The need for systems thinking to advance Alzheimer's disease research

Despite extensive research efforts to mechanistically understand late-onset Alzheimer's disease (LOAD) and other complex mental health disorders, curative treatments remain elusive. We emphasize the multiscale multicausality inherent to LOAD, highlighting the interplay between interconnected pathophysiological processes and risk factors. Systems thinking methods, such as causal loop diagrams and systems dynamic models, offer powerful means to capture and study this complexity. Recent studies developed and validated a causal loop diagram and system dynamics model using multiple longitudinal data sets, enabling the simulation of personalized interventions on various modifiable risk factors in LOAD. The results indicate that targeting factors like sleep disturbance and depressive symptoms could be promising and yield synergistic benefits. Furthermore, personalized interventions showed significant potential, with top-ranked intervention strategies differing significantly across individuals. We argue that systems thinking approaches can open new prospects for multifactorial precision medicine. In future research, systems thinking may also guide structured, model-driven data collection on the multiple interactions in LOAD's complex multicausality, facilitating theory development and possibly resulting in effective prevention and treatment options.