Pini_2026_Transl.Psychiatry__

Recent evidence demonstrating a marked reduction in endogenous brain lithium levels in mild cognitive impairment and Alzheimer's disease (AD) has renewed interest in lithium as a physiological modulator of brain aging and neurodegeneration. Experimental data indicate that lithium deficiency accelerates amyloid-beta deposition, tau pathology, synaptic and myelin loss, whereas physiological lithium replacement mitigates neuropathology and cognitive decline. Here, we argue that lithium's cognitive potential in AD has been underestimated due to the historical neglect of two interrelated mechanisms: modulation of the cholinergic system and preservation of brain connectivity. Lithium has long been shown to inhibit cholinesterase activity and to increase choline and glycine availability, suggesting a capacity to enhance central cholinergic tone. Given the established role of cholinergic dysfunction in AD, this mechanism may represent an unrecognized contributor to lithium's neurocognitive effects. In parallel, converging human neuroimaging evidence indicates that lithium modulates functional brain networks and is associated with improved white matter integrity, supporting a role in maintaining structural and functional connectivity. We propose brain connectivity as a systems-level integrator of lithium's effects on synaptic plasticity, neuroinflammation, myelination, and cholinergic signaling. Future trials in early AD should incorporate physiological-dose lithium, candidate cholinergic biomarkers, and multimodal connectivity imaging to clarify lithium's translational potential as a network-stabilizing intervention. To bridge prior clinical disappointments and the renewed lithium hypothesis, we further propose a de-risked trial strategy centered on biomarker-confirmed early disease, physiological-dose exposure, structured safety surveillance, and imaging-based target engagement.