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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. Establish an international, multicenter 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 in which the individuals are evaluated in a uniform manner at entry and longitudinally thereafter with standardized instruments.
2. In pre-symptomatic individuals, compare mutation carriers and non-carriers 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 the clinical and neuropathological phenotypes of autosomal dominant AD to those of late-onset "sporadic" AD (using the data sets established by ADNI and by NACC).
4. Maintain the DIAN Central Archive, an integrated database 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.
5. All DIAN participants who wish to know their mutation status will have the costs of genetic counseling and clinical mutation testing paid for by the grant. The clinical genetic counseling and testing is provided as an optional participant benefit and is not part of the DIAN research design.
Observational Model: Cohort, Time Perspective: Prospective
University of California, Los Angeles
National Institute on Aging (NIA)
Published on BioPortfolio: 2014-08-27T03:23:22-0400
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