Energy constraints and neural strategy transitions in Alzheimer’s: A game-theoretic model

While many mechanisms have been proposed to drive Alzheimer’s disease, particularly the accumulation of amyloid plaques and hyperphosphorylation of tau proteins, emerging evidence suggests that they may be the byproducts of earlier damage rather than initiating events. Instead, metabolic dysfunction and the inability of neural cells to support their energetic demands may be a more plausible trigger for subsequent pathological cascade (the neuron energy crisis hypothesis). Here we highlight how type 2 diabetes (T2D) can contribute to neurodegeneration by impairing brain energy metabolism. We present a game-theoretic framework, where neurons face trade-offs between energy efficiency and information fidelity. We show that under metabolic stress, neural networks can evolve toward smaller group sizes that prioritize energy efficiency over information quality, which may underlie the observed collapse of cognitive capacity during neurodegeneration. We conclude with a discussion of interventions, ranging from antidiabetic drugs to cognitive engagement and sensory stimulation, aimed at reducing metabolic stress and preserving cognitive function.