Dominantly Inherited Alzheimer Network (DIAN)

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 (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).

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. Primary enrollment will focus on recruitment of asymptomatic adult
children who are more than 15 years younger than the estimated age of symptom onset.
Enrollment of new participants with very mild, mild, or 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