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

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

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.

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)