Alzheimer Disease (AD), one of the major health problem in US and worldwide, is a neurodegenerative disorder that is characterized clinically by progressive dementia caused by pathological changes in brain tissue preceding clinical symptoms by 15-20 years. Diagnostic methods are urgently needed for screening populations for early (preclinical) signs of AD pathology when drug intervention could be most efficient, and providing means for monitoring therapeutic efficacy in clinical drug trials. Recently proposed by National Institute of Aging and Alzheimer Association A/T/N (amyloid/ tau/ neurodegeneration) approach classifies stages of AD by means of AD-related tissue pathology. While brain amyloid plaques and tau neurofibrillary tangles can now be measured in vivo using PET tracers, the neurodegeneration is mostly measured in vivo as tissue atrophy by MRI-based morphological studies. However, histopathological studies demonstrated that the neuronal loss in AD significantly exceeds loss of tissue volume. The objective of this project is to introduce a new, potentially widely available, in vivo MRI-based neuroimaging biomarker that would detect loss of neurons at the very earlier AD stages when this loss is not recognized by volumetric measurements (pre-atrophic neurodegeneration). Our innovative approach relies on MRI-based quantitative Gradient Recalled Echo (qGRE) technique developed in our lab. Preliminary data demonstrate that the qGRE identifies two types of tissues in the hippocampus of people with preclinical and mild AD: one type – tissue with markedly lower neuronal content (that we term Dark Matter as it appears dark on qGRE images), and another type – tissue with a relatively preserved concentration of neurons (that we term Viable Tissue). Based on this approach, we plan to achieve the following Specific Aims: Aim 1 will establish pre-atrophic neurodegeneration as a new imaging biomarker of neuronal loss that precedes tissue atrophy and can detect loss of neurons in early, preclinical, AD stages. Aim 2 will establish pre-atrophic neurodegeneration as a biomarker identifying losses of brain functional connectivity and cognitive performance in early AD. Aim 3 will integrate qGRE-based biomarker of pre-atrophic neuronal loss with plasma Aβ42/Aβ40 measurement that would significantly improve upon individual qGRE and plasma Aβ42/Aβ40 tests with regard to sensitivity and specificity for an early detection of AD pathology. Aim 4 will explore an association between brain topographies of AD-related genes and pre-atrophic neurodegeneration at earlier stages of AD. In Summary, successful completion of the aims of this proposal could significantly improve the current imaging paradigm for monitoring individual patients over time, and for use as a more sensitive measure of the neurodegenerative aspects of AD pathology as compared with current measurements of tissue atrophy.