BACKGROUND: The COVID‐19 pandemic has disproportionately impacted vulnerable populations. The elderly, including individuals with Alzheimer's Disease and Related Dementias (ADRD) are at an increased risk due to a variety of factors ranging from the molecular, to the physiological and social domains. Here we describe the development of a neural network‐inspired, expanded Adverse Outcome Pathways (AOP) approach to examine the relations, outcomes and potential interventions across scales at the intersections of these acute and long‐term health crises. METHOD: Using an Adverse Outcome Pathway (AOP) approach we compared key events and their relationships in COVID‐19 and ADRD. However, whereas current AOP approaches are often limited and centralized around the molecular domain we expand these to encompass a range of domains across scales such as the neuropsychological and social factors. Inspired by neural network modeling approaches we also extend the traditional AOP framework to explicitly include: inhibitory and excitatory mechanisms, causal recurrence, strength of interactions and advantageous pathways. RESULT: By including an analysis that spans molecular pathways, system level vulnerabilities, psychological, environmental and social factors we are able to assess commonalities of events (e.g., macrophage activation, systemic inflammation, environmental exposures and disproportionately affected racial/ethnic communities). In addition, by utilizing higher order and systems perspectives, we were able to better identify mechanistic differences (e.g., vulnerabilities of specific brain regions, timescale of bio‐cognitive consequences, sex‐gender differences), as well as chart interactions resulting in comorbidities and resilience factors. CONCLUSION: In recent years the global ADRD research field has strongly shifted to a conceptual framework that recognizes the essential role of interactions between levels of biosocial organization. The COVID‐19 pandemic has also revealed the crucial biopsychosocial connections of disease vulnerability, resistance and management. AOPs are powerful tools in clarifying key linkages in these multifactorial diseases. However, AOPs have also showed their limitation by biasing molecular events as the prime initiating events. Our hybrid approach integrates multiscale elements to more effectively develop a mechanistic framework and identify pathways to health. Taken together, this new approach can help bridge the divide across bio‐molecular events and higher level factors such as health disparities in COVID and the ADRD spectrum.
ADRD and COVID‐19: A multi‐scale framework for elucidating and addressing mechanisms and outcomes