Path: /clinical-trials/lithium-orotate-ad-nct07459959
NCT ID: NCT07459959
Phase: Phase 1/Phase 2
Status: Not yet recruiting
Sponsor: Johns Hopkins University (NIH collaboration)
Study Start: June 2026 (estimated)
Completion: August 2029 (estimated)
This Phase 1/2 clinical trial evaluates lithium orotate — a novel oral formulation of lithium — as a potential disease-modifying treatment for early Alzheimer's disease. Lithium orotate represents an innovative approach to lithium delivery, offering potentially enhanced CNS penetration and improved tolerability compared to traditional lithium carbonate formulations.
The trial focuses on biomarker-confirmed early-stage AD patients, targeting both neuroinflammation and tau pathology — two critical mechanisms that drive disease progression. By using lithium orotate at doses of 240–720 mg/day over 9 weeks, this study investigates whether this formulation can achieve therapeutic benefit with an improved safety profile.
| Feature |
This Trial (LiO-AD) |
Prior AD Lithium Trials |
| Formulation |
Lithium orotate |
Lithium carbonate |
| Dose |
240-720 mg/day |
0.5-0.8 mEq/L serum |
| Population |
Biomarker-confirmed early AD |
MCI to moderate AD |
| Duration |
9 weeks |
12-24 months |
| Primary Outcomes |
Feasibility + safety |
Cognitive endpoints |
Lithium orotate (LiC₉H₇N₃O₂) is a lithium salt of orotic acid, a naturally occurring compound involved in nucleotide metabolism. Unlike lithium carbonate, which delivers lithium as a simple ionic salt, lithium orotate forms a complex that may enhance cellular uptake and CNS penetration.
Potential Advantages:
- Enhanced bioavailability at lower doses
- Improved CNS distribution
- Reduced renal workload (lower lithium exposure per dose)
- Potentially better tolerability in elderly patients
Lithium orotate has shown promise in preclinical models of neurodegeneration:
- Neuroprotection: Reduces excitotoxicity and oxidative stress in neuronal cultures
- Tau pathology: Inhibits GSK-3β, reducing tau phosphorylation
- Autophagy: Enhances clearance of protein aggregates
- Neuroinflammation: Modulates microglial activation patterns
The orotate moiety itself may contribute to neuroprotective effects through mitochondrial support and nucleotide synthesis pathways.
Lithium orotate inherits the GSK-3β inhibitory activity of lithium ion:
- Inhibits GSK-3β activity by competing with magnesium ions at the ATP-binding site
- Reduces tau phosphorylation at multiple epitopes (Ser199, Thr231, Ser396)
- Decreases tau aggregation propensity
- May protect against tau-mediated synaptic dysfunction
Neuroinflammation is a key driver of AD progression:
- Modulates microglial polarization toward anti-inflammatory phenotype
- Reduces pro-inflammatory cytokines (IL-1β, TNF-α)
- May protect against neuroinflammation-mediated neuronal loss
Lithium promotes autophagy through multiple mechanisms:
- mTOR-independent activation via inositol depletion
- Enhanced lysosomal function
- Improved clearance of pathological protein aggregates
| Parameter |
Value |
| Design |
Randomized, double-blind, placebo-controlled |
| Duration |
9 weeks treatment |
| Participants |
40 patients |
| Allocation |
1:1 randomization (20 active, 20 placebo) |
Inclusion Criteria:
- Age 55-85 years
- Biomarker-confirmed early Alzheimer's disease (MCI due to AD or mild dementia)
- Confirmed amyloid pathology (PET or CSF)
- Confirmed tau pathology (CSF p-tau elevated)
- Stable medications for at least 4 weeks
- Able to swallow tablets
Exclusion Criteria:
- Current lithium use
- Significant renal disease (eGFR < 60 mL/min/1.73m²)
- Significant thyroid disease
- Bipolar disorder
- Contraindications to MRI
- Active psychiatric illness
| Arm |
Intervention |
Dose |
Duration |
| Active |
Lithium orotate tablets |
240-720 mg/day (titrated) |
9 weeks |
| Placebo |
Matching placebo tablets |
N/A |
9 weeks |
Dosing is titrated based on tolerability and serum lithium levels.
-
Feasibility
- Recruitment rate (target ≥80% enrollment)
- Retention rate (target ≥80% adherence)
- Completion of all study procedures
-
Safety and Tolerability
- Incidence of adverse events
- Renal function (creatinine, eGFR)
- Thyroid function (TSH, T4)
- Tolerability assessment
-
CSF Biomarkers
- Change in CSF lithium concentration
- Change in neurofilament light chain (NfL)
- Change in total tau and phosphorylated tau
-
Clinical Measures
- Neuropsychiatric Inventory (NPI)
- Cognitive testing (ADAS-Cog, MMSE)
- Clinical Dementia Rating (CDR)
-
Pharmacokinetics
- Plasma lithium levels
- CSF lithium levels (subset)
- Population PK modeling
Traditional lithium carbonate has shown mixed results in AD trials, with efficacy limited by the need for relatively high serum levels that cause tolerability issues. Lithium orotate offers several potential advantages:
- Enhanced CNS penetration: The orotate carrier may facilitate crossing the blood-brain barrier
- Lower effective doses: May achieve therapeutic CNS concentrations at lower total lithium exposure
- Improved tolerability: Reduced peripheral lithium burden may minimize renal and thyroid side effects
- Novel mechanism exploration: The orotate moiety itself may provide additional neuroprotective benefits
The trial focuses on early-stage AD for several reasons:
- Greater reserve: Earlier-stage patients have more remaining neurons and synaptic capacity
- Biomarker confirmation: Ensures AD pathology is present before treatment
- Modified disease course: Disease-modifying therapies may be more effective before extensive neuronal loss
- Regulatory support: FDA increasingly supports early-intervention trials
The 9-week duration serves multiple purposes:
- Proof-of-concept: Sufficient time to assess safety, tolerability, and biomarker changes
- Efficient design: Faster than multi-year trials for early-phase evaluation
- Informs future trials: Data guides dose selection and duration for Phase 2/3
This trial connects to several existing NeuroWiki pages:
- Lithium orotate demonstrates acceptable safety and tolerability
- CSF biomarker changes suggest target engagement (reduced p-tau, NfL)
- Cognitive measures show trend toward improvement
- Supports advancement to larger Phase 2 trial
- Trial establishes safety profile for lithium orotate in AD
- Provides PK/PD data to optimize dosing for future studies
- Generates hypotheses about which patients respond best
- Contributes to understanding of lithium's neuroprotective mechanisms
- Significant tolerability issues emerge
- No biomarker signal detected
- Trial terminates early due to safety concerns
| Milestone |
Expected Date |
| Trial start |
June 2026 |
| Enrollment complete |
December 2027 |
| Trial completion |
August 2029 |
| Results publication |
2029-2030 |
This trial is MODERATELY RELEVANT to Alzheimer's disease treatment strategies:
- Novel formulation: Lithium orotate may improve on traditional lithium
- Biomarker-confirmed: Ensures proper patient selection
- Dual mechanism: Targets both neuroinflammation and tau pathology
- Shorter duration: Results available sooner than multi-year trials
- Early phase: Safety and efficacy not yet established
- Small sample: 40 patients limits generalizability
- 9-week duration: May miss long-term effects
- Placebo-controlled: 50% chance of receiving placebo
- Lithium orotate could complement anti-amyloid therapies
- May be combined with other disease-modifying agents in development
- Does not interfere with symptomatic treatments (cholinesterase inhibitors, memantine)