The neurobiological foundation of effective repetitive transcranial magnetic brain stimulation in Alzheimer's disease

Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS), are promising candidate therapeutics for Alzheimer's disease (AD). We review the evidence supporting the fundamental mechanisms of action of rTMS treatments in AD. rTMS exerts profound effects at different neurobiological and systems neurophysiological levels. By engaging distinct pre- and postsynaptic structures within the stimulated neural network, it directly or indirectly influences various cellular and molecular components. In AD, rTMS influences synaptic plasticity, inducing lasting structural changes and broad reorganization of functional and structural connectivity at the macroscale level. Importantly, it modulates neurotransmitter circuits characteristically disrupted in AD and restores the excitation/inhibition balance by targeting glutamatergic and γ-aminobutyric acid (GABA)ergic pathways. Moreover, rTMS increases neurotrophic factors, counteracts amyloid and tau accumulation, and mitigates neuroinflammation by reducing microglial activation and pro-inflammatory cytokines release. Therefore, maturing preclinical evidence could guide future precision medicine therapeutic strategies based on personalized NIBS in AD patients. Highlights: Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS), are promising candidate therapeutics for Alzheimer's disease (AD). rTMS modulates neuroplasticity, neurotransmission, and neuroinflammation. Preclinical research shows disease-specific neurobiological effects of rTMS in AD. Promising data from AD patients suggest the translatability of animal model results. Preclinical data may guide precision medicine strategies through personalized NIBS.