DIAN Observational Study and Sample Description

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The Dominantly Inherited Alzheimer Network (DIAN; U01AG032438) studies the development of dominantly inherited AD in verified mutation carriers in comparison with their non-carrier siblings, who serve as a naturally occurring control group. All DIAN participants are assessed longitudinally with comprehensive and state-of-the-art clinical, cognitive, genetic, imaging, and biomarker protocols, and all data are collected in a standard and uniform manner for entry into a central repository.

DIAN’s specific aims

  1. Establish an international, multicenter registry of individuals (mutation carriers and noncarriers; asymptomatic and symptomatic) who are biological adult children of a parent with a known causative mutation for AD in the APP, PSEN1, or PSEN2 genes, in which the individuals are evaluated in a uniform manner at entry and longitudinally thereafter with standard instruments to include:
    1. The clinical and cognitive batteries of the Uniform Data Set (UDS) and additional neuropsychological and personality measures
    2. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) structural (magnetic resonace imaging, or MRI, functional (18Fluorodeoxyglucose positron emission tomography, or FDG PET), and amyloid imaging (Pittsburgh Compound-B, or PIB) PET protocols
    3. In accordance with the ADNI protocols, collection of biological fluids (blood; CSF) for DNA analysis and assays of putative biomarkers of AD
    4. Uniform histopathological examination of cerebral tissue in individuals who come to autopsy
  2. In asymptomatic individuals, compare mutation carriers and noncarriers to determine the order in which changes in clinical, cognitive, neuroimaging, and biomarker indicators of AD occur prior to the occurrence of dementia.
  3. In symptomatic individuals, compare their clinical and neuropathological phenotypes with autosomally dominant Alzheimer’s disease (ADAD) those of late-onset “sporadic” AD (using the data sets established by ADNI and by NACC).
  4. Maintain an integrated data base incorporating all information obtained from individuals in the registry to permit analyses within, between, and among the various data domains and also to disseminate the data to qualified investigators in a user-friendly manner.

DIAN is substantially supported by ADNI’s imaging protocols and by the Alzheimer’s Disease Cooperative Study (ADCS). This support notably strengthens DIAN’s goal to obtain data in a standard and uniform manner by providing clinical and cognitive monitoring of all DIAN sites, providing uniform neuropathologic assessments of autopsied DIAN cases, and extending the standardized procedures to image and biomarker data collection and quality control through established ADNI protocols.

Sample characteristics (targeted)

  • Up to 600 participants, age 18 and older
  • Members of a family with a known pathogenic mutation for AD; must be a child of an affected parent, although the mutation may be identified in consanguineous relatives (currently in one of three genes: APP, PSEN1, PSEN2).
  • 80% asymptomatic and 20% symptomatic
  • 50% of the asymptomatic sample will be mutation carriers and 50% will be noncarriers (consistent with autosomal dominant inheritance)
  • Age distribution such that 50% are within 3 years of parental age at onset (AAO) and 30% are 3 to 10 years before parental AAO

Inclusion criteria

  • Written informed consent obtained from the participant and collateral source prior to any study-related procedures.
  • Participant is aged > 18 inclusive and the child of an affected individual (clinically or by testing) in a pedigree with a known mutation for autosomal dominant AD.
  • 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 his/her full-blooded siblings and who can serve as collateral sources for the study.
  • Participant is fluent in English at the 6th grade level or above [Note: Although DIAN participants initially were limited to English speakers, translations of the DIAN protocols into other languages is under way.].

Visit frequency

All asymptomatic DIAN participants, with the exception of those who are 5 years older than estimated age of symptom onset, will return for in-person visits every other year. If an in- person follow up visit is missed, the participant should be scheduled for an in-person visit the following year.

Those asymptomatic participants who are ≥ 5 years older than estimated age at onset will cease in-person clinic visits and transition to annual remote visits (phone calls) until study termination, unless the participant is aware that they are positive for an ADAD mutation and has disclosed this information to the coordinator/study staff. In this case, they will maintain their every other year in-person visit schedule.

Symptomatic participants (CDR > 0 at clinical evaluation) will be seen in-person yearly and continue in the study as long as useful data are being obtained and participant burden is minimized.

In the years between in-person visits, telephone follow-up with the asymptomatic participant and collateral source will be performed to inquire about cognitive change. For all asymptomatic DIAN participants regardless of their knowledge of their mutation status, if a remote visit identifies cognitive decline, the participant will be invited for an in-clinic visit.

Procedures

All participants are invited to complete:

  • Clinical assessment
  • Cognitive assessments
  • Blood for genetic analysis
  • MRI (3T)
  • FDG PET
  • Pittsburgh Compound B (PIB) PET
  • Tau PET (at participating sites only)
  • Lumbar puncture for cerebrospinal fluid (CSF) and fasted blood
  • Autopsy (possible)

Participation in all assessments is expected but not mandatory except for the clinical and cognitive batteries. The clinical assessment, MRI, PET PIB, FDG PET, psychometric testing, and CSF studies may be completed over a few days or in several visits spread over no more than 12 weeks. All participants are invited to provide autopsy permission in the event of death.