Dominantly Inherited Alzheimer Network (DIAN)

M
Martin Farlow, MD

Primary Investigator

Enrolling By Invitation
18 years - 100 years
All
Phase N/A
2 Locations

Brief description of study

What is the purpose of this study?

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. The overall purpose of this research is to understand the changes that occur in dominantly inherited Alzheimer disease.

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.
THIS STUDY IS ENROLLING BY INVITATION ONLY

Detailed description of study

What will happen during the study?
 
DIAN participants ages 18 or older will complete longitudinal clinical assessment, psychometrics, blood genetics and biomarker studies, LP, MRI, FDG PET and PET PIB imaging.  Optional sub-studies may be available at performance sites, for example, tissue collection (e.g., dermal fibroblasts).  Participants will be members of a family with a known ADAD mutation and must be a child of an affected parent (clinically or by testing); the mutation may be identified in consanguineous relatives (currently in one of three genes: APP, PSEN1, PSEN2).  Fifty percent of the participants will be mutation carriers (due to autosomal dominant inheritance) and the other fifty percent will serve as sibling controls.
 
This study aims to:
  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).

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Healthy, Alzheimer's Disease
  • Age: 18 years - 100 years
  • Gender: All

Inclusion Criteria
Participant is cognitively normal or if demented does not require nursing home-level care.
Participant has identified two persons (minimum of one) who are not their full-blooded siblings who can serve as collateral sources for the study.
Participant is fluent in English at the 6th grade level or above
 
Exclusion Criteria
Pregnant women should not complete any in-person visit measures
Treatment with blood thinners, e.g. Warfarin
Coagulation abnormalities
Lumbar spinal surgery within the last 6 months prior to screening, or any lumbar spinal surgery that interferes with anatomy of the inter-vertebral spaces.
History of chronic or repeat CSF leakage following previous LP(s)
Active infectious process
Current or recent participation in research studies involving radioactive agents
Pacemakers
Electronically, magnetically, and mechanically activated implants
Metallic splinters in the eye
Ferromagnetic haemostatic clips in the central nervous system

Additional Information:

Participants will be paid for their participation.

Updated on 07 May 2025. Study ID: NEUR-NIA-FARL-DIANOBSERV, 1903023852
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