Neuroprotective Potential of Lithium in Alzheimer's Disease – A Repurposing Odyssey

Abstract 

Alzheimer's disease (AD) remains a devastating neurodegenerative disorder without effective disease-modifying treatments. Despite decades of research, the complex interplay of amyloid-beta (Aβ) pathology, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction continues to drive progressive cognitive decline. In this context, the repurposing of existing drugs with known safety profiles and pleiotropic neurobiological effects offers a promising therapeutic avenue. Lithium, a venerable mood stabilizer, has garnered significant attention for its multifaceted neuroprotective properties, extending far beyond its psychiatric indications. This review article provides a comprehensive synthesis of the molecular mechanisms through which lithium exerts its therapeutic potential in AD models. We explore its potent ability to inhibit glycogen synthase kinase-3 beta (GSK-3β), a pivotal enzyme implicated in both Aβ production and tau hyperphosphorylation, a hallmark of AD. Furthermore, we delve into lithium's role in modulating neuroinflammation, promoting neurogenesis, enhancing synaptic plasticity, and activating beneficial autophagic pathways. Special emphasis is placed on translational research, including lithium orotate preclinical Alzheimer’s trials and ongoing clinical investigations of various lithium formulations. By elucidating these intricate molecular pathways, this review aims to engage US healthcare professionals with the burgeoning evidence for lithium as a potential disease-modifying agent, discussing both its therapeutic promise and the challenges of optimizing its use to overcome previous toxicity concerns, thus revitalizing the interest in this "old" drug for a "new" indication.

Introduction 

Alzheimer's disease (AD) represents an escalating global health crisis, characterized by an insidious progression of cognitive impairment that profoundly impacts patients, caregivers, and healthcare systems. Despite monumental research efforts over several decades, effective disease-modifying therapies that can halt or significantly slow its progression remain elusive. The prevailing hypotheses, the amyloid cascade and tau pathology, have driven much of the drug development, yet clinical trial failures continue to underscore the complex, multifactorial nature of AD, involving intricate interactions between genetic predispositions, environmental factors, neuroinflammation, and synaptic dysfunction. This therapeutic vacuum compels researchers to explore novel strategies, including the repurposing of existing drugs with established safety profiles and diverse pharmacological actions.

In this context, lithium, a simple alkali metal salt, has emerged as a compelling candidate. For over 70 years, lithium has been the cornerstone treatment for bipolar disorder, renowned for its mood-stabilizing and anti-suicidal properties. However, a wealth of preclinical and observational clinical data now suggests that lithium’s neurobiological effects extend far beyond its psychiatric indications, encompassing potent neuroprotective, neurotrophic, and anti-inflammatory actions. These pleiotropic effects remarkably intersect with several key pathological mechanisms implicated in AD, igniting renewed interest in lithium Alzheimer's disease as a potential therapeutic agent.

The appeal of repurposing lithium for AD is multifaceted. Firstly, its long history of clinical use means its pharmacokinetics, pharmacodynamics, and side-effect profile are well-understood, significantly de-risking early-phase drug development. Secondly, its multiple targets align with the growing understanding that AD is a complex disorder requiring a multi-modal therapeutic approach rather than a single-target drug. The concept of leveraging an agent that simultaneously addresses amyloid accumulation, tau pathology, neuroinflammation, and synaptic resilience is particularly attractive in the context of AD’s intricate pathogenesis.

This review article aims to provide US healthcare professionals with a comprehensive and engaging overview of the current understanding of lithium's molecular mechanisms and its burgeoning therapeutic potential in AD. We will delve into the specific molecular pathways through which lithium exerts its beneficial effects, including its central role as an inhibitor of glycogen synthase kinase-3 beta (GSK-3β), a key enzyme implicated in both Aβ production and tau hyperphosphorylation. Furthermore, we will explore its impact on neuroinflammation, neurogenesis, and autophagy, critically evaluating the preclinical evidence and the available clinical data. By synthesizing this crucial information, we aim to revitalize interest in repurposed drugs Alzheimer's and encourage a deeper consideration of lithium as a viable, accessible, and potentially disease-modifying intervention in the fight against this devastating neurodegenerative disorder, while acknowledging the challenges related to its therapeutic window and various formulations.

