Elucidating the mechanisms of stress and resilience to cognitive aging and Alzheimer's disease

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia worldwide and represents one of the most serious health issues for the elderly. Today, intensive research is being conducted in disease-modifying drugs and new prevention strategies. One fundamental step towards designing successful interventions and ultimately delaying the onset of AD clinical syndrome is the identification of modifiable factors associated with resistance to the two major AD pathologies - amyloid β (Aβ) plaques and neurofibrillary tangles. In this context, the role of stress and resilience in AD has attracted increasing interest. Importantly, although previous studies suggest that resilience (both psychological and biological) may act as a buffer and protect individuals against the deleterious effects of stress, the link between stress and cognition respectively AD pathophysiology, in the context of resilience over time remains understudied. Understanding the sequential manner in which stress, resilience and AD pathology interact could add to our knowledge of the evolution of AD and may ultimately aid in determining when and how prevention strategies should be used in future intervention studies. To address these knowledge gaps the current proposal presents a unique opportunity to examine longitudinal data collected from a large population of older adults that are part of natural history, non-interventional imaging studies: the Harvard Aging Brain Study and the Instrumental Activities of Daily Living Study. The overall objective is to investigate the impact of stress and resilience on longitudinal trajectories of AD-related brain pathology and cognitive function. The central hypothesis is that the pathological mechanisms induced by stress may be a key factor predisposing individuals to long-term cognitive changes and ultimately AD. We plan to test this hypothesis using a multi-disciplinary approach combining psychological and biological measures of stress, psychological and biological measures of resilience, with in vivo measurements of AD pathology (amyloid (Aβ) and tau) and cognitive measures – all data collected at multiple time points within these highly characterized cohorts. Using longitudinal mixed-effects as well as structural equation panel models combined with crossed- lagged analyses, we will determine the direction and temporal associations between stress and cognition (aim 1) respectively AD pathology (aim 2) and whether resilience moderates these associations. The current proposal may yield important novel information regarding the mechanisms by which stress confers an increased risk to AD in humans, enhancing our understanding of the risk factors as well as the neurobiological cause of this disease. Importantly, identifying modifiable factors associated with resistance to AD pathologies will be fundamental to promoting healthy aging and designing successful interventions. As such, the results from this project will help set the stage for a future R01 application that will continue to investigate the impact of stress and resilience in aging and AD, as well as establish a bio-behavioral prevention project to promote successful aging, both from a biological and psychological perspective.