Mechanisms and Predictors of Brain Aging in Healthy Aging, Preclinical AD and MCI

健康衰老和病理之间的区别是不精确的，并且由于重叠而模糊不清

The distinction between healthy aging and pathology is imprecise and is clouded by overlap among normal brain aging markers and neural changes associated with Alzheimer’s disease (AD). Even in the case of beta-amyloid deposition, a key hallmark of AD, 20-30% of healthy older individuals show elevated amyloid, yet it remains unclear if these individuals will necessarily progress to dementia. Therefore, there is significant need for studies designed to investigate novel, lesser-studied mechanisms of brain aging, which may help disambiguate the neural changes that are early indicators of a pathological trajectory vs. signs of normal aging. The present study aims to provide new insight into neurocognitive aging with a multimodal investigation of important and understudied mechanisms of brain aging from molecular changes (iron accumulation and Aβ deposition) to synaptic changes (neurite complexity) to changes in brain function (BOLD modulation of activation) and their influence on cognition in middle-aged, older and MCI individuals. Critically, we propose to prospectively study healthy aging individuals who systematically vary in risk for AD (cognitively healthy low risk for AD, cognitively healthy elevated risk for AD) alongside individuals with Mild Cognitive Impairment (MCI), who are more likely to be in the early stages of neuropathological development. Through this approach, we aim to help elucidate some of the mechanisms underlying key aspects of brain and cognitive aging in healthy adults and also to distinguish which age-related brain changes may signal preclinical AD vs. non-pathological aging. The first aim proposes to examine brain iron accumulation as an early marker for cognitive and neural decline. We will study the impact of increased brain iron on cognitive performance and fMRI measured brain activation in healthy aging, preclinical AD and MCI. Secondly, we aim to examine the effect of synaptic complexity on cognitive performance and brain activation across risk groups. We will examine the relationship of both iron accumulation and synaptic complexity measures to beta-amyloid accumulation in preclinical aging and MCI to gauge whether these variables may serve as sensitive biomarkers for pathological aging. Finally, we plan to test the hypothesis that differences in neural modulation to cognitive difficulty as measured with fMRI may serve as a biomarker for preclinical AD. Completion of the current study is expected to advance understanding of the mechanisms and predictors of healthy brain aging versus a pathological aging trajectory.