Last updated on February 2018

Dominantly Inherited Alzheimer Network (DIAN)


Brief description of study

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.

Detailed Study 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 (A42), the sequence of preclinical changes initially will involve A42 (production and clearance; reduced levels in cerebrospinal fluid [CSF]), followed by evidence for cerebral deposition of A42 (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 (mutation carriers and non-carriers; pre-symptomatic and symptomatic) who are biological adult children of a parent with a known causative mutation for AD in the APP, PSEN1, or PSEN2 genes and assess participants every 2 years with the uniform DIAN protocol.
  2. 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 mutation carriers (using non-carriers as controls), determine the temporal ordering and rate of intraindividual change in clinical, cognitive, behavioral, imaging, and fluid biomarkers of AD prior to estimated age of symptom onset.
    2. In symptomatic mutation carriers, compare the clinical and neuropathological phenotypes of ADAD to those of LOAD, using datasets such as ADNI.
  3. 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, exploratory investigation of new biomarker analytes, imaging modalities and techniques, perform exploratory genetic analysis to test whether novel AD genes identified through GWAS and sequencing of late onset AD cases also influence variation in age at onset of changes in biomarker endophenotypes in FAD kindred, and generate genome-wide DNA methylation data for pilot study and perform exploratory analyses to look for changes in DNA methylation in longitudinal samples from DIAN participants.
  4. 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).

Clinical Study Identifier: NCT00869817

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Osaka City University

Osaka City, Japan
6.1miles
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Recruitment Status: Open


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