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Study Design

ADNI is a global research study that actively supports the investigation and development of treatments that slow or stop the progression of AD. In this multisite longitudinal study, researchers at 63 sites in the US and Canada track the progression of AD in the human brain with clinical, imaging, genetic and biospecimen biomarkers through the process of normal aging, early mild cognitive impairment (EMCI), and late mild cognitive impairment (LMCI) to dementia or AD. The overall goal of ADNI is to validate biomarkers for use in Alzheimer’s disease clinical treatment trials.

ADNI has made a global impact, both by developing a set of standardized protocols to allow comparison of results from multiple center and by its data-sharing policy which makes available all ADNI data without embargo to qualified researchers worldwide. To date, over 1000 scientific publications have used ADNI data. A number of other initiatives related to AD and other diseases have been designed and implemented using ADNI as a model. ADNI has been running since 2004 and is currently funded until 2021.

DATA SHARING

One defining characteristic of ADNI is the commitment by all cores to share data without embargo and within hours of collection. All data generated by the ADNI study investigators are entered into the data repository hosted at the Laboratory of Neuroimaging (LONI) at the University of Southern California, the LONI Image & Data Archive (IDA). Qualified researchers worldwide can submit an online data access request and generally begin using ADNI data including cognitive/neuropsychological, image, biofluid and genetic data sets within a few days of request submission.

Thousands of data use applications have been received from investigators from across the globe and multiple disciplines leading to millions of data downloads.  One measure of the success of this open data sharing approach is the number of scientific publications arising from ADNI data: currently over 1500 in a wide variety of fields including areas outside of Alzheimer’s disease.  Current usage stats are shown on the ADNI Data Usage Stats page and the list of ongoing investigations may be perused on the Ongoing Investigations page.

ADNI also contributes data to a number of consortia and big data projects which have the potential to unlock many of the mysteries of neurological diseases, including the Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) consortium and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) Alzheimer’s Disease Big Data Challenge #1 for the discovery of novel predictive AD biomarkers.

Studies using ADNI cross-sectional and longitudinal data from multiple modalities have reported that:

  • AD pathology is already present in people with no outward sign of memory loss and these cognitively normal people may already have subtle brain atrophy
  • There are typical patterns of amyloid deposition, declines in glucose metabolism, and structural brain changes that occur in AD
  • Cognitive decline is more closely linked to tau then Aß deposition
  • AD is characterized by the progressive disruption of the brain connectome. As the disease progresses, there are fewer connections between essential brain regions.
  • Many genes in addition to APOE4 underlie AD. ADNI data has helped to identify or confirm 10 of the approximately 20 genes currently identified
  • Cerebrovascular disease can accelerate disease progression in AD
  • Both the cognitively normal and MCI groups are pathologically heterogeneous. Some people show no signs of AD, some show signs of progressing to AD quickly, and others show signs of progressing to dementias other than AD

 

Background & Rationale

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that results in a loss of mental function caused by the deterioration of brain tissue. It is the most common cause of dementia among people over the age of 65, affecting an estimated 5.5 million Americans, yet no prevention methods or cures have been discovered. For more information about Alzheimer’s disease, visit the Alzheimer’s Association. The goal of the ADNI study is to track the progression of the disease using biomarkers, together with clinical measures, to assess the brain’s structure and function over the course of four disease states. Details about ADNI cohorts can be found in the About section.

ADNI Participant Stages across ADNI 1/GO/2/3 Select each stage for details
MCI – Mild Cognitive Impairment
  • EMCI – Early Mild Cognitive Impairment: ADNI GO/2
  • MCI – Mild Cognitive Impairment: ADNI1/3
  • LMCI – Late Mild Cognitive Impairment: ADNI GO/2

MCI participants have reported a subjective memory concern either autonomously or via an informant or clinician. However, daily living activities are essentially preserved, there are no significant levels of impairment in other cognitive domains, and no signs of dementia exist. Levels of MCI (early or late) are determined using the Wechsler Memory Scale Logical Memory II.

SMC – Significant Memory Concern
ADNI 2

ADNI 2 added a new cohort, the Significant Memory Concern (SMC).  Subjective memory concerns have been shown to be correlated with a higher likelihood of progression, thereby minimizing the stratification of risk among normal controls and addressing the gap between healthy elderly controls and MCI.

The key inclusion criteria that distinguish the SMC cohort are a self-report significant memory concern from the participant, quantified by using the Cognitive Change Index and the Clinical Dementia Rating (CDR) of zero. SMC participants score within the normal range for cognition, and the informant does not equate the expressed concern with progressive memory impairment

CN – Normal Aging/Cognitively Normal
ADNI 1/GO/2/3

CN participants are the control subjects in the ADNI study. They show no signs of depression, mild cognitive impairment, or dementia.

