Repurposing oncology drugs for Alzheimer’s: multi-omic convergence targeting cell-cycle, proteostasis, immunometabolism, and senescence

Overview of the oncology-to-Alzheimer’s disease (AD) repurposing framework. Shared vulnerabilities between cancer and AD (cell cycle dysregulation, autophagy/mTOR, DNA repair, neuroinflammation, senescence) provide therapeutic entry points. Computational nomination integrates transcriptomic signature reversal (CMap/LINCS), network proximity, and machine-learning inference with real-world evidence (RWE). Hits are advanced through phenotypic high-content screening (HCS), pharmacokinetic/BBB triage, and biomarker-led validation (Aβ/tau reduction, synaptic and microglial restoration). Rational orthogonal combinations (e.g., senolytics + anti-inflammatories, TKIs + microglial modulators, IDO1 inhibitors, rapalogs, anti-Aβ antibodies) feed into adaptive clinical trial designs with cognitive and circuit-level endpoints. This end-to-end pipeline bridges mechanism, repurposing, and translation. Alzheimer’s disease (AD), the predominant dementia etiology, imposes a $1.5 trillion global burden in 2025, exacerbated by inexorable failures in amyloid-tau-centric monotherapies amid < 1 % trial success rates. This review synthesizes cross-disciplinary pathobiology underpinning oncology drug repurposing for AD, leveraging inverse epidemiological antagonism and convergent hallmarks: aberrant neuronal cell-cycle re-entry, proteostasis, mTORC1 hyperactivation impairing lysosomal flux, kynurenine pathway-driven immunometabolic decoupling, PARP1-mediated NAD + parthanatos, maladaptive neuroinflammation, and senescence-associated secretory phenotype (SASP)-amplified gliosis. Computational nomination pipelines—transcriptomic signature reversal, network proximity in multi-omic knowledge graphs, and ligand-based docking—prioritize pleiotropic oncology agents: c-Abl/Src TKIs enhancing autophagic Aβ/tau clearance; multikinase modulators resolving mast cell-microglial dyshomeostasis; rapalogs restoring proteostasis; IDO1 antagonists normalizing astrocytic lactate shuttling; PARPi mitigating genomic instability; HDACi reinstating synaptic epigenomes; and senolytics purging senescent glia. Phase I/II trials evince biomarker modulation with geriatric-adapted dosing, yet underscore translational hurdles: BBB penetration, off-target liabilities, and polypharmacy in APOE ε4-enriched cohorts. A precision roadmap advocates orthogonal combinations, delivery-first PBPK modeling, and biomarker-anchored adaptive platforms to recalibrate AD’s networked trajectory toward disease-modifying efficacy.