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
Bateman, Randall J; Benzinger, Tammie L; Berry, Scott et al. (2016) The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model. Alzheimers Dement :
Su, Yi; Blazey, Tyler M; Owen, Christopher J et al. (2016) Correction: Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group. PLoS One 11:e0163669
Soosman, Steffan K; Joseph-Mathurin, Nelly; Braskie, Meredith N et al. (2016) Widespread white matter and conduction defects in PSEN1-related spastic paraparesis. Neurobiol Aging 47:201-209
Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos et al. (2016) BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease. Brain 139:2766-2777
Miller-Thomas, Michelle M; Sipe, Adam L; Benzinger, Tammie L S et al. (2016) Multimodality Review of Amyloid-related Diseases of the Central Nervous System. Radiographics 36:1147-63
Muenchhoff, Julia; Poljak, Anne; Thalamuthu, Anbupalam et al. (2016) Changes in the plasma proteome at asymptomatic and symptomatic stages of autosomal dominant Alzheimer's disease. Sci Rep 6:29078
Tang, Mengxuan; Ryman, Davis C; McDade, Eric et al. (2016) Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol 15:1317-1325
Su, Yi; Blazey, Tyler M; Owen, Christopher J et al. (2016) Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group. PLoS One 11:e0152082
Jin, Yan; Su, Yi; Zhou, Xiao-Hua et al. (2016) Heterogeneous multimodal biomarkers analysis for Alzheimer's disease via Bayesian network. EURASIP J Bioinform Syst Biol 2016:12
Roe, Catherine M; Barco, Peggy P; Head, Denise M et al. (2016) Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals. Alzheimer Dis Assoc Disord :

Showing the most recent 10 out of 29 publications