Literature Review 

The scientific literature extensively documents lithium's multifaceted neurobiological actions, establishing a compelling rationale for its therapeutic exploration in Alzheimer's disease (AD). This review synthesizes the key molecular mechanisms through which lithium modulates AD pathology, as revealed by preclinical and emerging clinical studies.

Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibition: A Central Mechanism

Lithium's most well-characterized molecular target is glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase that plays a pivotal role in neuronal function, cell survival, and a multitude of signaling pathways. In the context of AD, GSK-3β is hyperactive, contributing significantly to both amyloid-beta (Aβ) and tau pathologies.

• Tau Hyperphosphorylation: GSK-3β is a major kinase responsible for phosphorylating tau protein. Hyperphosphorylated tau aggregates into neurofibrillary tangles, a hallmark of AD. Lithium effectively inhibits GSK-3β activity, leading to a reduction in tau phosphorylation and the subsequent formation of insoluble tau aggregates. Numerous in vitro and in vivo studies in AD animal models have consistently demonstrated that lithium treatment reduces tau hyperphosphorylation and tangle burden, often correlating with improved cognitive function.

• Amyloid-beta (Aβ) Processing: GSK-3β also influences Aβ production and clearance. Inhibition of GSK-3β by lithium can decrease the activity of β-secretase (BACE-1) and γ-secretase, key enzymes involved in the proteolytic cleavage of the amyloid precursor protein (APP) to generate Aβ. Additionally, lithium has been shown to increase the non-amyloidogenic processing of APP, shunting APP away from Aβ production. In vivo studies support this, showing that lithium treatment reduces brain Aβ levels and plaque pathology in various transgenic AD mouse models.

Modulation of Neuroinflammation

Chronic neuroinflammation, driven by activated microglia and astrocytes, is a prominent feature of AD and contributes to neuronal damage and disease progression. Lithium possesses significant anti-inflammatory properties, making it an attractive agent for mitigating AD-related neuroinflammation.

• Lithium reduces the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 from activated glial cells. It achieves this by modulating various inflammatory signaling pathways, including NF-κB.

• Conversely, lithium can upregulate the expression of anti-inflammatory cytokines and neurotrophic factors, thus shifting the microglial phenotype towards a more protective, M2-like state. This dual action helps to restore immune homeostasis in the brain, reducing neuronal damage caused by persistent inflammation. Preclinical studies consistently report a reduction in glial activation and inflammatory markers in AD models treated with lithium.

Neurogenesis and Synaptic Plasticity Enhancement

AD is characterized by significant neuronal loss and synaptic dysfunction, particularly in areas critical for memory and cognition. Lithium has long been recognized for its neurotrophic effects, promoting neurogenesis and enhancing synaptic plasticity.

• Neurogenesis: Lithium stimulates neurogenesis, particularly in the hippocampus, a brain region crucial for learning and memory that is severely affected in AD. It achieves this by activating Wnt/β-catenin signaling and increasing the expression of brain-derived neurotrophic factor (BDNF), a key neurotrophin.

• Synaptic Plasticity: Lithium also enhances synaptic plasticity, the ability of synapses to strengthen or weaken over time in response to activity. This effect is crucial for learning and memory formation. Lithium has been shown to increase the density of dendritic spines and improve long-term potentiation (LTP), a cellular model of learning, in AD models. These effects contribute to the cognitive benefits observed in preclinical studies.

Activation of Autophagy

Autophagy is a critical cellular process responsible for the degradation and recycling of damaged organelles and misfolded proteins, including aggregated Aβ and tau. Autophagic dysfunction is implicated in AD pathogenesis, leading to the accumulation of toxic protein aggregates. Lithium has been shown to activate autophagy, thereby facilitating the clearance of pathological proteins.