About Biomarkers

A biomarker, or biological marker, is a substance, measurement or indicator of a biological state. Biomarkers may exist before clinical symptoms arise. ADNI uses various biomarkers to help predict the onset of Alzheimer’s disease.

 

The graph depicts biomarkers as indicators of AD. The curves indicate changes in five biomarkers from normal to abnormal over the course of AD (normal cognition to dementia)

  1. b-amyloid (A?) measured in cerebrospinal fluid or by amyloid PET imaging
  2. Neurodegeneration indicated by tau protein measured in cerebrospinal fluid, or by synaptic dysfunction, measured by FDG-PET
  3. Brain atrophy, mostly in the medial temporal lobe, measured by structural MRI
  4. Memory loss, measured by cognitive tests
  5. Clinical function, indicated by general cognitive decline measured by cognitive tests.

Changes 1-3 are indicated by biomarkers that can be observed prior to a dementia diagnosis, while changes 4-5 are the classic indicators of dementia diagnosis.

Study Objectives

Explore the distinct goals of each ADNI phase below; overall objectives can be found on the About page.

During the four phases of the ADNI study, to the extent possible, participants were carried forward from previous phases for continued monitoring, while new participants were added with each phase to further investigate the evolution of Alzheimer’s disease.

ADNI enrolls participants between the ages of 55 and 90 who are recruited at 57 sites in the United States and Canada. After obtaining informed consent, participants undergo a series of initial tests that are repeated at intervals over subsequent years, including a clinical evaluation, neuropsychological tests, genetic testing, lumbar puncture, and MRI and PET scans.

View the clinical study schedule for all phases of ADNI below.

 

Select each phase for details

Participant Pool:
  • 135-500 Normal Controls (new)
  • 295-330 Normal Controls (rollover from ADNI2; approximate)
  • 150-515 Mild Cognitive Impairment (MCI) (new)
  • 275-320 Mild Cognitive Impairment (MCI) (rollover from ADNI2; approximate)
  • 85-185 Mild Alzheimer’s Disease dementia (AD) (new)
  • 130-150 Mild Alzheimer’s Disease dementia (AD) (rollover from ADNI2; approximate)
 Objectives:
  1. Longitudinal changes in cognition and associated biomarkers

Determine and define those measures of cognition and function, including composite measures, and those biomarker measures, which capture longitudinal change with the highest statistical power to detect treatment effects in clinical trials. Longitudinal change of cerebral tau measured with 18F-AV-1451 PET (AV-1451) will be correlated/compared with other measures.

  1. Prediction of cognitive decline

Determine which clinical, cognitive, and biomarker measures that best predict decline of cognition in CN, MCI, and AD participants. In addition, determine which biomarker changes correlate with cognitive decline, with focus on AV-1451 PET.

  1. Validation

Validate biomarker measures obtained at Baseline and longitudinally by correlating results with “gold standard” clinical measurements and pathology.

  1. Clinical trial design

Determine the optimum outcome measures with attention to cognitive decline and AV-1451 PET (tau PET) , predictors of cognitive decline, and inclusion/exclusion criteria for clinical trials of cognitively normal participants (for secondary preclinical AD trials), MCI patients (for prodromal AD trials) and participants with early dementia due to AD.

  1. Discovery

To determine the effects of other known disease proteins found in AD brains and genes, as well as newly discovered genes, proteins, and analytes that provide useful information concerning the pathogenesis/diagnosis of AD.

