In most cases of Alzheimer's diseased (AD), it is impossible to identity the triggering event which leads to the neurodegenerative process. However, in a small subset (2-3%) of familial Alzheimer disease (FAD) kindreds, several mutations have been found in a chromosome 21 gene, APP encoding the precursor of the Abeta peptide that is deposited in amyloid plaques. Detailed family studies have shown that AD is genetically heterogeneous and linkage studies using markers from other chromosomes have led to the localization of a late-onset (more 65 years) FAD locus mapping within or close to the APOE gene on chromosome 19. More recently, the extended FAD pedigree collections made possible through the efforts of the Massachusetts ADRC over the past ten years have allowed our laboratory in collaboration to localize a major FAD locus on chromosome 14. Among the FAD pedigrees screened in our Boston-Toronto study, six independent pedigrees individually yielded lod scores exceeding the conventional significance value of 3. The magnitude and robustness of these scores indicate definitively that there is a chromosome 14 locus that most likely accounts for a major proportion (70-90%) of early-onset FAD (lessor 65 years). The goal of this proposal is to employ a variety of strategies including positional cloning, physical mapping, and testing of candidate genes to ultimately isolate, identify, and characterize the FAD gene defect on chromosome 14. Given our extensive collection of well characterized early-onset FAD pedigrees and the large amount of preliminary data that we have already amassed concerning the chromosome 14 FAD locus, we are in a uniquely ideal position to successfully carry out the studies described in this application. The knowledge obtained from the proposed studies could provide critical clues to the causes of both inherited and sporadic AD, and ultimately provide vital information for designing treatments aimed at strategically intervening with the effects of discovered FAD gene defects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005134-15
Application #
6267273
Study Section
Project Start
1998-04-15
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Dujardin, Simon; Bégard, Séverine; Caillierez, Raphaëlle et al. (2018) Different tau species lead to heterogeneous tau pathology propagation and misfolding. Acta Neuropathol Commun 6:132
Wang, Qi; Guo, Lei; Thompson, Paul M et al. (2018) The Added Value of Diffusion-Weighted MRI-Derived Structural Connectome in Evaluating Mild Cognitive Impairment: A Multi-Cohort Validation1. J Alzheimers Dis 64:149-169
Wang, Tingyan; Qiu, Robin G; Yu, Ming (2018) Predictive Modeling of the Progression of Alzheimer's Disease with Recurrent Neural Networks. Sci Rep 8:9161
DeVos, Sarah L; Corjuc, Bianca T; Commins, Caitlin et al. (2018) Tau reduction in the presence of amyloid-? prevents tau pathology and neuronal death in vivo. Brain 141:2194-2212
Lee, Christopher M; Jacobs, Heidi I L; Marquié, Marta et al. (2018) 18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal. J Alzheimers Dis 62:1691-1702
Eftekharzadeh, Bahareh; Daigle, J Gavin; Kapinos, Larisa E et al. (2018) Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron 99:925-940.e7
Agogo, George O; Ramsey, Christine M; Gnjidic, Danijela et al. (2018) Longitudinal associations between different dementia diagnoses and medication use jointly accounting for dropout. Int Psychogeriatr 30:1477-1487
Crum, Jana; Wilson, Jeffrey; Sabbagh, Marwan (2018) Does taking statins affect the pathological burden in autopsy-confirmed Alzheimer's dementia? Alzheimers Res Ther 10:104
Emerson, Sarah C; Waikar, Sushrut S; Fuentes, Claudio et al. (2018) Biomarker validation with an imperfect reference: Issues and bounds. Stat Methods Med Res 27:2933-2945
Petyuk, Vladislav A; Chang, Rui; Ramirez-Restrepo, Manuel et al. (2018) The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target. Brain 141:2721-2739

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