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Dominantly Inherited Alzheimer Network (DIAN) (DIAN)

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ClinicalTrials.gov Identifier: NCT00869817
Recruitment Status : Recruiting
First Posted : March 26, 2009
Last Update Posted : March 30, 2023
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Washington University School of Medicine

Study Description
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Brief Summary:
The purpose of this study is to identify potential biomarkers that may predict the development of Alzheimer's disease in people who carry an Alzheimer's mutation.

Condition or disease
Alzheimer's Disease

Detailed Description:

Dominantly inherited Alzheimer's disease (AD) represents less than 1% of all cases of AD and is an important model for study because the responsible mutations have known biochemical consequences that are believed to underlie the pathological basis of the disorder. Three major hypotheses will be tested:

  • First, that there is a period of preclinical (presymptomatic) AD in individuals who are destined to develop early-onset dementia (gene carriers) that can be detected by changes in biological fluids and in neuroimaging correlates in comparison with individuals who will not develop early-onset dementia (non-carriers).
  • Second, because all identified causative mutations for AD affect the normal processing of amyloid precursor protein (APP) and increase brain levels of amyloid-beta 42 (Aβ42), the sequence of preclinical changes initially will involve Aβ42 (production and clearance; reduced levels in cerebrospinal fluid [CSF]), followed by evidence for cerebral deposition of Aβ42 (amyloid imaging), followed by cerebral metabolic activity (functional imaging), and finally by regional atrophy (structural imaging).
  • Finally, that the phenotype of symptomatic early-onset familial AD, including its clinical course, is similar to that of late-onset "sporadic" AD.

The following specific aims will be used to test these hypotheses:

  1. Maintain the established international DIAN registry of individuals (MCs and non-carriers (NC), symptomatic and asymptomatic) who are biological adult children of an affected parent with an APP, PSEN1, or PSEN2 mutation causing AD and assess participants every 2 years with the uniform DIAN protocol.
  2. Recruit to the registry 50 new asymptomatic participants, both MCs and NCs, in Year 1 of the next budget period to maintain the total DIAN cohort at ~250 individuals. These new participants will include those who are more than 15 years younger than the estimated age of symptomatic onset (EAO) to explore the earliest observable biomarker changes of preclinical AD.

  3. Maintain the integrated DIAN database and biospecimen repository to disseminate data and tissue to qualified investigators (within and outside of DIAN) in a user-friendly manner and to permit analyses within, between, and among the various data domains that will include:

    1. In asymptomatic MCs (using NCs as controls), determine the temporal ordering and rate of intraindividual change in clinical, cognitive, imaging, and fluid biomarkers of AD prior to EAO
    2. In symptomatic MCs, compare the clinical and neuropathological phenotypes of ADAD to those of LOAD, using datasets such as ADNI.
  4. Utilize the DIAN cohort and its database and biospecimen repository to support new scientific studies, including use of exome chip technology to examine potential modifiers of age at symptomatic onset. Pursue other new scientific initiatives that are funded independently of the DIAN grant but are conducted within the DIAN infrastructure at no cost to DIAN including: Dermal fibroblasts and induced pluripotent stem cells (iPSCs), examine biomarker surrogates for neurogeneration in CSF including Visinin-like protein-1 (VILIP-1), Tau seeding assay, Stable Isotope Leucine Kinetics (SILK) in DIAN participants, determine the exact Abeta species that underlie AD pathology using Mass spectrometry, exome sequencing on all DIAN participants to search for both positive and negative modifiers of EYO, and amyloid imaging crossover to [18F]florbetapir.
  5. Provide genetic counseling to any and all DIAN participants who wish to learn their mutation status and, for those who decide to learn their status after counseling, provide genetic testing by Clinical Laboratory Improvement Amendments (CLIA)-approved laboratories (i.e., outside of DIAN).
Study Design
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Study Type : Observational
Estimated Enrollment : 700 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Dominantly Inherited Alzheimer Network (DIAN)
Study Start Date : January 2009
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2024

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort
1
Mutation Positive
2
Mutation Negative


Outcome Measures
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Primary Outcome Measures :
  1. Positive predictive power of a biomarker or group of biomarkers [ Time Frame: Variable follow-up assessment based on age in relation to age at onset of affected parent. ]
  2. Biomarkers obtained by blood draw, lumbar puncture, MRI, FDG PET, PET amyloid imaging [ Time Frame: Variable follow-up assessment based on age in relation to age at onset of affected parent ]
  3. Clinical markers also examined from clinical interview and cognitive testing [ Time Frame: Variable follow-up assessment based on age in relation to age at onset of affected parent ]

Biospecimen Retention:   Samples With DNA
buffy coat, plasma, cerebral spinal fluid

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Mutation carriers and non-carriers from families with a mutation (which is different from the genetic risk factor Apo-E4) known to cause Alzheimer's disease.
Criteria

Inclusion Criteria:

  • Written informed consent obtained from participant and collateral source prior to any study-related procedures.
  • Aged 18 (inclusive) or older and the child of an affected individual (clinically or by testing) in a pedigree with a known mutation for ADAD.
  • Cognitively normal to very mild or mild cognitive impairment (CDR score range 0-1.0). Primary enrollment will focus on the recruitment of asymptomatic adult children who are more than 15 years younger than the estimated age of symptom onset. Enrollment of new participants with moderate cognitive impairment is allowed with the prior approval of the DIAN Coordinating Center.
  • Has two persons who are not their full-blooded siblings who can serve as collateral sources for the study.
  • Fluent in a language approved by the DIAN Coordinating Center at about the 6th grade level (international equivalent) or above.

Exclusion Criteria:

  • Under age 18
  • Medical or psychiatric illness that would interfere in completing initial and follow-up visits
  • Requires nursing home level care
  • Has no one who can serve as a study informant
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00869817


Contacts
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Contact: Alisha Daniels, MD,MHA (314) 273-9057
Contact: DIAN Obs Admin Core NEURO-DIANCoordinatingCenter@email.wustl.edu

Locations
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Sponsors and Collaborators
Washington University School of Medicine
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Randall J. Bateman, MD Washington University School of Medicine
Study Director: Alisha Daniels, MD,MHA (314) 273-9057
More Information
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Additional Information:

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00869817    
Other Study ID Numbers: IA0147
U19AG032438 ( U.S. NIH Grant/Contract )
UF1AG032438 ( U.S. NIH Grant/Contract )
First Posted: March 26, 2009    Key Record Dates
Last Update Posted: March 30, 2023
Last Verified: March 2023
Keywords provided by Washington University School of Medicine:
Alzheimer's disease
antecedent biomarkers
Amyloid Precursor Protein (APP) mutation
 presenilin I (PS1) mutation
presenilin 2 (PS2) mutation
Autosomal Dominant Alzheimer's Disease
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
 Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders