Thalamic anterior nucleus hyperconnectivity drives early-stage functional compe…

We hypothesize that in early Alzheimer’s disease (CDR 0.5-1), the anterior thalamic nuclei develop functional hyperconnectivity with hippocampal circuits as a compensatory response to entorhinal cortex degeneration, preserving episodic memory function. However, this hyperconnectivity creates a metabolically vulnerable state where increased neuronal activity elevates extracellular adenosine through ectonucleotidase pathways, suppressing synaptic efficacy and promoting amyloid-beta oligomerization at hyperconnected synapses. The transition from hyper-to hypo-connectivity marks a point of metabolic failure where compensatory mechanisms become pathological drivers. Testable predictions: (1) anterior thalamic nuclei will show increased functional connectivity correlated with preserved hippocampal CA1 activity in early AD; (2) microdialysis studies will reveal elevated extracellular adenosine at hyperconnected thalamic-hippocampal synapses; (3) PET amyloid burden will preferentially accumulate in thalamic hub regions exhibiting early hyperconnectivity; (4) inhibition of adenosine A1 receptors in mouse models will accelerate the hyper-to-hypoconnectivity transition and worsen cognitive outcomes.