Alzheimer's disease is a devastating eurodegenerative disorder affecting more than 5 million older people in the U.S.A. for which there is not treatment. It is imperative to define the earliest cellular, mechanisms that drive the earliest onset of dementia in order to develop novel disease modifying therapeutic approaches. The thrust of this PPG entitled Neurobiology of Mild Cognitive Impairment in the Elderly continues to be to elucidate the cellular and molecular basis or chain of events leading from no cognitive impairment (NCI) to mild cognitive impairment (MCI), the time-point considered the most likely therapeutic window. Moreover, we will refocus our efforts to include NCI subjects with pathology suggestive of AD, in order to resolve the neuropathogenic sequela underlying preclinical AD. We will implement a series of interrelated circuit-based projects centered on the cholinergic basal forebrain cortical (CBF) projection system, which displays early cellular pathology prior to MCI (preclinical AD), plays a pivotal role in the onset of clinical dementia and is the basis for most of the current FDA approved drugs for AD. The investigations proposed for this competitive renewal application of the Program Project brings together a number of basic and clinician scientists from Chicago and outside universities to investigate circuit based neuronal system dysfunction at a very early stage in the disease progress termed preclinical AD compared to prodromal AD (mild cognitive impairment). The Program Project consists of an Administrative Core with a Clinical/Tissue Distribution component and a Statistics and Data Management Core. In addition the following four research projects complete the program: 1) Tau abnormalities and Mild Cognitive Impairment in the Elderly (Lester Skip Binder, Northwestern University Medical School); 2) Age-Related Neuropathology and Mild Cognitive Impairment in the Elderly (James Lah, Emory University School of Medicine); 3) Cholinergic Basal Forebrain Neurotrophic Abnormalities and Mild Cognitive Impairment in the Elderly (Elliott Mufson, Rush Medical Center); and Synaptic Abnormalities and Mild Cognitive Impairment in the Elderly (Milos Ikonomovic, University of Pittsburgh). Each core supports all research projects and all projects interact.

Public Health Relevance

The proposed research program will allow the understanding of alterations in brain pathophysiology that can differentiate preclinical individuals from those with prodromal AD (MCI) so that treatment strategies can be targeted at the earliest phases of the disease. The proposed studies are relevant to the NIA mission to support research aimed at defining the cellular, proteomic and molecular processes of dementia at its earliest stage of onset

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Opanashuk, Lisa A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Joseph's Hospital and Medical Center
United States
Zip Code
Kelly, Sarah C; He, Bin; Perez, Sylvia E et al. (2017) Locus coeruleus cellular and molecular pathology during the progression of Alzheimer's disease. Acta Neuropathol Commun 5:8
McKay, Erin; Counts, Scott E (2017) Multi-Infarct Dementia: A Historical Perspective. Dement Geriatr Cogn Dis Extra 7:160-171
Perez, Sylvia E; Nadeem, Muhammad; Malek-Ahmadi, Michael H et al. (2017) Frontal Cortex and Hippocampal ?-Secretase Activating Protein Levels in Prodromal Alzheimer Disease. Neurodegener Dis 17:235-241
Marquié, Marta; Normandin, Marc D; Meltzer, Avery C et al. (2017) Pathological correlations of [F-18]-AV-1451 imaging in non-alzheimer tauopathies. Ann Neurol 81:117-128
Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E (2017) Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders. Ageing Res Rev 34:51-63
Krivinko, Josh M; Erickson, Susan L; Abrahamson, Eric E et al. (2017) Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice. Neurobiol Aging 54:59-70
Sorrentino, Vincenzo; Romani, Mario; Mouchiroud, Laurent et al. (2017) Enhancing mitochondrial proteostasis reduces amyloid-? proteotoxicity. Nature 552:187-193
Mahady, Laura J; Perez, Sylvia E; Emerich, Dwaine F et al. (2017) Cholinergic profiles in the Goettingen miniature pig (Sus scrofa domesticus) brain. J Comp Neurol 525:553-573
Counts, Scott E; Mufson, Elliott J (2017) Regulator of Cell Cycle (RGCC) Expression During the Progression of Alzheimer's Disease. Cell Transplant 26:693-702
Powers, Brian E; Kelley, Christy M; Velazquez, Ramon et al. (2017) Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring. Neuroscience 340:501-514

Showing the most recent 10 out of 270 publications