PROJECT SUMMARY The goal of the proposed study is to develop novel cognitive and neuroimaging markers to detect subtle cognitive and neural changes in association with beta-amyloid (Aβ) deposition and tau-protein neurofibrillary tangles (NFT), pathological hallmarks of Alzheimer's disease (AD), among clinically intact older adults. Recent advances in in vivo positron emission tomography (PET) have significantly increased our awareness of the presence of Aβ plaques in approximately 20-50% of cognitively normal older adults who are now considered as preclinical AD. Differentiating healthy older adults from those who are in the preclinical stage of AD, however, remains to be challenging, in part because behavioral and neural measures that are sensitive and specific to detect the presence of Aβ plaques in the stage of preclinical AD are largely lacking. Furthermore, the co-presence of NFT pathology in these individuals makes it difficult to link AD pathologies to specific cognitive function. Identifying how brain aging and AD pathology affect cognition and the underlying neural systems would offer more sophisticated behavioral phenotypes and neural markers with clinical utility in aiding early diagnosis and treatment monitoring that otherwise may remain undetected with traditional neuropsychological tests. We will recruit 50 healthy young adults and 125 cognitively normal elderly who will undergo cognitive experimental, neuroimaging, and neuropsychological assessments. Aim 1 will test the hypothesis that Aβ deposition and NFTs in cognitively normal elderly will differentially impact a set of cognitive component tasks that disproportionately tax frontoparietal and medial temporal lobe functions. Aim 2 will test that Aβ deposition and NFTs differentially affect brain activation and connectivity patterns measured by structural and functional MRI during cognitive tasks that use a gradient degree of frontoparietal and medial temporal lobe function. Aim 3 will compare the sensitivity and specificity in detecting the effect of Aβ deposition and NFTs on cognition between cognitive component tasks and traditional neuropsychological assessments. A successful completion of the aims will elucidate the mechanistic link between AD pathologies and cognitive consequences in the early stage of the disease and contribute to novel behavioral and neuroimaging markers of early AD. The developed cognitive task battery has a potential to be developed as a screening test for the presence of AD pathologies in a non-invasive, more accessible, and more affordable manner for clinically intact older adults.