Further Reading
Participant Pool:
  • 150 Normal Controls (new)
  • 450-500 CN and MCI (rollover from ADNI1; approximate)
  • 150 EMCI (new)
  • 200 EMCI (rollover from ADNI GO; approximate)
  • 150 LMCI (new)
  • 200 mild AD (new)
Objectives:
  1. Determine the relationships among clinical, imaging, genetic, and biochemical biomarker characteristics of the entire spectrum of Alzheimer’s disease (AD) as the pathology evolves.
  2. Inform the neuroscience of AD, identify diagnostic and prognostic markers and outcome measures that can be used in clinical trials, and help develop the most effective clinical trial scenarios.
  3. Develop uniform standards for acquiring longitudinal multisite MRI and PET data on patients with AD, MCI, and elderly controls.
  4. Perform longitudinal clinical, cognitive, MRI, PET (18F-Florbetapir and FDG), and blood and CSF biomarker studies on 550 newly enrolled subjects in addition to continuing these studies for approximately 700 subjects from ADNI1 and ADNI GO for an additional 5 years.
  5. Collect blood samples for DNA and RNA extraction. Newly enrolled subjects will also have samples collected for Cell Immortalization and APOE genotyping.
  6. Validate the clinical diagnoses and imaging and biomarker surrogates through neuropathological examination of ADNI1, ADNI GO, and ADNI2 participants who come to autopsy.
Participant Pool:
  • 200 EMCI (new)
  • 500 Normal Controls and MCI (rollover from ADNI1)
Objectives:
  1. Define and characterize the stage of the AD spectrum that precedes MCI by enrolling 200 subjects in the mildest symptomatic phase of AD (EMCI).
  2. Perform F18 amyloid imaging on the CN and LMCI subjects from ADNI1 and the newly enrolled EMCI subjects. FDG PET will be performed in association with F18 amyloid imaging.
  3. Establish a national network for F18 amyloid imaging and test hypotheses concerning the prevalence and severity of brain amyloid accumulation and its relationship to current and previous changes of clinical state, MRI, FDG-PET, CSF and plasma biomarkers from ADNI1.
  4. Collect 3T MRI on all newly enrolled subjects at Baseline, Month 3, Month 6, and Month 12.
  5. Continue longitudinal clinical/cognitive and 1.5T MRI studies of approximately 500 LMCI and Cognitively Normal subjects from ADNI1 for an additional 2 years.
  6. Collect and analyze blood and CSF biomarkers from all newly enrolled EMCI and follow-up subjects.
  7. Collect blood samples for DNA and RNA extraction. Newly enrolled subjects will also have samples collected for Cell Immortalization and APOE genotyping.
Participant Pool:
  • 200 Normal Controls
  • 400 MCI
  • 200 Mild AD
Objectives:
  1. Develop improved methods that create uniform standards for acquiring longitudinal, multi-site MRI and PET data on patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and elderly controls.
  2. Acquire a generally accessible data repository which describes longitudinal changes in brain structure and metabolism as well as clinical/cognitive and biomarker data for the validation of imaging surrogates.
  3. Develop methods which will provide maximum power to determine treatment effects in trials involving these patients.
  4. Test a series of hypotheses based on the clinical and biomarker data.

Collaborative Studies

Several Alzheimer’s disease initiatives have repurposed the study methods and research network developed through ADNI. The overall goal of these studies is to help define the rate of AD progression. By partnering with related studies of AD, ADNI researchers can access data from a larger study cohort, thereby enhancing their scientific results.

Select each study for details

Worldwide ADNI

WW-ADNI is a collaborative effort of scientists from around the world convened by the Alzheimer’s Association and is the umbrella organization for neuroimaging initiatives being carried out globally. World Wide ADNI (WW-ADNI) unites leading international investigators in a common effort to:

  • Help predict and monitor the onset and progression of Alzheimer’s disease
  • Establish globally recognized standards to identify and diagnose Alzheimer’s disease
  • Document cognitive changes linked to physical changes
  • Share data across the international research community

Each WW-ADNI site collects clinical and biomarker data from participants. Biomarker data may include imaging data (MRI, PET) or fluid biomarker data (CSF, plasma). WW-ADNI has a goal of making most of the clinical, neuropsychological, imaging, and biological data gathered available to the scientific community.

The Active WW-ADNI Sites include:
  • North American ADNI (NA-ADNI)
  • European ADNI (E-ADNI)
  • Australian Imaging, Biomarker & Lifestyle (AIBL)
  • Japan ADNI (J-ADNI)
  • Korea ADNI
  • Argentina ADNI
  • China ADNI
  • India ADNI
Global Alzheimer’s Association Interactive Network (GAAIN)

The Global Alzheimer’s Association Interactive Network (GAAIN) unites a diverse and geographically distributed network of data partners within a federated data platform designed to foster cohort discovery, collaboration, and sharing. GAAIN represents the first open access, federated Alzheimer’s disease data discovery platform of its kind. With GAAIN:

  • Researchers can discover clinical, genetic, imaging and other data collected across many independent studies; build cohorts and connect with GAAIN data partners.
  • Study investigators can meet data sharing objectives and develop new collaborations.

GAAIN is funded by the Alzheimer’s Association and strives to further the association’s goal of accelerating the development of Alzheimer’s disease preventions, treatments, and a cure.

More information about GAAIN can be found here.

Further Reading

ADNI Depression Study

Through dynamic partnerships with the Alzheimer’s Disease Neuroimaging Initiative (ADNI-II) and industry sponsorship, the ADNI-D study is well positioned to successfully address the impact of reduced cerebral blood flow (hypoperfusion), cortical atrophy, and amyloid deposition on cognitive impairment and accelerated cognitive decline in Late Life Depression (LLD) in the context of previously documented relationships between cognitive impairment and subcortical white matter abnormalities and genetic risk factors. ADNI-D is focused on establishing improved diagnostic approaches and targeted treatment trials aimed at LLD and cognitive impairment (CI) associated with LLD, ultimately leading to improved health outcomes and reduced healthcare costs.

