Dementia is characterized by progressive cognitive impairment and is the most frequent cause of death in the United States after heart disease, cancer and stroke. The most common cause of dementia is Alzheimer's disease (AD) but many other forms have been identified. Those dementias that have no clear distinguishing histological features remain largely unclassified. However, many dementias including AD exhibit familial clustering. Indeed some cases, particularly those with an early age of onset, show an autosomal dominant pattern of inheritance. Genetic linkage studies have already identified mutations causing Alzheimer's disease, Prion diseases and Huntington's disease. We propose to use a molecular genetic approach to further our understanding of the underlying causes of dementia. During the last twelve months we have identified several families multiply affected by adult onset (late and early onset) dementia. We are collecting family history , clinical and neuropathological information on these families and have begun to collect blood samples for linkage studies. In some of these families a diagnosis of Alzheimer's disease has been made whilst in others either there was no firm diagnosis or a diagnosis of another dementing illness was made. These dementing diseases may represent phenotypic variants of the known causes of dementia or genetically distinct disorders. Two of the families are multiply affected by hereditary dysphasic dementia (HDD), a cortical dementia of adult onset and autosomal dominant inheritance. Clinical and neuropathological investigations describe a unique phenotype that fits within the Pick- Alzheimer spectrum. We will use a genetic linkage strategy to test the known causes of dementia in these and other families e.g., mutations within the amyloid precursor protein (APP) gene and the prion protein gene and linkage to the chromosome 14 familial AD (FAD) locus and the Huntington's locus on chromosome 4. If linkage to the APP gene, the prion protein gene or the HD locus is detected, the gene will be sequenced to identify the mutation causing disease. Families showing linkage to the FAD locus on chromosome 14 will be used for other studies in our laboratory. If these causes of dementia can be excluded, a genetic linkage strategy will be used to map the disease loci. A positional cloning strategy will be used to clone the HDD gene. If the HDD locus is a novel gene, preliminary characterization of the gene and the gene product will be undertaken.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
3P50AG005681-15S1
Application #
6295443
Study Section
Project Start
1998-08-15
Project End
1999-04-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Schaffert, Jeff; LoBue, Christian; White, Charles L et al. (2018) Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease. Neuropsychology 32:410-416
Kamara, Dennis M; Gangishetti, Umesh; Gearing, Marla et al. (2018) Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease. J Alzheimers Dis 62:1815-1826
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10
Schindler, Suzanne E; Sutphen, Courtney L; Teunissen, Charlotte et al. (2018) Upward drift in cerebrospinal fluid amyloid ? 42 assay values for more than 10 years. Alzheimers Dement 14:62-70
Su, Yi; Flores, Shaney; Hornbeck, Russ C et al. (2018) Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies. Neuroimage Clin 19:406-416
Lewczuk, Piotr; Riederer, Peter; O'Bryant, Sid E et al. (2018) Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry. World J Biol Psychiatry 19:244-328
Blue, Elizabeth E; Bis, Joshua C; Dorschner, Michael O et al. (2018) Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Dement Geriatr Cogn Disord 45:1-17
Kaur, Antarpreet; Edland, Steven D; Peavy, Guerry M (2018) The MoCA-Memory Index Score: An Efficient Alternative to Paragraph Recall for the Detection of Amnestic Mild Cognitive Impairment. Alzheimer Dis Assoc Disord 32:120-124
Joseph-Mathurin, Nelly; Su, Yi; Blazey, Tyler M et al. (2018) Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease. Alzheimers Dement (Amst) 10:669-677
Rao, Shuquan; Ghani, Mahdi; Guo, Zhiyun et al. (2018) An APOE-independent cis-eSNP on chromosome 19q13.32 influences tau levels and late-onset Alzheimer's disease risk. Neurobiol Aging 66:178.e1-178.e8

Showing the most recent 10 out of 952 publications