui 
Medical University 
032 
Subei People's Hospital 
066 
Chongqing General Hospital 
033 
Affiliated Hospital of Nantong University 
067 
Dongfang Hospital, Beijing University 
of Chinese Medicine 
034 
Xuzhou Mine General Hospital 
068 
Zigong First People's Hospital