Repurposed Drugs for Alzheimer’s Disease: Integrating Mechanistic Efficacy and Global Feasibility Through a Translational Decision Matrix
Salma Younas1, Abhigna Mallepally2, Sankranthi Sarath Chandra3, Aditya Jain4, Aditi Narsinghpura5, Sweta Sahu6
1University of the Punjab, 2Gandhi Hospital, Hyderabad, 3Kurnool Medical College, 4Shyam Shah Medical College, Rewa, 5Kasturba Medical College, Mangalore, 6JJM Medical College
Objective:
To evaluate the clinical efficacy and global feasibility of repurposed drugs for Alzheimer’s disease by integrating cognitive, biomarker, safety, and accessibility data into a translational Efficacy–Feasibility Matrix, identifying candidates that balance mechanistic promise with real-world scalability for equitable, population-level dementia prevention and treatment.
Background:
Repurposed therapeutics, originally approved for non-Alzheimer’s indications, represent a pragmatic and globally scalable approach to disease modification. While dozens of agents have reached clinical testing, the field lacks an integrated framework to prioritize candidates based on both biological efficacy and implementation feasibility.
Design/Methods:
We systematically reviewed human Phase 2/3 randomized or controlled trials (2000–2025) of repurposed agents in mild cognitive impairment or Alzheimer’s disease. Drugs were grouped into mechanistic classes (metabolic, vascular, immune, infectious, neurotrophic/synaptic). Each was scored (0–3) for efficacy signal strength (cognition + biomarker outcomes) and feasibility (cost, accessibility, delivery simplicity, safety). These scores populated an Efficacy–Feasibility Matrix to identify high-priority, globally accessible candidates.
Results:
Among 10 drug classes, metabolic modulators dominated the efficacy axis. GLP-1 receptor agonists (liraglutide, semaglutide) achieved the strongest combined cognitive and biomarker signals (efficacy = 3) but low feasibility (1) due to cost and delivery complexity. Immune stimulation (GM-CSF) also demonstrated short-term biomarker gains but poor accessibility (feasibility = 0). In contrast, metformin, nilvadipine, lithium, and low-dose levetiracetam achieved moderate efficacy (1–2) and high feasibility (2–3), emerging as pragmatic global candidates. Infection-targeted approaches (antibiotics, antivirals) showed transient or mixed benefit yet excellent scalability.
Conclusions:
Repurposed Alzheimer’s therapeutics occupy distinct translational niches: biologics (GLP-1s, GM-CSF) show strong mechanistic efficacy but limited scalability, while inexpensive oral agents (metformin, lithium, nilvadipine) offer feasible, population-level potential. The Efficacy–Feasibility Matrix provides a novel decision-analytic framework to rank repurposed drugs not only by biological promise but also by their readiness for global implementation, bridging clinical pharmacology with equitable access.
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