During the last two decades many genes have been shown to cause autosomal dominant forms of early onset dementing illnesses. These rare disorders have provided enormous insight into the pathogenesis of more common variants of the same diseases. Several of the most promising new therapeutics are based on the A hypothesis, a hypothesis largely supported by the causative mechanisms of disease mutations in autosomal dominant families. As these putative therapeutics are tested in clinical trials there is a growing need to use familial Alzheimer disease (FAD) kindreds both to understand the natural history of the earliest clinical and preclinical phases of the disease and to test the efficacy of the therapeutics in a setting, where if the A hypothesis is correct, they should have a dramatic effect on prognosis. During the last funding cycle, DIAN has developed a network of sites and has begun to characterize a large series of FAD kindreds with known disease-causing mutations. The goal of the next funding period will be to continue longitudinal follow up of these kindreds to identify the earliest detectable changes associated with development of disease and to characterize the temporal series of events that occurs up to and including the diagnosis of symptomatic AD. The goal of the Genetics Core of the DIAN initiative is to provide genetic information and useful biological materials to the research community for the study of AD. We have already collected samples from 326 individuals and extracted DNA. We will initiate collection of an additional 50 new individuals during the next funding period. Since these individuals are part of FAD kindreds with known causative mutations we will screen each sample for the known mutation in that family and genotype all families for known disease modifying alleles such as APOE e4. In this renewal application we will also genotype all mutation carriers using an Exome Chip to identify novel genes modifying age at onset of biomarker changes/symptoms. Blood from each individual will be sent to the National Cell Repository for Alzheimers Disease (NCRAD) for banking in the cell repository. Currently NCRAD has immortalized cell lines on 326 indiivduals from 129 DIAN families. Under separate funding DIAN has also collected skin biopsies from 44 individuals representing 16 different mutations in APP, PSEN1 and PSEN2.

Public Health Relevance

Alzheimers disease is a common neurodegenerative disease with no effective treatment. The goal of this Core is to provide mutation status and other relevant genetic data (e.g. APOE genotype) to investigators studying families in the DIAN cohort. This information can be used in analyses to help identify novel early changes in clinical and biomarker parameters among individuals carrying disease-causing mutations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Cooperative Agreement (UF1)
Project #
2UF1AG032438-07
Application #
8863373
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-07-16
Budget End
2019-12-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Besser, Lilah; Kukull, Walter; Knopman, David S et al. (2018) Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set. Alzheimer Dis Assoc Disord 32:351-358
Kinnunen, Kirsi M; Cash, David M; Poole, Teresa et al. (2018) Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study. Alzheimers Dement 14:43-53
Lee, Seonjoo; Zimmerman, Molly E; Narkhede, Atul et al. (2018) White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer's disease. PLoS One 13:e0195838
Xiong, Chengjie; Luo, Jingqin; Chen, Ling et al. (2018) Estimating diagnostic accuracy for clustered ordinal diagnostic groups in the three-class case-Application to the early diagnosis of Alzheimer disease. Stat Methods Med Res 27:701-714
Karch, Celeste M; Hernández, Damián; Wang, Jen-Chyong et al. (2018) Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network. Alzheimers Res Ther 10:69
Day, Gregory S; Gordon, Brian A; Perrin, Richard J et al. (2018) In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease. Neurology 90:e896-e906
Oxtoby, Neil P; Young, Alexandra L; Cash, David M et al. (2018) Data-driven models of dominantly-inherited Alzheimer's disease progression. Brain 141:1529-1544
Chhatwal, Jasmeer P; Schultz, Aaron P; Johnson, Keith A et al. (2018) Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing. Brain 141:1486-1500
Franzmeier, Nicolai; Düzel, Emrah; Jessen, Frank et al. (2018) Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease. Brain 141:1186-1200
Hsu, Simon; Gordon, Brian A; Hornbeck, Russ et al. (2018) Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther 10:67

Showing the most recent 10 out of 59 publications