LiO-AD: Lithium Orotate in Alzheimers Disease Feasibility, Biomarker Engagement, and Clinical Response

Overview

The goal of this clinical trial is to assess feasibility, safety, tolerability, and central nervous system target engagement of oral lithium orotate in adults with biomarker-confirmed early Alzheimer's disease. The main questions it aims to answer are: * Can participants be recruited, retained, and remain adherent (target ≥80%) over 9 weeks of treatment, and what is the frequency and severity of adverse events? * Does lithium orotate increase cerebrospinal fluid (CSF) lithium concentration from baseline to 9 weeks compared with placebo? Researchers will compare daily lithium orotate to matched placebo to see if lithium orotate demonstrates acceptable feasibility, safety, and tolerability and engages the central nervous system target (CSF lithium). Participants will: * Be randomized in a double-blind manner to receive lithium orotate or placebo for 9 weeks, with titration from week 1: 240 mg/day (10mg elemental lithium) to week 2: 480 mg/day (20mg elemental lithium) and week 3: 720 mg/day (30mg elemental lithium) if tolerated; dose reductions are permitted for side effects. * Attend study visits for safety monitoring, adherence support (caregiver pill logs/diaries), and review of concomitant medications and adverse events. * Provide blood samples and undergo lumbar punctures at baseline and post-treatment to measure CSF and serum lithium and Alzheimer's-related biomarkers; complete brief cognitive testing and neuropsychiatric symptom assessments.

Interventions

• Drug Lithium orotate
  Lithium orotate (LiO) oral capsules, over-encapsulated to match placebo. Dosing uses a structured titration over 3 weeks followed by maintenance through week 9: Week 1: 240 mg/day Week 2: 480 mg/day Week 3: 720 mg/day (target dose), with option to down-titrate to 480 mg/day or 240 mg/day if side effects occur (note that 240mg LiO = \~10mg elemental Li) Key distinguishing features: Population: adults with biomarker-confirmed early Alzheimer's disease. Central nervous system target engagement a
• Drug Matched Placebo (Capsules)
  Matched placebo oral capsules, over-encapsulated to be indistinguishable from lithium orotate in appearance, weight, packaging, labeling, and dosing instructions. The dosing schedule mirrors the active arm to maintain blinding: Week 1: one capsule daily (matching 240 mg/day schedule) Week 2: two capsules daily (matching 480 mg/day schedule) Week 3 through Week 9: three capsules daily (matching 720 mg/day target), with option to maintain a lower capsule count if down-titration is required to mir

Primary outcome measures

• Feasibility (Recruitment, Retention) [Time frame: Baseline up to Week 9]
• Feasibility (Visit Completion) [Time frame: Baseline up to Week 9]
• Feasibility (Adherence) [Time frame: Baseline up to Week 9]
• Safety (Frequency of Adverse Events) [Time frame: Baseline up to Week 11 (includes Safety Follow-up)]
• Safety (Adverse Events Relatedness) [Time frame: Baseline through Week 11 (includes Safety Follow-up)]
• Safety (Adverse Events Severity) [Time frame: Baseline through Week 11 (includes Safety Follow-up)]
• Safety (Renal function) [Time frame: Baseline through Week 11 (includes Safety Follow-up)]
• Safety (Thyroid functioning) [Time frame: Baseline through Week 11 (includes Safety Follow-up)]
• Tolerability (Dose Modifications) [Time frame: Baseline up to Week 9]
• Tolerability (Discontinuations) [Time frame: Baseline to Week 9]

Secondary outcome measures (4)

• Central Nervous System Target Engagement (CSF Lithium Change) [Time frame: Baseline up to Week 9]
• Change in neurofilament light chain (NfL) [Time frame: Baseline up to Week 9]
• Neuropsychiatric Symptoms (NPI-Q) [Time frame: Baseline up to Week 9]
• Delayed Recall [Time frame: Baseline up to Week 9]

Eligibility criteria

Inclusion criteria

• Diagnosis of Alzheimer's disease confirmed by biomarkers (imaging or biofluid evidence of amyloid-beta and tau pathology)
• Mild stage of Alzheimer's disease: Clinical Dementia Rating (CDR) ≤ 1 or Quick Dementia Rating System (QDRS) ≤ 8
• Medically stable and able to attend study visits and complete study procedures
• On stable doses of any psychotropic medications for at least 4 weeks before the baseline visit
• Not currently receiving anti-amyloid monoclonal antibody therapy

Exclusion criteria

• New or unstable neurological disorder or unstable psychiatric illness that could affect safety or study results
• Clinically significant kidney or thyroid problems that pose safety concerns, or abnormal safety labs judged to be related to study drug and requiring discontinuation
• Use of thiazide diuretics during the dosing period (unless stopped at least 4 weeks before baseline)
• Chronic daily use of non-aspirin NSAIDs (including COX-2 inhibitors); short courses require study team approval and may require temporary study drug hold and safety labs before resuming
• Starting excluded therapies during the active treatment period (e.g., anti-amyloid monoclonal antibody treatment)
• Noncompliance with essential study procedures that would prevent collection of primary safety or feasibility endpoints (e.g., repeated missed visits or refusal of critical labs)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07459959 · IRB00540477

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