Therapeutic Invention for Alzheimer's Disease and Mechanism of Action

 Mechanism of Action

The proposed mode of action can be reconstructed as a cascade of successive interventions. First, reducing pathogenic Aβ species should diminish an upstream trigger or facilitating factor for tau misfolding, tau propagation, neuroimmune activation, and synaptic toxicity

Second, a tau-targeted intervention should reduce the downstream effector of synaptic degeneration, trans-synaptic propagation, and clinical deterioration

Third, improving autophagy–lysosome function should restore the degradation of aggregation-prone proteins and damaged organelles, improve lysosomal acidification, and reduce intracellular levels of APP-βCTF, Aβ, and tau, as well as the associated lysosomal stress. Fourth, supporting mitophagy should reduce mitochondrial dysfunction, oxidative stress, and neuroinflammatory amplification, while decreasing Aβ and tau burden and preserving memory-related synaptic functions in preclinical systems

Fifth, stabilizing the BBB/NVU should restore regulated molecular exchange, reduce impairment of Aβ clearance across the NVU, improve capillary blood flow and drainage, and limit the entry of blood-borne inflammatory signals and cells Sixth, controlling vascular inflammation and leukocyte–endothelial interactions should attenuate immune cell recruitment into the dysfunctional NVU, a mechanism that, in animal models of Alzheimer’s disease, reduces Aβ deposits, tau hyperphosphorylation, and memory loss  Seventh, modulating chronic inflammation should reduce the maladaptive glial and peripheral immune signaling that sustains the pathology throughout the preclinical and clinical course spanning several years

Proposed Implementation

Biological classification: use a biomarker-guided framework to identify individuals with pathology relevant to Alzheimer’s disease and determine the dominant mechanisms before intervention; the project repeatedly supports multimodal biomarker-based characterization rather than selection based solely on symptoms