Most epidemiologic studies of risk factors for Alzheimer's diseas are limited to clinically diagnosed disease. The proposed study offers the opportunity to integrate pathologic clinical data, and thereby examine the mechanisms through which risk factors for Alzheimer's disease lead to clinical expression of the disease. Preliminary data for two risk factors, the apolipoprotein E Epsilon 4 allele and years of formal education, suggest that they lead to a clinical disease through dissimilar mechanisms. Although both are associated with clinical disease the epsilon 4 allele is related to recognized Alzheimer's disease pathology, but years of formal education is not We will test the hypotheses that the apolipoprotein E epsilon 4 allele alters risk of clinical disease through its association with amyloid deposition and neurofibrillary changes, that years of formal education and female gender alte risk of clinical disease through their association with neuronal counts and synaptic density and that subcortical brain infarctions alter risk of clinical disease by increasing the likelihood that Alzheimer's disease pathology is clinically expressed. The study will also characterize the relation of age to pathologic and clinical expression of disease and describe how age modifies th relation of post-mortem indices to the clinical expression of Alzheimer's disease. The findings from the proposed study may have profound implications for therapeutic intervention and disease prevention. Hypothesis testing requires risk factor information, longitudinal structured quantitative clinica data collected proximate to death and brain tissue. The proposed project will collect new post-mortem data and link it to available risk factor information and clinical data in innovative analyses. The Religious Orders Study (ROS) which performs annual clinical evaluations on more than 650 nuns, priests, and brothers over the age of 65 who have agreed to brain donation after death, provides and ideal source of longitudinal clinical data and of brain tissue fo the proposed project.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Anderson, Dallas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rush University Medical Center
United States
Zip Code
Bennett, Rachel E; Robbins, Ashley B; Hu, Miwei et al. (2018) Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease. Proc Natl Acad Sci U S A 115:E1289-E1298
Hanko, Veronika; Apple, Alexandra C; Alpert, Kathryn I et al. (2018) In vivo hippocampal subfield shape related to TDP-43, amyloid beta, and tau pathologies. Neurobiol Aging 74:171-181
Tasaki, Shinya; Gaiteri, Chris; Mostafavi, Sara et al. (2018) Multi-omic Directed Networks Describe Features of Gene Regulation in Aged Brains and Expand the Set of Genes Driving Cognitive Decline. Front Genet 9:294
De Jager, Philip L; Ma, Yiyi; McCabe, Cristin et al. (2018) A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research. Sci Data 5:180142
Wang, Xulong; Philip, Vivek M; Ananda, Guruprasad et al. (2018) A Bayesian Framework for Generalized Linear Mixed Modeling Identifies New Candidate Loci for Late-Onset Alzheimer's Disease. Genetics 209:51-64
Chibnik, L B; White, C C; Mukherjee, S et al. (2018) Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies. Mol Psychiatry 23:1521-1529
Arvanitakis, Zoe; Leurgans, Sue E; Fleischman, Debra A et al. (2018) Memory complaints, dementia, and neuropathology in older blacks and whites. Ann Neurol 83:718-729
Capuano, Ana W; Wilson, Robert S; Leurgans, Sue E et al. (2018) Sigmoidal mixed models for longitudinal data. Stat Methods Med Res 27:863-875
Felsky, Daniel; Patrick, Ellis; Schneider, Julie A et al. (2018) Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain. Mol Neurodegener 13:38
Lamar, Melissa; Yu, Lei; Rubin, Leah H et al. (2018) APOE genotypes as a risk factor for age-dependent accumulation of cerebrovascular disease in older adults. Alzheimers Dement :

Showing the most recent 10 out of 355 publications