Project 2 in the Johns Hopkins Alzheimer's Disease Research Center (ADRC) is entitled "The roles of AB, tau and synaptic loss in early AD". The overarching goal of this project is to understand the mechanisms that allow some individuals to tolerate substantial Alzheimer's disease (AD) pathology, whereas others with similar brain abnormalities develop MCI or dementia. We will use a collection of brains from prospectively followed subjects from the ADRC, known as the Johns Hopkins ADRC Autopsy Cohort (JHAAC). The JHAAC includes brain tissue from a substantial number of subjects who were cognitively normal shortly before death, but were found to have substantial AD pathology on autopsy, referred to as 'asymptomatic AD'. The JHAAC also includes brain tissue from controls, subjects with MCI and patients with AD. We will examine three hypotheses in this project.
Aim 1 : We will test the hypothesis that amyloid-beta (AP) oligomers, not AB deposits, are responsible for cognitive decline. We will determine whether AP40, AP42 and AB oligomers distinguish the cognitive phenotypes of subjects with similar levels of AD pathology, as measured by the standard Braak and CERAD scales. In addition, we will examine whether the significant AB accumulation seen in the brains of the subset of cognitively normal subjects with substantial AD pathology is due to quantitative differences in the amount, bioactivity or distribution of enzymes purported to degrade or transport AB in vivo.
Aim 2 : We will test the hypothesis that the process that couples AB deposition with neuronal/synaptic abnormalities is associated with Tau phosphorylation or cleavage. We propose to quantitate the amount of Tau phosphorylation and fragmentation in JHAAC brain specimens to determine the strength of the relationship between these biochemical changes and cognitive status. We will also examine whether quantitative differences in the regional distribution of AB monomers, AB oligomers or glycogen synthetase kinase (GSK) 3a and 3B are associated with Tau phosphorylation or cleavage.
Aim 3 : On the assumption that synaptic dysfunction and degeneration underlies the cognitive impairment in AD, we will test the hypothesis that enhanced synaptic plasticity allows for normal cognition in the face of significant AD pathology.

Public Health Relevance

Understanding the biochemical mechanisms that underiie the accumulation of Alzheimer's pathology in the brains of some elderiy subjects (amyloid plaques and neurofibrillary tangles) and determining why some subjects with Alzheimer's pathology become demented and others remain cognitively normal is of crucial importance in developing strategies to combat Alzheimer's disease, a neurodegenerative disorder which affects over 6 million Americans.

National Institute of Health (NIH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Gracia-Garcia, Patricia; de-la-Camara, Concepcion; Santabarbara, Javier et al. (2015) Depression and incident Alzheimer disease: the impact of disease severity. Am J Geriatr Psychiatry 23:119-29
Marano, Christopher M; Workman, Clifford I; Lyman, Christopher H et al. (2015) Structural imaging in late-life depression: association with mood and cognitive responses to antidepressant treatment. Am J Geriatr Psychiatry 23:12-Apr
Ning, Jing; Bandeen-Roche, Karen (2014) Estimation of time-dependent association for bivariate failure times in the presence of a competing risk. Biometrics 70:10-20
Reagh, Zachariah M; Roberts, Jared M; Ly, Maria et al. (2014) Spatial discrimination deficits as a function of mnemonic interference in aged adults with and without memory impairment. Hippocampus 24:303-14
Ho, Cheng-Ying; Troncoso, Juan C; Knox, David et al. (2014) Beta-amyloid, phospho-tau and alpha-synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer's and Parkinson's disease patients. Brain Pathol 24:25-32
Beecham, Gary W; Hamilton, Kara; Naj, Adam C et al. (2014) Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias. PLoS Genet 10:e1004606
Leal, Stephanie L; Tighe, Sarah K; Jones, Craig K et al. (2014) Pattern separation of emotional information in hippocampal dentate and CA3. Hippocampus 24:1146-55
Ayers, Jacob I; Xu, Guilian; Pletnikova, Olga et al. (2014) Conformational specificity of the C4F6 SOD1 antibody; low frequency of reactivity in sporadic ALS cases. Acta Neuropathol Commun 2:55
Semba, Richard D; Moghekar, Abhay R; Hu, Jason et al. (2014) Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease. Neurosci Lett 558:37-40
Wendell, Carrington R; Waldstein, Shari R; Zonderman, Alan B (2014) Nonlinear longitudinal trajectories of cholesterol and neuropsychological function. Neuropsychology 28:106-12

Showing the most recent 10 out of 320 publications