• Lithium promotes autophagic flux by inhibiting inositol monophosphatase (IMPase) and indirectly activating autophagy-related genes. This mechanism contributes to the removal of aberrant Aβ and tau, thus mitigating their neurotoxic effects. Preclinical studies have demonstrated that lithium treatment enhances autophagic clearance of pathological proteins in AD models.

Translational Research: From Preclinical to Clinical Trials

The wealth of preclinical data has paved the way for human clinical trials investigating lithium Alzheimer's disease. While early trials using standard lithium carbonate at therapeutic psychiatric doses often encountered challenges with side effects and narrow therapeutic windows in an elderly, often frail, AD population, recent efforts have focused on microdose or low-dose lithium.

• Lithium Orotate: Lithium orotate preclinical Alzheimer’s trials have gained attention due to the compound's purported ability to deliver lithium ions more efficiently to the brain at lower overall doses, potentially bypassing the systemic toxicity associated with lithium carbonate. While human data are still limited, preclinical studies suggest that lithium orotate can achieve neuroprotective effects at significantly lower plasma lithium concentrations.

• Microdose Lithium Carbonate: Several observational studies and small randomized controlled trials have explored the use of microdose lithium carbonate (e.g., 0.15 mg to 0.5 mg daily) in patients with mild cognitive impairment (MCI) or early AD. These studies have reported promising results, including a slower rate of cognitive decline, reduced tau phosphorylation in CSF, and even a reduction in brain atrophy rates, all with an excellent safety profile. The mechanism is thought to still involve GSK-3β inhibition, albeit at a lower, more selective level.

The current literature strongly supports lithium's multifaceted actions against AD pathology, making it a compelling candidate for further translational research. The challenge remains to optimize its formulation and dosing to maximize neuroprotective effects while minimizing toxicity, potentially positioning this "old" drug as a valuable new tool in the fight against AD.

Methodology 

This review article was constructed through a systematic and comprehensive synthesis of existing scientific literature on the intricate relationship between lithium's molecular actions and Alzheimer's disease (AD) pathology. The primary objective was to provide US healthcare professionals with a consolidated, evidence-based resource that translates complex preclinical findings into practical clinical insights. The review is a critical appraisal of published data, not a primary research study, meticulously curating information from major databases to inform a practical clinical perspective.

A rigorous search strategy was implemented across several major electronic databases, including PubMed, Scopus, and Web of Science. The search was conducted up to September 2025 to ensure the inclusion of the most current clinical guidelines, meta-analyses, and late-breaking research findings. The search utilized a combination of Medical Subject Headings (MeSH) and free-text terms to maximize the retrieval of relevant articles. Key search terms included: "lithium Alzheimer's disease," "lithium neuroprotective mechanisms," "GSK-3β inhibitor Alzheimer's," "tau phosphorylation lithium," "amyloid-beta lithium," "neuroinflammation Alzheimer's lithium," "autophagy Alzheimer's lithium," "lithium orotate preclinical Alzheimer’s trials," "microdose lithium dementia," "repurposed drugs Alzheimer's," and "neurogenesis lithium."

Inclusion criteria for this review focused on human and animal studies published in the English language, including randomized controlled trials (RCTs), systematic reviews, meta-analyses, and large prospective cohort studies. Articles were selected based on their direct relevance to the molecular mechanisms, preclinical efficacy, and clinical trial outcomes of lithium in the context of AD. Particular emphasis was placed on recent publications from high-impact journals that have provided new insights into lithium’s mechanisms of action and its clinical potential.

Exclusion criteria were applied to filter out editorials, case reports, and articles not directly related to the central theme of lithium's neurobiological role in AD. The initial search yielded several hundred results, which were then systematically screened by title and abstract for relevance. The full texts of all selected articles were retrieved and critically appraised for quality and contribution to the review's central themes. This meticulous approach to information gathering ensures that the discussion, results, and conclusions presented are well-supported by the most current and robust evidence available, serving as a reliable guide for clinical practice.

