A central insight gained from the current cycle of AG011378 is that in someone destined to develop Alzheimer's disease (AD) dementia, different biomarkers become abnormal in a sequential manner. Based on results from the current grant cycle, we proposed a biomarker-based disease model which posits that amyloid biomarkers become abnormal first, perhaps 15 years before the onset of overt clinical symptoms. Neuronal injury biomarkers become abnormal next, followed later by incident mild cognitive impairment (MCI). While we believe the model is largely correct, some in the field dispute this and therefore empiric evaluation is needed. This renewal will evaluate and extend our hypothetical biomarker model by following a large, population- based cohort of cognitively normal (CN) subjects studied with biomarkers for up to 10 years, and thus address major gaps in understanding disease progression. The central objective of this renewal is to understand how imaging biomarkers of AD pathophysiology (AD-P) change in the preclinical and early MCI phases of AD in relation to each other, and then to identify practical implications of sequential biomarker change. A notable strength of this renewal is our large - perhaps the largest in the world - existing cohort of CN subjects from an epidemiologically defined sample who have already undergone all imaging studies at baseline. Subjects for this renewal (n~1500) will be participants in the Mayo Clinic Study of Aging, an epidemiological sample of non- demented subjects in Olmsted County, MN. As outlined in the Introduction, we have significantly revised this A1 application in response to the study section critique.
Aim 1. Establish cut-points for amyloid PET, TF-fMRI, FDG-PET, sMRI, CSF A42 and tau demarcating normal from abnormal. A major question in the field at present is how to appropriately define AD biomarker cut-points that separate normal from abnormal.
Aim 2. Model validation: test the hypothesis that AD imaging biomarkers become abnormal in a specific temporal order. Our initial model was consistent with the amyloid cascade hypothesis in that amyloid biomarkers become abnormal first followed by FDG-PET and MR. However, this has been challenged. We will formally test this hypothesis using three different approaches and will extend and refine our existing model of biomarker evolution based on these findings. These results could alter current notions of AD pathogenesis.
Aim 3. To integrate AD-P biomarker evidence with other predictors to enhance risk prediction for incident MCI. This will provide practical guidance for using AD biomarkers for clinical counseling.
Aim 4. To provide practical guidance for using AD biomarkers in secondary prevention clinical trials.

Public Health Relevance

In the current grant cycle of AG011378, we proposed a hypothetical model describing the order in which biomarkers of Alzheimer's disease (AD) evolve over time. This model has conceptually influenced the development of new diagnostic criteria and also the design of modern disease modifying therapeutic trials. Our goals in this renewal are to test if this model is correct and where indicated, revise it and in so doing provide practicl information for counseling patients regarding the implications of abnormal AD biomarkers and to aid in designing therapeutic clinical trials in preclinical AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011378-23
Application #
8850359
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Hsiao, John
Project Start
1993-06-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
23
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Weiner, Michael W; Harvey, Danielle; Hayes, Jacqueline et al. (2017) Effects of traumatic brain injury and posttraumatic stress disorder on development of Alzheimer's disease in Vietnam Veterans using the Alzheimer's Disease Neuroimaging Initiative: Preliminary Report. Alzheimers Dement (N Y) 3:177-188
Pichler, Michael; Vemuri, Prashanthi; Rabinstein, Alejandro A et al. (2017) Prevalence and Natural History of Superficial Siderosis: A Population-Based Study. Stroke 48:3210-3214
Raman, Mekala R; Tosakulwong, Nirubol; Zuk, Samantha M et al. (2017) Influence of preeclampsia and late-life hypertension on MRI measures of cortical atrophy. J Hypertens 35:2479-2485
Wiepert, Daniela A; Lowe, Val J; Knopman, David S et al. (2017) A robust biomarker of large-scale network failure in Alzheimer's disease. Alzheimers Dement (Amst) 6:152-161
Zeydan, Burcu; Lowe, Val J; Schwarz, Christopher G et al. (2017) Pittsburgh compound-B PET white matter imaging and cognitive function in late multiple sclerosis. Mult Scler :1352458517707346
Zeydan, Burcu; Deelchand, Dinesh K; Tosakulwong, Nirubol et al. (2017) Decreased Glutamate Levels in Patients with Amnestic Mild Cognitive Impairment: An sLASER Proton MR Spectroscopy and PiB-PET Study. J Neuroimaging 27:630-636
Kantarci, Kejal; Murray, Melissa E; Schwarz, Christopher G et al. (2017) White-matter integrity on DTI and the pathologic staging of Alzheimer's disease. Neurobiol Aging 56:172-179
Jones, David T; Graff-Radford, Jonathan; Lowe, Val J et al. (2017) Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum. Cortex 97:143-159
Kantarci, Kejal; Lowe, Val J; Boeve, Bradley F et al. (2017) AV-1451 tau and ?-amyloid positron emission tomography imaging in dementia with Lewy bodies. Ann Neurol 81:58-67
Vemuri, Prashanthi; Lesnick, Timothy G; Przybelski, Scott A et al. (2017) Age, vascular health, and Alzheimer disease biomarkers in an elderly sample. Ann Neurol 82:706-718

Showing the most recent 10 out of 282 publications