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 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