Keywords: System’s thinking; Alzheimer’s disease; Causal loop diagram; Group model building; Multicausality.

Author Jeroen Uleman on the article: 

Alzheimer’s disease (AD) is a complex, multicausal disorder involving several spatiotemporal scales and scientific domains. While many studies focus on specific parts of this system, the complexity of AD is rarely studied as a whole. This is crucial because interventions that aim to target single causes have not yet resulted in effective prevention or treatment of AD.

In this paper, we apply systems thinking to map out known causal mechanisms and risk factors ranging from intracellular to psychosocial scales in sporadic AD.

System’s thinking has been increasingly and effectively applied to other complex diseases, such as obesity [1], concussion [2] and depression [3].

We report on the first systemic causal loop diagram (CLD) for AD, which is the result of an interdisciplinary group model building (GMB) process. The GMB was based on the input of experts from multiple domains and all proposed mechanisms were supported by scientific literature. The CLD elucidates interaction and feedback mechanisms that contribute to cognitive decline from midlife onward as described by the experts.

As an immediate outcome, we observed several non-trivial reinforcing feedback loops involving factors at multiple spatial scales, which are rarely considered within the same theoretical framework. We also observed high centrality for modifiable risk factors such as social relationships and physical activity, which suggests they may be promising leverage points for interventions. This illustrates how a CLD from an interdisciplinary GMB process may lead to novel insights into complex disorders.

Additionally, the CLD is the first step in the development of ‘digital twin’ models that quantify the effects of interventions on various risk factors on individuals at risk of AD. In this way, we aim to move from the one-fits-all, single-cause paradigm that dominates the field, and move toward systematic, multidisciplinary and individualized interventions.

[1] Crielaard et al (2020) https://onlinelibrary.wiley.com/doi/full/10.1111/obr.13044

[2] Kenzie et al (2018) https://www.frontiersin.org/articles/10.3389/fneur.2018.00203/full

[3] Wittenborn et al (2016) https://dx.doi.org/10.1017%2FS0033291715002044

Uleman, J. F., Melis, R. J. F., Quax, R., Zee, E. A. van der, Thijssen, D., Dresler, M., Rest, O. van de, Velpen, I. F. van der, Adams, H. H. H., Schmand, B., Kok, I. M. C. M. de, Bresser, J. de, Richard, E., Verbeek, M., Hoekstra, A. G., Rouwette, E. A. J. A., Olde Rikkert, M. G. M. (2021) Mapping the  multicausality of Alzheimer’s disease through group model building. GeroScience 43, 829–843. https://doi.org/10.1007/s11357-020-00228-7