Summary: A new meta-analysis of six randomized controlled trials shows that lithium supplementation does not significantly slow cognitive decline in people with mild cognitive impairment or Alzheimer’s disease. While preclinical evidence suggests lithium supports resilience against amyloid and tau pathology, these benefits failed to translate to clinical outcomes using traditional lithium salts.
Researchers suggest that bioavailability limitations and amyloid binding may blunt lithium’s therapeutic potential in humans. Future work will evaluate newer formulations—such as lithium orotate—that may cross the blood–brain barrier more efficiently and reduce toxicity.
Key Facts:
- No Clinical Benefit: Across 435 participants, lithium did not improve cognitive scores or behavioral symptoms compared to placebo.
- Formulation Matters: Conventional lithium salts may poorly penetrate the brain, limiting therapeutic effects despite strong preclinical signals.
- Future Potential: Emerging formulations like lithium orotate may enhance brain delivery and warrant targeted trials in early-stage AD.
Source: Fujita Health University
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.
Aron et al. (2025) 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 made available online on November 6, 2025 and will be published in Volume 180 of the journal Neuroscience and Biobehavioral Reviews on January 01, 2026.
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,” described 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,” described Dr. Saito.
Prof. Iwata described “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 maybe 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.
Funding information
This work was supported by JSPS KAKENHI Grant Number 15K19750.
Key Questions Answered:
A: Current clinical evidence shows no significant cognitive benefit compared to placebo.
A: Conventional salts show no clear effect, while newer forms like lithium orotate may hold future potential.
A: Animal work indicates lithium supports cognitive resilience and reduces AD pathology, motivating further research into optimized formulations.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuropharmacology and Alzheimer’s disease research news
Author: Hisatsugu Koshimizu
Source: Fujita Health University
Contact: Fujita Health University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Lithium for Alzheimer’s disease: Insights from a meta-analysis” by Taro Kishi et al. Neuroscience and Behavioral Reviews
Abstract
Lithium for Alzheimer’s disease: Insights from a meta-analysis
We read with great interest the article by Aron and colleagues, titled “Lithium deficiency and the onset of Alzheimer’s disease” (Aron et al., 2025).
The authors revealed that endogenous lithium (LIT) in the brain supports cognitive preservation during ageing. In mouse models, dietary depletion of endogenous LIT increased amyloid-β and phospho-tau accumulation, neuroinflammation, and synaptic and axonal loss, and accelerated cognitive decline, mediated in part through GSK3β activation. Further, endogenous LIT deficiency induced transcriptomic alterations overlapping with Alzheimer’s disease (AD).
Notably, LIT supplementation, particularly LIT orotate (LIT-O), which evades amyloid binding, prevented pathological changes and memory loss. These results indicate that endogenous LIT homeostasis disruption may represent an early event in AD pathogenesis and that endogenous LIT replacement could have preventive or therapeutic potential.
Two previous pairwise meta-analyses, including three studies, reported a possible association between LIT supplementation and cognitive impairment prevention in individuals with AD (Matsunaga et al., 2015; Singulani et al., 2024). Recently, we completed a double-blind, randomized, placebo-controlled trial (DBRPCT) of LIT carbonate (LIT-C) supplementation in individuals with AD (Matsunaga, 2025).
The other two DBRPCTs of LIT-C in this population have been reported (Devanand et al., 2022; NCT03185208, 2025). To date, six studies have investigated LIT supplementation in individuals with mild cognitive impairment (MCI) and AD (Devanand et al., 2022; Forlenza et al., 2011; Hampel et al., 2009; Matsunaga, 2025; NCT03185208, 2025; Nunes et al., 2013) but revealed inconsistent results (Table 1).
To address this, we conducted a random-effects model meta-analysis, incorporating the most recent studies and designed to detect even small between-group differences (Higgins et al., 2024), to evaluate whether LIT supplementation slows cognitive decline in individuals with AD.
