Identifying Associations between Brain Iron, Neurocognitive Networks and Protective Factors

Alzheimer’s disease involves accumulation of pathological levels of amyloid-beta (Aâ) and phospho-tau proteins. However, a significant proportion of individuals with AD pathology do not have clinical AD, indicating contributions of other factors. Increasing evidence suggests that age-related accumulation of brain iron contributes to the manifestation of AD-related memory declines. Further, the effects of brain pathologies can be moderated by cognitive reserve and brain resilience. Our recent neuroimaging results suggest that brain iron concentration levels, measured with in vivo quantitative susceptibility mapping, contributes to the disruption of brain memory networks independent of levels of Aâ and tau. In addition, our results suggest that brain iron concentration appears initially more closely related to inflammatory markers than AD pathology biomarkers in cerebrospinal fluid (CSF). Finally, our preliminary results indicate that an antioxidant rich diet may protect against brain iron accumulation. This proposal seeks to identify disruptive effects of iron on neurocognitive networks and potential modifiers. We will also define the interplay between brain iron, AD pathology, inflammatory markers on AD-like cognitive declines. We propose to study 120 healthy older adults using neuroimaging measures including fMRI and QSM, measures of CSF and plasma Aâ, 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 abnormalities. A subset of participants will be complete the same CSF and imaging measures approximately 3 years later. We aim to identify (1) effects of iron 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 brain iron disrupts memory circuits independently of AD pathology and synergistically interacts with AD pathology to accelerate AD-like cognitive declines 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.