Alzheimer's disease (AD) is the most common neurodegenerative disease, afflicting over 4 million people over the age of 65 years, in the U.S. Current medications treat the symptoms but not the underlying causes of disease. There is therefore an urgent need to understand the pathogenic mechanisms of disease to enable rational drug design. During the last twenty years genetic studies of familial early onset AD have dramatically changed our understanding of the disease by demonstrating that mutations in three different genes cause disease via a common biochemical pathway involving B-amyloid (Ali) metabolism. Genetic epidemiology has demonstrated that late onset AD (LOAD) also has a strong genetic component. However, to date only the e4 allele of apolipoprotein E, present in only 50% of LOAD cases, has been convincingly demonstrated to influence risk for LOAD. There is therefore a clear need for new approaches to understanding the genetics of LOAD. We will use intermediate traits, or endophenotypes to identify novel genetic risk factors for LOAD. Endophenotypes may be continuous variables that are correlated with disease but measurable in many or all individuals, avoiding the heterogeneity associated with clinical diagnoses and allowing the use of quantitative statistical methods. Endophenotypes may also provide a biological model of disease and the possible effects of the associated genetic variation. Several promising endophenotypes are protein biomarkers found in cerebrospinal fluid (CSF) including amyloid-beta (A(3), tau, serpin peptidase inhibitor, clade C (antithrombin), member 1 (ATI11), serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 (ACT), carnosine dipeptidase 1 (CNDP1) andA-2- glycoprotein 1, zinc (ZAG). These proteins are present in all individuals, show variability amongnon- demented individuals and change with disease. The goal of this study is to identify cis-acting genetic variation that is associated with CSF levels of these AD biomarkers, and to test in independent datasets whether this variation also influences age at onset of AD or risk for AD. Functional studies will be employed to determine the biological effects of the associated genetic variation. These data will inform our models of age at onset of AD, AD diagnosis (project 2) and our studies of the interaction between preclinical AD and post-stroke dementia (project 1). As a proof of principle regarding this approach we have already identified genetic variants in A/MPTthat show significant association with both CSF tau and ptau181 levels. Further study shows that this association is limited to individuals with evidence of A(3deposition. Genetic variation in this region also appears to be associated with expression levels of tau mRNA in individuals with amyloid deposition and age at onset of LOAD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG003991-30
Application #
8425017
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
30
Fiscal Year
2013
Total Cost
$108,935
Indirect Cost
$37,265
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin et al. (2018) Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 14:205-214
Maxwell, Taylor J; Corcoran, Chris; Del-Aguila, Jorge L et al. (2018) Genome-wide association study for variants that modulate relationships between cerebrospinal fluid amyloid-beta 42, tau, and p-tau levels. Alzheimers Res Ther 10:86
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
Brainstorm Consortium (see original citation for additional authors) (2018) Analysis of shared heritability in common disorders of the brain. Science 360:
Ibanez, Laura; Dube, Umber; Davis, Albert A et al. (2018) Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease. Front Neurosci 12:230
Schultz, Stephanie A; Gordon, Brian A; Mishra, Shruti et al. (2018) Widespread distribution of tauopathy in preclinical Alzheimer's disease. Neurobiol Aging 72:177-185
Broce, Iris; Karch, Celeste M; Wen, Natalie et al. (2018) Correction: Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Med 15:e1002504
Javaherian, Kavon; Newman, Brianne M; Weng, Hua et al. (2018) Examining the Complicated Relationship Between Depressive Symptoms and Cognitive Impairment in Preclinical Alzheimer Disease. Alzheimer Dis Assoc Disord :
Liao, Fan; Li, Aimin; Xiong, Monica et al. (2018) Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest 128:2144-2155
Jansen, Willemijn J; Ossenkoppele, Rik; Tijms, Betty M et al. (2018) Association of Cerebral Amyloid-? Aggregation With Cognitive Functioning in Persons Without Dementia. JAMA Psychiatry 75:84-95

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