Inter-Individual Immune Variability in Aging, Frailty and Alzheimer Disease

Abstract

Aging is associated with profound changes the human immune system, including 'immunosenescence' (the accumulation of senescent immune cells) and `inflammageing' (a chronic low-grade `sterile' inflammatory state) which are in turn influenced by 'immunobiography' (prior infectious/non-infectious exposures). The relationship between these processes and important clinical outcomes in older adults such as inadequate vaccine responses, the accumulation of frailty and presentation of age-related disease, has been inadequately explored in human studies to date. This thesis addresses this research gap by coupling high-throughput translational immunology techniques and clinically-relevant cohorts - focusing on frailty and Alzheimer's Disease (AD) - to help elucidate these relationships. In study one, using blood samples from 200 donors aged 24-97, age was associated with increased markers of inflammageing (MMP-1, GDF-15, IL-6, IL-8) whilst frailty was associated with endothelial dysfunction (ICAM-1, VCAM-1). Frail individuals demonstrated greater spontaneous cytokine release, but similar induced cytokine responses to non-frail, hinting at early immune dysregulation with the accumulation of frailty, independent of age itself. In study two, adaptive immune responses were examined in a longitudinal study of vaccine responses in older nursing home residents - those living with significant frailty and comorbidity most vulnerable to infectious disease. Significant longitudinal relationships were observed between baseline markers of inflammageing/immunosenescence and poorer vaccine response. Most strikingly, a CMV-related expansion of immunosenescent CD4+ TEMRA cells was robustly associated with poorer vaccine response at both 5-weeks and 6-months. In study three, the role of inflammageing in AD progression was examined in a well-characterised longitudinal cohort of 333 older adults with mild-moderate AD. Peripheral markers of inflammageing correlated more with AD risk factors rather than AD severity and did not predict AD progression. Rather, underlying neurodegeneration (plasma p-tau217), neuroinflammation (plasma GFAP) and delirium predicted AD progression over 18 months. Finally, study four explored the relationship between immunobiography and cognitive decline/AD using a novel bead-based sero-assay to measure IgG to 50 common pathogens in >6,000 biological samples from >5,000 individuals. IgG to HSV1, CMV, and Helicobacter Pylori were consistently associated with poorer cognitive performance in older adults. However, serologically-defined exposure was not directly associated with AD pathology/progression. These findings provide potential therapeutic targets to enhance vaccine responses in older adults, highlight emerging prognostic biomarkers for AD, and support preventative strategies such as broadly-protective vaccination to prevent accumulation of age-related illness in older adults. These data add novel insight into our understanding of age-related immune variability.