Identifying Associations between Brain Iron, Neurocognitive Networks and Protective Factors

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Identifying Associations between Brain Iron, Neurocognitive Networks and Protective Factors Alzheimer’s disease (AD) involves accumulation of pathological levels of amyloid-beta (Aβ) and phospho-tau proteins. However, a significant proportion of individuals with AD pathology do not have clinical AD, indicating contributions of other factors. Novel in-vivo measures are required to track other factors contributing to AD-related cognitive declines. Increasing evidence suggests that age-related accumulation of brain iron and its correlates contribute to the manifestation of memory declines. Our recent neuroimaging results suggest that high brain iron concentration, measured with in vivo quantitative susceptibility mapping (QSM), is associated poor connectivity within brain memory networks. This proposal seeks to identify associations between QSM-based iron concentration and neurocognitive changes toward a goal of improving AD biomarkers. We will also define the interplay between QSM-based iron signal, AD pathology, inflammatory markers on cognitive declines. Finally, we will test the possibility that brain iron accumulation may be slowed by an antioxidant rich diet. We propose to study 140 healthy older adults using neuroimaging measures including fMRI and QSM, measures of CSF and plasma Aβ, p-tau and t-tau and inflammatory markers. Additional structural neuroimaging measures will include regional volumes, FLAIR imaging for quantification of WMH volumes and diffusion tensor imaging for quantification of regionally distributed white matter connectivity. A subset of participants will be complete the same CSF and imaging measures approximately 3 years later. We aim to identify (1) effects of QSM-based iron signal on functional and structural brain networks supporting cognition; (2) associations between brain iron, inflammatory markers, AD pathology and cognitive declines and; (3) modifiers of brain iron or its effects on cognition. We will test hypotheses that high QSM-based brain iron is associated with low connectivity in memory circuits independently of AD pathology but may and synergistically interacts with AD over time. We will also test the hypothesis that reserve factors will offset the effects of brain iron on cognitive functions via mechanisms of brain maintenance or plastic functional brain reorganization of large-scale brain functional networks in some older adults.