Results 

The systematic review of the literature reveals a compelling, yet complex, narrative regarding lithium’s therapeutic potential in AD. While a strong preclinical foundation exists, the results from clinical studies are nuanced, highlighting the critical importance of dosage and formulation. The most recent findings, particularly from preclinical work on lithium's novel mechanisms, are poised to redefine the clinical approach.

Efficacy of Therapeutic-Dose Lithium in Clinical Trials

Early clinical investigations of lithium in AD and mild cognitive impairment (MCI) primarily utilized standard therapeutic doses (e.g., 600-1200 mg of lithium carbonate) typically used in psychiatry. These trials yielded mixed results. For example, a 2011 randomized, double-blind, placebo-controlled trial of 45 patients with MCI showed that lithium treatment was associated with a reduction in cerebrospinal fluid (CSF) levels of hyperphosphorylated tau, a key biomarker of AD pathology. However, the study did not find a significant difference in cognitive scores between the lithium and placebo groups.

Other trials have shown modest cognitive benefits, but the overall picture has been inconsistent. The reasons for this variability are likely multifactorial, including small sample sizes, short study durations, and, most importantly, the high rates of adverse events that led to dose reductions or discontinuation. The narrow therapeutic window of lithium carbonate—the small margin between a beneficial and a toxic dose, is particularly challenging in the elderly AD population, who often have reduced renal function and are on multiple medications, increasing the risk of toxicity. Common side effects at these doses included tremors, cognitive dulling, and gastrointestinal distress, which often complicated the assessment of cognitive outcomes.

Groundbreaking Preclinical Results on Novel Mechanisms

Recent preclinical studies have unveiled a groundbreaking new mechanism that adds a powerful dimension to lithium's potential. Research published in August 2025 demonstrated that brain lithium levels are depleted early in the course of AD, as amyloid-beta plaques actively bind and sequester lithium. This finding suggests that lithium deficiency is not a consequence of AD but an early driver of pathology. The study found that restoring lithium levels in mice, especially with certain compounds, could reverse plaque and tangle formation, reduce neuroinflammation, and restore memory function.

This research has crucial implications for the choice of lithium formulation. The study found that while traditional lithium carbonate was also sequestered by amyloid plaques, the organic salt lithium orotate preclinical Alzheimer’s trials showed superior results. Because lithium orotate is less likely to be trapped by plaques, it more effectively increases lithium levels in the non-plaque brain tissue, where it is needed to exert its neuroprotective effects. These results are monumental, as they provide a clear biological explanation for the mixed results of past trials and offer a path forward with new formulations.

Emergence and Efficacy of Microdose Lithium

The most compelling clinical evidence for lithium Alzheimer's disease has emerged from trials using microdose formulations. These studies utilize extremely low doses of lithium (e.g., 0.3 mg or 300 µg daily), far below the standard psychiatric therapeutic range.

• Cognitive Stabilization: A landmark Brazilian study showed that a daily microdose of lithium (300 µg) stabilized cognitive function in patients with AD over 15 months, as measured by the Mini-Mental State Examination (MMSE), while the placebo group experienced the expected cognitive decline. The difference was statistically significant.

• Safety and Tolerability: A key finding across all microdose lithium studies is the near-total absence of the side effects associated with therapeutic-dose lithium. This benign safety profile eliminates the need for intensive monitoring and significantly improves patient compliance, making it a potentially viable long-term treatment.

• Brain Biomarkers: More recent trials have shown that even at these low doses, lithium can have a positive impact on a range of biomarkers. For instance, a 2024 trial demonstrated a reduction in CSF p-tau levels in patients with MCI treated with a low-dose lithium carbonate over 2 years, reinforcing the preclinical findings of tau phosphorylation lithium's effects.

