A new perspective published in the journal Translational Psychiatry explores the potential cognitive benefits of low-dose lithium in the context of Alzheimer's disease (AD). This builds upon a recent Nature study that observed significantly reduced endogenous lithium levels in the brains of individuals with AD and mild cognitive impairment (MCI). The Nature study also found that a diet deficient in lithium accelerated several neuropathological markers and cognitive decline in mouse models. Conversely, lithium orotate treatment in transgenic AD mice alleviated cognitive deficits and neuropathology, sparking renewed interest in the therapeutic potential of physiological lithium restoration for AD.
The authors of the current study hypothesize that lithium's impact on the cholinergic system and its ability to influence brain connectivity might explain the positive preclinical findings in AD models. The cholinergic system plays a crucial role in cognition, and the efficacy of cholinesterase inhibitors in improving function in mild to moderate AD is well-established. Although lithium's effect on serum cholinesterase activity was noted decades ago, its potential contribution to cognitive protection has largely been overlooked. A pilot study investigating lithium supplementation in AD patients, while not showing significant cognitive improvement, did reveal increased red blood cell (RBC) glycine and choline levels. The researchers propose that these peripheral changes might mirror similar beneficial alterations in brain glycine and choline, with choline supporting cholinergic tone and glycine potentially offering neuroprotective effects through glutamatergic signaling.
Furthermore, studies using functional magnetic resonance imaging (fMRI) in individuals with bipolar disorder (BD) indicate that lithium can modulate network-level communication within the brain. Long-term lithium exposure in older adults with BD has been linked to enhanced white matter integrity, a metric that typically deteriorates in dementia. While clinical trials have explored lithium in AD, the specific effects on brain connectivity have not been extensively reported. However, across various studies, lithium treatment consistently correlates with indicators of preserved brain structural integrity, such as increased white and gray matter volumes. This suggests that lithium could contribute to maintaining structural connectivity, particularly in older populations, by supporting local circuit processing and tract conduction, which are fundamental to network organization.
The early stages of Alzheimer's disease, characterized by preclinical and prodromal phases with detectable network abnormalities but limited irreversible damage, represent a critical window for intervention. Interventions aimed at stabilizing brain networks are believed to be most effective during this period. Low-dose lithium trials in MCI patients have demonstrated acceptable tolerability and feasibility in older individuals. Future trials should prioritize low initial doses, carefully define serum targets below the typical bipolar disorder ranges, implement slow titration, and include diligent monitoring of thyroid and renal function. Additionally, comprehensive evaluation of potential side effects such as tremor, gastrointestinal issues, confusion, extrapyramidal signs, cardiac conduction abnormalities, and changes in gait is essential. The overarching objective is to conduct thorough investigations into low- or physiological-dose lithium replacement, incorporating measures of target engagement to assess its efficacy and safety.
The compelling evidence from human brain samples and preclinical models strongly suggests that endogenous lithium can influence brain aging and Alzheimer's pathology. A deeper exploration of its cognitive effects in AD necessitates understanding its cholinergic properties and its role in modulating brain connectivity. The observed link between lithium exposure and white matter integrity, even outside the context of AD, may indicate a mechanism through which lithium helps preserve cholinergic tract integrity. Future research should focus on evaluating metabolic changes and cholinergic outcomes, with an emphasis on safe and early intervention strategies to harness lithium's potential in combating Alzheimer's disease.