Alzheimer's disease (AD) affects over 55 million individuals globally, with no disease-modifying therapy achieving sustained cognitive restoration. We propose a radical reframing: AD represents not a ground state pathology, but a pathologically stable local minimum---a thermodynamic trap that single-target interventions lack sufficient energy to escape.
The Local Minimum Trap
In thermodynamic terms, a ground state represents the lowest possible energy configuration of a system. A local minimum, by contrast, is a stable configuration that is not the lowest energy state. The Alzheimer's brain has fallen into a local minimum of proteostasis failure, chronic neuroinflammation, and mitochondrial dysfunction.
"Reducing amyloid alone leaves inflammation and mitochondrial dysfunction intact. The coupled failure modes compensate for any single intervention. To escape, one must provide enough energy to overcome the barrier separating it from ground state."
The Three-Phase Protocol
Phase 1: Proteostasis Reset
Systemic delivery of targeted AAV9-LNP vectors encoding optimized genes for Tau-Phosphatase and Amyloid-Beta degrading enzymes (Neprilysin and IDE variants) to enforce accelerated cellular proteostasis across the cortical manifold.
Phase 2: Neuroinflammation Resolution
Microglial Reprogramming via TREM2 agonist activation coupled with continuous infusion of stabilized BDNF mimetics to resolve chronic neuroinflammation and immediately stabilize synaptic transmission coherence.
Phase 3: Mitochondrial Rescue
Targeted delivery of mitochondria-specific SS-peptides and high-flux NAD+ precursors (NMN packaged in neurotrophin-receptor targeted exosomes) to normalize respiratory chain function and reverse global energy deficit.
Thermodynamic Analysis
We model the AD brain as a system with Gibbs free energy landscape containing multiple local minima:
$$G_{AD} = H_{aggregation} + H_{inflammation} + H_{energy} - TS_{network}$$
Our protocol provides the work necessary to overcome this barrier: $W_{total} > \Delta G_{barrier}$. By addressing all three axes simultaneously, we prevent compensatory stabilization and force the system to collapse into its natural ground state.
Ask ugly questions. Find beautiful answers.