Targeting Oligodendrocyte Dysfunction in Alzheimer’s Disease: a New Frontier for Drug Repurposing with Antihistamines and Serotonin Receptor Agonists

Emerging data highlight oligodendrocyte dysfunction and myelin degeneration as early contributors to the pathology of Alzheimer’s disease (AD), questioning the conventional neuron-focused amyloid-tau model. This comprehensive review recapitulates both clinical and preclinical data linking oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs) to amyloid-β secretion, accelerated cellular ageing, and loss of metabolic and trophic support. Simultaneously, microglial activation and neuroinflammation exacerbate damage to myelin and impair remyelination. High-field imaging technologies are associated with white matter pathology that is evident decades before the onset of cortical atrophy, highlighting the pathogenic importance of glial pathology. We discuss pharmacological strategies to correct OL dysfunction by drug repurposing: first-generation H₁-antihistamine clemastine, which induces OPC maturation by M₁ muscarinic antagonism and ERK/mTOR signalling; H₃-receptor antagonists/inverse agonists (e.g. pitolisant) increase neurotransmitter release and induce CREB-mediated remyelination; and serotonergic GPCR agonists (5-HT₄, 5-HT₆, 5-HT_2C) shift APP processing toward non-amyloidogenic pathways, enhance synaptic proteostasis, and protect OLs against 5-HT toxicity. We provide mechanistic details, comparative profiles, and translational considerations, including blood–brain barrier penetration, pharmacokinetics, and safety considerations, as well as patient stratification. We also cover preclinical models and early clinical trials that demonstrate cognitive benefits and advantages in myelin repair. The limitations of monotherapies imply the promise of combinatorial regimens that attack both histaminergic and serotonergic systems. We present a clinical translation roadmap featuring adaptive, biomarker-responsive trials that utilise enhanced myelin imaging; personalised and multi-omics approaches to medicine; and transdisciplinary collaboration among neuroscience, pharmacology, regulatory bodies, and patient–caregiver groups. The translation of repurposed glial-targeting therapies to clinical practice will require adaptive, biomarker-guided trials, advanced myelin imaging, and intersectoral coordination among neuroscience, pharmacology, and regulatory partners, including engagement with patients and caregivers, as well as ethical input.