Dominantly Inherited Alzheimer Network (DIAN)

Alzheimer's Disease Clinical Trial

— DIAN  

Official title:

Dominantly Inherited Alzheimer Network (DIAN)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00869817
• Other study ID #: IA0147
• Secondary ID: U19AG032438UF1AG
• Status: Recruiting
• Start date: January 2009
• Est. completion date: July 2025

Study information

• Verified date: April 2024
• Source: Washington University School of Medicine
• Contact: Alisha Daniels, MD,MHA
• Phone: (314) 273-9057
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 700
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Locations

Country	Name	City	State
Argentina	Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia" (FLENI) Instituto de Investigaciones Neurológicas Raúl Correa	Buenos Aires
Argentina	Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI)	Salta
Australia	Mental Health Research Institute, University of Melbourne	Melbourne	Victoria
Australia	Sir James McCusker Alzheimer's Disease Research Unit, Edith Cowan University	Perth	Western Australia
Australia	Neuroscience Research Australia	Sydney	New South Wales
Brazil	Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo
Canada	McGill University Research Centre for Studies in Aging	Verdun	Quebec
Colombia	Grupo Neurociencias de Antioquia	Medellín
Germany	German Center for Neurodegenerative Diseases (DZNE) Munich, and University Hospital Ludwig-Maximilians-Universitat (LMU) Munich	Munich
Germany	German Center for Neurodegenerative Diseases (DZNE) Tübingen and Hertie-Institute for Clinical Brain Research, University of Tübingen	Tübingen
Japan	Niigata University	Niigata
Japan	Osaka City University	Osaka City
Japan	Tokyo University	Tokyo
Korea, Republic of	Asan Medical Center	Seoul	Songpa-Gu
Mexico	Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suarez"	Mexico City
Spain	Hospital Clinic Barcelona	Barcelona	Catalunya
United Kingdom	Institute of Neurology, Queen Square	London
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Indiana University-Indiana Alzheimer Disease Center	Indianapolis	Indiana
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	Columbia University	New York	New York
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Butler Hospital	Providence	Rhode Island
United States	Washington University in St. Louis School of Medicine	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	National Institute on Aging (NIA)

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Colombia,  Germany,  Japan,  Korea, Republic of,  Mexico,  Spain,  United Kingdom, 

References & Publications (5)

Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007 Mar;64(3):343-9. doi: 10.1001/archneur.64.3.noc60123. Epub 2007 Jan 8. — View Citation

Galvin JE, Powlishta KK, Wilkins K, McKeel DW Jr, Xiong C, Grant E, Storandt M, Morris JC. Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study. Arch Neurol. 2005 May;62(5):758-65. doi: 10.1001/archneur.62.5.758. — View Citation

Godbolt AK, Cipolotti L, Anderson VM, Archer H, Janssen JC, Price S, Rossor MN, Fox NC. A decade of pre-diagnostic assessment in a case of familial Alzheimer's disease: tracking progression from asymptomatic to MCI and dementia. Neurocase. 2005 Feb;11(1):56-64. doi: 10.1080/13554790490896866. — View Citation

Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006 Aug 8;67(3):446-52. doi: 10.1212/01.wnl.0000228230.26044.a4. — View Citation

Morris JC, McKeel DW Jr, Storandt M, Rubin EH, Price JL, Grant EA, Ball MJ, Berg L. Very mild Alzheimer's disease: informant-based clinical, psychometric, and pathologic distinction from normal aging. Neurology. 1991 Apr;41(4):469-78. doi: 10.1212/wnl.41.4.469. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Positive predictive power of a biomarker or group of biomarkers		Variable follow-up assessment based on age in relation to age at onset of affected parent.
Primary	Biomarkers obtained by blood draw, lumbar puncture, MRI, FDG PET, PET amyloid imaging		Variable follow-up assessment based on age in relation to age at onset of affected parent
Primary	Clinical markers also examined from clinical interview and cognitive testing		Variable follow-up assessment based on age in relation to age at onset of affected parent

External Links

•   DIAN Website
•   Washington University St. Louis Knight Alzheimer's Disease Research Center