Researchers outline how low-dose lithium could be tested as a carefully monitored approach to preserving cholinergic function and brain networks before Alzheimer’s disease progresses.
Perspective: Revisiting the cognitive abilities of lithium in Alzheimer’s disease: The role of cholinergic systems and brain connections. Image credit: Nanzeeba / Shutterstock
With a new perspective that can be used as a “press article” in a journal translational psychiatryresearchers discuss the cognitive benefits of lithium in Alzheimer’s disease (AD).
A recent Nature study reported that levels of endogenous lithium in the brains of people with Alzheimer’s disease and mild cognitive impairment (MCI) are significantly reduced. They also showed that dietary lithium depletion promotes tau phosphorylation, amyloid-beta (Aβ) deposition, myelin and synapse loss, and cognitive decline in mouse models.
In transgenic AD mice, lithium orotate supplementation treatment ameliorated cognitive deficits and neuropathology, renewing interest in physiological lithium restoration in AD. The study authors speculate that lithium’s interaction with the cholinergic system and its effects on brain connectivity may help explain the promising preclinical findings reported in Alzheimer’s disease models.
The cholinergic system and lithium
In 1980, lithium carbonate was shown to inhibit serum cholinesterase activity in patients with endogenous depression. Subsequently, the cholinergic hypothesis of Alzheimer’s disease was clinically validated, and several cholinesterase inhibitors, such as galantamine, donepezil, and rivastigmine, improved function and cognition in mild to moderate Alzheimer’s disease. However, the reported effects of lithium on serum cholinesterase activity remain largely ignored.
Given the known benefits of cholinesterase inhibition in Alzheimer’s disease and the role of acetylcholine in cognition, the authors argue that lithium’s effects on serum cholinesterase may contribute to the cognitive protection observed in mouse models. Previously, the authors investigated the effects of lithium supplementation in Alzheimer’s disease patients in a pilot study. Although no significant cognitive improvement was observed, some clinical and biochemical effects were observed.
In particular, lithium was associated with a significant increase in red blood cell (RBC) glycine and choline levels. Because some small metabolites exhibit equilibrium between the brain and red blood cells, the authors hypothesized that these peripheral increases may be accompanied by parallel changes in brain glycine and choline. Preclinical evidence suggests that increased brain choline supports cholinergic tone, while glycine modulates glutamatergic signaling and may exert neuroprotective effects.
Effects of lithium on brain connectivity
Functional magnetic resonance imaging (fMRI) studies of the human brain in bipolar disorder (BD) suggest that lithium may alter temporal changes in network-level communication. Lithium monotherapy in BD patients was associated with a shift to a healthier pattern of mania-related indices. Additionally, changes in network metrics were proportional to changes in symptoms.
Another study reported that long-term exposure to lithium in older adults with BD was associated with improved white matter integrity. Clinical trials have investigated lithium in Alzheimer’s disease, but no brain connectivity results have been reported. Nevertheless, in studies outside of Alzheimer’s disease, lithium is often associated with indicators consistent with preservation of brain structural integrity. For example, lithium treatment was associated with increased white and gray matter volume in healthy volunteers.
Larger white matter volumes and regional gray matter volumes support ductal conduction that supports local circuit processing and network organization. Furthermore, in older adults with BD, given the burden of vascular disease, long-term exposure to lithium was associated with diffuse measurements of white matter integrity, which typically worsen in dementia. The association of lithium with white matter integrity in this group strengthens the idea that lithium may help maintain structural connectivity in older adults.
Clinical trial strategy that avoids risks
The pathology of Alzheimer’s disease begins several years before dementia. Modern biomarker models define preclinical and progenitor stages with detectable network abnormalities and dysfunction of amyloid, synapses, and tau, but with relatively limited irreversible cleavage. At this stage, the authors argue that interventions aimed at stabilizing brain networks may be most effective. Trials of low-dose lithium in MCI suggest that this approach is tolerable and feasible in older adults.
Therefore, future trials should begin with lower doses, serum targets below the BD range, slow titration, thyroid and kidney monitoring, hydration counseling, and consideration of drug interactions. Additionally, testing should include systematic evaluation of tremors, gastrointestinal symptoms, confusion, extrapyramidal signs, cardiac conduction abnormalities, and worsening of gait. Overall, the goal is an in-depth investigation of the replacement of low or physiological doses with target engagement measures.
conclusion
Taken together, this perspective argues that evidence from human brain samples and preclinical models suggests that endogenous lithium can modulate brain aging and Alzheimer’s disease pathology. A deeper understanding of its cognitive effects in Alzheimer’s disease warrants incorporating its cholinergic properties and ability to alter brain connectivity. The authors suggest that the association between lithium exposure and white matter integrity observed primarily outside of Alzheimer’s disease may partially reflect maintenance of cholinergic tract integrity. Future studies should evaluate metabolic changes and cholinergic endpoints, with a focus on safety and early intervention.
Reference magazines:
- Pini L, Imbimba BP, Pomara N (2026). Reconsidering the cognitive performance of lithium in Alzheimer’s disease: The role of the cholinergic system and brain connections. Translational psychiatry. Press article. Doi: 10.1038/s41398-026-04307-9, https://www.nature.com/articles/s41398-026-04307-9
