Neurofilaments (NFs) are not only important for axonal integrity and nerve conduction in large myelinated axons but they are also thought to be crucial for receptor and synaptic functioning. Therefore, NFs may play a critical role in cognitive functions, as cognitive processes are known to depend on synaptic integrity and are modulated by dopaminergic signaling. Here, we present a theory-driven interdisciplinary approach that NFs may link inflammation, neurodegeneration, and cognitive functions. We base our hypothesis on a wealth of evidence suggesting a causal link between inflammation and neurodegeneration and between these two and cognitive decline (see Fig. 1), also taking dopaminergic signaling into account. We conclude that NFs may not only serve as biomarkers for inflammatory, neurodegenerative, and cognitive processes but also represent a potential mechanical hinge between them, moreover, they may even have predictive power regarding future cognitive decline. In addition, we advocate the use of both NFs and MRI parameters, as their synthesis offers the opportunity to individualize medical treatment by providing a comprehensive view of underlying disease activity in neurological diseases. Since our society will become significantly older in the upcoming years and decades, maintaining cognitive functions and healthy aging will play an important role. Thanks to technological advances in recent decades, NFs could serve as a rapid, noninvasive, and relatively inexpensive early warning system to identify individuals at increased risk for cognitive decline and could facilitate the management of cognitive dysfunctions across the lifespan.