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.
***
Reference
DOI: 10.1016/j.neubiorev.2025.106458
About Fujita Health University
Fujita Health University (FHU) is a private medical university located in Aichi, Japan. Established in 1964, it houses one of the largest university hospitals in Japan. It's 900 member faculty provides diverse learning and research opportunities to medical students worldwide. Guided by its founding philosophy of "Our creativity for the people" Fujita Health University believes that it's students can shape the future through creativity and innovation. FHU has earned global recognition, ranking eighth among all universities and second among private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. The university ranked fourth worldwide in the 2024 THE University Impact Rankings for contributions to the "Good Health and Well-being" SDG (Sustainable Development Goals) of the United Nations (UN). In June 2021, the university made history as the first Japanese institution to host the THE Asia Universities Summit. In 2024, Fujita Health University was awarded the Forming Japan’s Peak Research Universities (J-PEAKS) Program by the Japanese government to establish an innovative academic drug discovery ecosystem and hub of a multi-university consortium for research and education.
Website: https://www.fujita-hu.ac.jp/en/index.html
About Professor Taro Kishi from Fujita Health University School of Medicine
Dr. Taro Kishi holds a medical doctorate (M.D./Ph.D.) in psychiatry and currently serves as Professor of Psychiatry at Fujita Health University School of Medicine, Japan, with over 20 years of academic experience. He has authored more than 250 peer-reviewed publications and is internationally recognized for his work in evidence-based psychiatry, clinical trials, meta-analyses, and pharmacogenetics of schizophrenia and mood disorders. A former postdoctoral fellow at Zucker Hillside Hospital, New York, Dr. Kishi’s research has significantly influenced psychiatric treatment guidelines. His contributions to psychiatric pharmacotherapy and personalized medicine highlight his commitment to advancing clinical and translational research in mental health.
Funding information
This work was supported by JSPS KAKENHI Grant Number 15K19750.
END