The prevention of cognitive decline and dementia is a major public health priority. The Memory and Aging Project (MAP) has made considerable progress elucidating the complex relationships between risk factors, common neuropathologies and resilience markers that increase or decrease the rate of cognitive decline, and risk of dementia. In nearly 200 peer-reviewed manuscripts, we reported genetic, medical, experiential, and psychological factors associated with increased or decreased rates of cognitive decline and dementia risk. We reported that Alzheimer's, vascular, and Lewy body pathologies (AD, CVD, LBD) explain about 40% of the variation of cognitive decline, and that resilience markers (e.g., cortical presynaptic proteins and locus coeruleus neurons) were associated with a slower rate of decline accounting for 8% of the variation, and that many risk factors with little direct relation o pathologies or resilience markers accounted for >10% of the variation of decline, controlling for pathologies. Additional factors related to cognitive decline await discovery. The overall goal of the planned continuation of MAP is to discover additional proteins associated with the slope of cognitive decline, after accounting for the effects of common pathologies. We use the term "residual cognitive decline" to describe this innovative primary study outcome. Methods to interrogate the genome, and therefore, the proteome, have improved markedly over the past decade, making the discovery of proteins that underlie cognitive decline both timely and feasible. We plan to continue collecting clinical and post-mortem data on MAP participants.
Aim 1, Discovery and Verification Phase, will combine "omics-wide" association studies with innovative integrative pathway analyses on genomic, epigenomic, and transcriptomic data from human brain from 500 MAP participants to discover proteins associated with residual cognitive decline;it will select 200 proteins for quantitation in human brain to verify that protein level i associated with residual cognitive decline.
Aim 2, Validation Phase, will quantify the 200 proteins selected and verified in Aim 1 with a new sample of 350 brains from MAP participants that will accrue by the end the funding period, followed by a joint statistical analysis to increas power (n=850).
Aim 3 will link the validated proteins to the wealth of available risk factor data t discover novel biologic pathways linking risk factors to cognitive decline and dementia. Our plan is supported by extensive and compelling new preliminary data that demonstrate its high likelihood of success and demonstrate that the study is innovative, high yield and low risk. The continuation of MAP will discover additional proteins associated with cognitive decline and novel biologic pathways linking risk factors to cognitive decline. These proteins will represent either unknown pathologies that increase rates of cognitive decline or resilience markers that decrease rates of cognitive decline. Both sets of proteins will offer new therapeutic targets for the prevention and treatment of cognitive decline and dementia. Thus, the study has the potential to have a high and sustained impact on aging and dementia research.

Public Health Relevance

The prevention of cognitive decline, MCI and dementia is a major public health priority. The proposed continuation of MAP will discover additional proteins associated with cognitive decline and novel biologic pathways linking risk factors to cognitive decline, MCI and dementia. These proteins, representing unknown pathologies and resilience markers associated with faster and slower rates of cognitive decline, will offer new therapeutic targets for the prevention and treatment of cognitive decline, MCI and dementia.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01AG017917-11A1S1
Application #
8875101
Study Section
Neurological, Aging and Musculoskeletal Epidemiology Study Section (NAME)
Program Officer
Anderson, Dallas
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
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