From the cellular to the chronic : towards a continuum of stress and aging in Alzheimer's disease
Keywords: Medicine.

Older adults bear a disproportionate share of the global disease burden, and this is likely to only increase with the rapidly aging population worldwide. Chronic, noncommunicable diseases are the leading drivers of morbidity and mortality among older adults, and these, in turn, are primarily driven by aging. Understanding the biological mechanisms that underlie the relationship between age and disease is of critical importance to global health and is foundational to the field of geroscience. One important area of geroscience research is understanding how lifetime adaptation to stress contributes to chronic disease. Stress can be understood as a state of threatened homeostasis, which can occur at different levels within an organism, including the molecular, cellular, and psychological level. Our bodies mount physiological responses in order to maintain stability in response to stressors, through a process known as "allostasis." Over time, or in the face of prolonged stress exposure, this process becomes dysregulated and can result in damage across different organ systems; this phenomenon is commonly referred to as "allostatic load." Allostatic load is an important feature of biological aging, but more research is needed to integrate our understanding of this phenomenon across different levels of biological organization in humans, especially in dis-ease contexts. This work is an effort to bridge this gap. It focuses on dementia — particularly Alzheimer's disease (AD) — as this is one of the leading causes of death among older adults. AD is characterized by memory loss and cognitive decline, and within the brain, it is accompanied by extensive atrophy, amyloid plaques (extracellular deposits of the amyloid-ß protein) and neurofibrillary tangles (composed of hyperphosphorylated tau protein aggregates). It is also preceded years, if not decades earlier, by an asymptomatic, preclinical stage involving abnormal aggregation of the amyloid-ß protein. The present research is aimed at demonstrating how a multi-level concept of stress can both predict — as well as deepen our understanding — of aging, AD, and dementia. This work is divided into three parts. First, we use data from a multiplex proteomics platform to construct a co-expression network of 3,868 cerebrospinal fluid (CSF) proteins. We identify a community of proteins devoted to the cellular stress response and linked to neuropathological and cognitive changes associated with preclinical AD. Second, we use a high-throughput immunoassay of CSF proteins and identify a regulator of the psychological stress response — corticotropin-releasing hormone (CRH) — to be differentially abundant in the context of dementia, compared to clinically unimpaired older adults. We observe associations between CRH and CSF biomarkers of AD pathology, as well as differences in grey matter volume in the prefrontal cortex, measured using magnetic resonance imaging. Finally, we examine the relationship between having two or more chronic conditions — or multimorbidity — and positron emission tomography measures of AD pathology. Multimorbidity can reflect allostatic load; we find that it has effects on cognition independent of amyloid plaque and neurofibrillary tangle burden.