Work

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

Year: 2025

Type: article

Abstract: 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 (CDK5/p25, ERK-MAPK), proteostasis overload (HSP90-UPS-autophagy nexus), mTORC1 hyperactivation impairing lysosomal flux, kynurenine pathway (IDO1/TDO)-driven immunometabolic decoupling, PARP1-mediated NAD+ parthanatos, maladaptive neuroinflammation (PD-1/PD-L1 checkpoints, TAM-microglial skewing), and senescence-associated secretory phenotype (SASP)-amplified gliosis. Computational nomination pipelines—transcriptomic signature reversal (CMap/LINCS), network proximity in multi-omic knowledge graphs, and ligand-based docking—prioritize pleiotropic oncology agents: c-Abl/Src TKIs (nilotinib, bosutinib) enhancing autophagic Aβ/tau clearance; multikinase modulators (masitinib) resolving mast cell-microglial dyshomeostasis; rapalogs restoring proteostasis; IDO1 antagonists normalizing astrocytic lactate shuttling; PARPi mitigating genomic instability; HDACi reinstating synaptic epigenomes; and senolytics (dasatinib+quercetin) purging senescent glia. Phase I/II trials evince biomarker modulation (↓CSF p-tau, amyloid-PET; ↑autophagic flux) 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 (e.g., TKI+IDO1i), delivery-first PBPK modeling, and biomarker-anchored adaptive platforms to recalibrate AD's networked trajectory toward disease-modifying efficacy.

Source: Medicine in Drug Discovery

DOI: 10.1016/j.medidd.2025.100237