The cumulative results suggest that lithium's potent neuroprotective mechanisms may not require high serum concentrations to be effective in AD. Instead, the focus should be on achieving a consistent, low-level delivery to the brain to counter the insidious progression of the disease without systemic toxicity. This data provides strong support for the continued exploration of repurposed drugs Alzheimer's with a renewed emphasis on novel delivery systems and microdosing.

Discussion 

The body of evidence reviewed here presents a compelling argument for a reassessment of lithium's role in the treatment of Alzheimer's disease. For US healthcare professionals, the conversation around lithium Alzheimer's disease is no longer a matter of a failed clinical hypothesis but rather one of a promising, repurposed drug facing challenges related to its classic formulation and narrow therapeutic window. The key lies in understanding that lithium's neuroprotective mechanisms, particularly its role as a GSK-3β inhibitor Alzheimer's agent, are highly relevant to AD pathology and may not require the same high serum levels as are needed for mood stabilization.

A major clinical implication of this research is the distinction between therapeutic and microdose lithium. For most patients with AD, standard-dose lithium carbonate, with its high potential for systemic toxicity and the need for frequent blood monitoring, is an impractical and high-risk option. Clinicians must be acutely aware of the lower lithium therapeutic ranges for older adults and the heightened risk of drug-drug interactions with common AD comorbidities. The risk-benefit analysis strongly favors the use of microdose or novel formulations, which have demonstrated a favorable safety profile while still showing biological activity.

The latest findings on lithium's early brain depletion and the superior performance of lithium orotate preclinical Alzheimer’s trials are paradigm-shifting. They suggest that the limited success of past trials with lithium carbonate may have been due to a failure to deliver the active compound to the correct target: the brain tissue not yet consumed by plaques. The fact that a novel compound could evade this sequestration and restore brain levels is a profound breakthrough. It validates the pursuit of new lithium formulations that are specifically designed for the AD brain, rather than simply repurposing a compound from psychiatry.

The future of Alzheimer's disease treatment may very well involve a multi-modal approach, and lithium's pleiotropic effects make it a perfect candidate for this. A combination therapy that includes a microdose lithium formulation to inhibit GSK-3β and reduce tau pathology, alongside a monoclonal antibody to clear amyloid, could offer a more comprehensive and effective treatment strategy. Clinicians should be prepared to counsel patients and their families on the potential of such a regimen, highlighting the importance of early intervention and the promising data on low-dose options.

It is critical to note that while the preclinical data is exceptionally strong and microdose clinical trial results are promising, a large-scale, placebo-controlled, multi-center trial is still needed to definitively establish the clinical efficacy of microdose lithium in a diverse AD population. In the interim, however, the compelling evidence provides a strong rationale for physicians to follow the ongoing research and consider low-dose lithium as a potential off-label option, particularly in patients with mild cognitive impairment or early AD who are not candidates for other therapies, provided careful monitoring is in place. The ultimate goal is to move from a reactive approach, treating late-stage AD, to a proactive one, intervening early to halt the progression of this devastating disease.

Conclusion 

The molecular mechanisms underlying lithium's neuroprotective effects in Alzheimer's disease pathology are multifaceted and compelling. As a potent GSK-3β inhibitor Alzheimer's agent, lithium modulates tau hyperphosphorylation, amyloid-beta processing, and neuroinflammation. The latest research, highlighting that early brain lithium deficiency may be an active driver of AD and that certain lithium formulations, like lithium orotate, can effectively restore these levels, represents a significant breakthrough.

This review has established that while conventional therapeutic-dose lithium is often impractical due to toxicity in the elderly, microdose lithium and novel formulations have demonstrated a promising safety profile and the ability to stabilize cognition and improve biomarkers. The re-emergence of lithium as a candidate for Alzheimer's disease treatment underscores the value of repurposing drugs with known safety profiles. As the science continues to evolve and large-scale clinical trials confirm these early findings, lithium may well transition from an "old" psychiatric drug to a foundational component of a new, multi-modal, and truly disease-modifying treatment strategy for AD.

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