A Multi-Targeted, Personalized, and Synergistic Approach to Modifying Disease Progression in Mild Cognitive Impairment and Early-Stage Alzheimer's Disease: Preclinical Rationale and Research Protocol”

Alzheimer's disease (AD) and related dementias affect over 55 million people worldwide,yet no existing therapy stops or reverses disease progression. These conditions arise froma complex interplay of pathological mechanisms, including neuroinflammation,mitochondrial dysfunction, gut dysbiosis, and disrupted neuronal networks. This researchprogram aims to develop and test a novel, multi-pronged intervention strategy for mildcognitive impairment (MCI), a high-risk stage for progression to AD, targeting theseinterconnected pathological pathways. Our approach integrates: 1) Enhanced drugdelivery of Curcumin and Resveratrol to the brain using exosome-mediated microglialtargeting, overcoming limitations of bioavailability and blood-brain barrier (BBB)penetration; 2) Mitochondrial enhancement via PGC-1alpha activation, achieved throughthe synergistic effects of Resveratrol, Curcumin, and intermittent fasting; 3) Gut-brain axismodulation using personalized probiotic formulations, designed with the aid of machinelearning algorithms based on individual microbiome and genetic profiles, and focusing onBacteroides fragilis and Akkermansia muciniphila; 4) Neuroinflammation control throughmodulation of the TLR4 signaling pathway in microglia, utilizing the anti-inflammatoryproperties of Curcumin and Resveratrol, and potentially incorporating repurposed drugs;and 5) Network optimization via personalized, closed-loop transcranial magneticstimulation (TMS) guided by real-time EEG feedback and AI-driven parameter optimization.This research challenges the conventional single-target approach to dementia treatment,offering a first-of-its-kind, multi-modal therapy that simultaneously tacklesneuroinflammation, mitochondrial failure, gut dysbiosis, and brain network dysfunction.By combining exosome-mediated drug delivery, personalized probiotics, and AI-drivenclosed-loop brain stimulation, this project redefines the way we approachneurodegeneration. We hypothesize that this multi-targeted, personalized approach willresult in synergistic therapeutic effects, leading to significant improvements in cognitivefunction, reduced neuroinflammation, enhanced mitochondrial function, restored gut-brain axis homeostasis, and optimized brain network activity in individuals with MCI. Theinitial phase of this project focuses on in vitro validation of the individual and combinedinterventions, followed by a Phase II clinical trial to assess safety and efficacy in humans. Ifsuccessful, this research has the potential to transform the treatment of MCI and preventor delay the progression to dementia. Millions await a disease-modifying therapy wherenone currently exists.Keywords: Alzheimer's disease, mild cognitive impairment, microglia, exosomes,probiotics, brain stimulation, PGC-1alpha, personalized medicine, neuroinflammation,gut-brain axis, Curcumin, Resveratrol, intermittent fasting, TLR4, closed-loop stimulation.