Submitted:
30 December 2025
Posted:
30 December 2025
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Abstract
Background: There is a critical need for effective therapeutics for Alzheimer’s disease. However, the majority of previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, a personalized, precision medicine approach, with increased data set size to include the potential contributors to cognitive decline for each patient, and treatment of the identified potential contributors, has emerged as a potentially more effective strategy. Recent proof-of-concept trials have provided clinical data that support this approach. Objective: To determine whether a precision medicine approach to Alzheimer’s disease at the mild cognitive impairment or early dementia stage is effective in a randomized controlled clinical trial. Methods: Seventy-three patients with mild cognitive impairment or early dementia, with Montreal Cognitive Assessment (MoCA) scores of 18 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, immune dysfunction, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Genetic and epigenetic evaluations were included, as well as Alzheimer’s-associated biomarkers. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Participants were randomly assigned to either a personalized, precision medicine protocol or standard of care treatment. Cognition and clinical symptoms were assessed at 0, 3, 6, and 9 months. Results: Relative to the standard of care protocol, statistically significant incremental effects of the precision medicine protocol were observed for broad neurocognitive functioning, composite memory (verbal plus visual), executive function, processing speed, cognitive symptom severity, and Alzheimer’s disease symptom severity. Furthermore, overall health was enhanced, with improvements in blood pressure, body mass index, glycemic index, lipid profiles, and methylation status. The treatment effect size for overall cognitive function was calculated to be greater than previously published clinical trials, seven times the effect size of the lecanemab trial and four times the effect size of the donanemab trial. Conclusion: A personalized, precision medicine approach represents an effective treatment for patients with mild cognitive impairment or early-stage dementia due to Alzheimer’s disease. In most cases, this treatment leads to cognitive improvement rather than simply retarding decline, and it does so without significant negative side effects such as brain edema, microhemorrhage, or atrophy.