Objectives
  • To clarify neurobiological substrates of cognitive dysfunction in LLD.
  • To clarify the impact of LLD on the rate of cognitive decline over 2.5 years.
  • Use biomarkers data employed in ADNI-2 and the NIA AD Genetics Consortium to determine the genotypes needed for the genome-wide association study (GWAS) for pathways and candidate gene studies that investigators may wish to pursue in future studies. Data from participants will be entered into the NIH Genome-Wide database and made available to the scientific community.
Study Design

This is a non-randomized non-treatment study. One hundred and twenty (120) subjects who meet criteria for Major Depression or LLD will be enrolled for a period of 30 months. Data from an additional 300 non-depressed subjects will be used from the previous ADNI studies for comparison. Depression history, symptom severity, and health information will be collected at the initial psychiatric visit to determine eligibility. A 3T MRI and18F-AV-45 amyloid imaging will be conducted at the ADNI site for the initial clinical visit. Collection of plasma and serum for biomarkers, clinical assessments, and cognitive assessments will be conducted at both time points. Blood samples will also be collected for genetic analysis.

Resources
Data Sharing

In order to provide the clinical data from this project to Initiative investigators, the Pharmaceutical Industry and the public, the entire clinical database (free of any identifying information such as name, address, or phone number) will be placed on a public website, which will be appropriately linked to the imaging database at LONI. The database will be frequently updated, and all cleaned clinical data acquired by the ADNI-CC will be provided in real-time.

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Department of Defense (DOD) ADNI

Veterans with traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) appear to have a greater associated risk of Alzheimer’s disease and dementia. The purpose of DOD ADNI is to examine the possible connections between TBI and PTSD, and the signs and symptoms of Alzheimer’s disease on Veterans as they age. The results of the DOD ADNI study will lead to greater efforts to develop treatment and prevention studies to help reduce these long-term effects of TBI and PTSD injuries.

Funded by the Department of Defense (DOD), this study is the first step towards a larger, more comprehensive study of dementia risk factors in Veterans.

Objectives
  • Optimize, standardize and validate imaging/biomarkers for AD clinical trials
  • Determine biomarkers with high sensitivity to detect a change
  • Determine biomarkers which predict future change: identify AD pathology
  • Improve clinical AD trials
  • Provide data to all investigators
  • Create a worldwide network for clinical trials
Study Design

Vietnam War Veterans between the ages of 60-80 years will be identified and contacted using Veterans Affairs records. The enrollment goal is 195 participants divided into three study groups. This study excludes mild cognitive impairment (MCI) and dementia subjects.

Study Participant Groups
  1. 65 moderate/severe TBI patients without PTSD
  2. 65 PTSD subjects without TBI
  3. 65 controls without PTSD or TBI, comparable to groups 1 and 2 in age, gender, and education
Resources
Data

ADNI will provide the following standardized data from enrolled participants. The following data will be available in the DOD ADNI Data Archive to qualified researchers:

  • Clinical and cognitive tests
  • AFQT, ASVAB
  • Medical history
  • Cerebral spinal fluid (including tau and phospho-tau levels)
  • Genetics blood test
  • MRI scans (min. 3T, and DTI processing on TBI subjects where available)
  • PET scans (using F18 Florbetapir, no FDG PET)
  • 1-year follow-up: all procedures repeated except for PET scan and lumbar puncture

Apply for access to DOD ADNI data >

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Participate in this study

If you are a Vietnam-era combat veteran suffering from TBI or PTSD and you are interested in participating in this study, please call 1-800-773-4883.

More information about DOD ADNI is available here.

Further Reading

 

Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL)

The Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) seeks to discover which biomarkers, cognitive characteristics, and health and lifestyle factors determine the development of AD.

Although AIBL and ADNI have many of the same goals, there are differences between the two projects. Read more about the AIBL study from their website.

Study Participants

AIBL has enrolled 1100 participants and collected over 4.5 years worth of longitudinal data.

  • 211 AD patients
  • 133 MCI patients
  • 768 comparable healthy controls
Data

AIBL follows ADNI 1 protocols. Available data includes:

  • Clinical and cognitive data
  • Image data: MRI, PET
  • Biomarkers data: blood, genotype, ApoE
  • Dietary/lifestyle assessment

More information about AIBL study data can be found here.

Apply for AIBL data >

Please read through the Access Data page before applying to access ADNI data. Separate Data Use Agreements and review processes exist for each study. Therefore, you will need to abide by a Data Use Agreement before you are authorized to access ADNI data and/or data from any of our collaborative studies.