Investigating lithium’s potential role in slowing cognitive decline in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline such as memory loss and behavioral disturbances that severely impair quality of life. Despite decades of research, effective disease-modifying therapies remain elusive, underscoring the urgent need for novel neuroprotective strategies.

Lithium (LIT), a well-known mood stabilizer for the treatment of bipolar disorder, shows neuroprotective effects, including inhibition of glycogen synthase kinase 3 beta, reduction of amyloid-β and tau accumulation, attenuation of neuroinflammation, and preservation of synaptic and axonal integrity. These findings have prompted interest in LIT supplementation to preserve cognitive function and slow AD progression.

A 2025 study demonstrated that endogenous LIT in the brain supports cognitive resilience during aging. In mouse models, LIT depletion accelerated cognitive decline and promoted hallmark AD pathologies, including amyloid-β and phospho-tau accumulation and neuroinflammation.

LIT supplementation, particularly LIT orotate (LIT-O), which minimizes amyloid binding, prevented these changes and preserved memory. These results suggest that disrupted LIT homeostasis may be an early event in AD pathogenesis and that restoring brain LIT levels could have therapeutic or preventive potential.

Translating these preclinical findings to humans requires careful evaluation, especially given safety concerns and limited efficacy associated with conventional formulations like LIT carbonate (LIT-C).

To address this gap, a research team led by Professor Taro Kishi from the Department of Psychiatry, Fujita Health University School of Medicine, Japan, along with Dr. Shinji Matsunaga from Aioiyama Honobono Memory Clinic, Dr. Youichi Saito from Nansei Hospital, and Prof. Nakao Iwata from the Department of Psychiatry, Fujita Health University School of Medicine, conducted a systematic review and meta-analysis of randomized, placebo-controlled trials (RCTs) assessing LIT supplementation in individuals with mild cognitive impairment (MCI) or AD.

The meta-analysis incorporated six RCTs comprising 435 participants, with study durations ranging from 10 weeks to 24 months. Different LIT formulations were evaluated, including LIT-C, LIT gluconate, and LIT sulfate.

The findings were published in Neuroscience and Biobehavioral Reviews.

The primary outcome was change in cognitive performance, primarily measured by the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, while secondary outcomes included behavioral and psychological symptoms, adverse events, and discontinuation rates.

Data were analyzed using standardized mean differences and risk ratios with 95% confidence intervals, applying a random-effects model to account for heterogeneity across studies.

The meta-analysis revealed that LIT supplementation did not significantly improve cognitive function compared with placebo.

“Our meta-analysis showed that LIT, including LIT-C, which was frequently used in clinical practice, did not significantly delay cognitive impairment progression in individuals with MCI and AD compared with placebo,” noted Prof. Kishi.

“Our meta-analysis also showed that secondary outcomes, including behavioral and psychological symptoms, adverse events, and discontinuation rates, likewise, showed no significant differences between LIT and placebo groups,” said Dr. Matsunaga.

“Meta-regression analysis demonstrated no association between baseline cognitive scores and the magnitude of LIT’s effect size for change in cognitive performance,” said Dr. Saito.

Prof. Iwata said that “although our meta-analysis demonstrated that no clear clinical benefit was observed with conventional LIT salts, our study offers several important insights.” It represents the most comprehensive synthesis of current clinical evidence on LIT supplementation in MCI and AD, incorporating both published and registry-based data from recent trials.

The findings highlight potential limitations of commonly used LIT formulations such as LIT-C, which exhibit higher ionization and greater amyloid binding, potentially reducing LIT’s bioavailability in the brain.

“Preclinical studies suggest that alternative formulations like LIT-O may be a potential alternative as it may cross the blood–brain barrier and enter cells more efficiently than LIT-C, potentially enabling lower dosage requirements and reduced toxicity,” added Prof. Kishi, emphasizing the need for future clinical trials to test this newer compound in human populations.

In conclusion, while LIT supplementation using conventional salts does not appear to slow cognitive decline in individuals with MCI or AD, the findings underscore the importance of exploring alternative LIT formulations and targeted supplementation strategies.

This meta-analysis bridges the gap between preclinical discoveries and clinical outcomes, providing valuable direction for future research aimed at harnessing LIT neuroprotective properties safely and effectively.

Well-designed, long-term clinical trials of LIT-O in individuals with early-stage AD or MCI are now warranted to determine whether LIT can meaningfully contribute to preventing or mitigating the progression of AD.