Alzheimer s Disease
Conditions
Brief summary
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
DRUGLithium 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 assessed via change in CSF lithium from baseline to week 9, measured by lumbar puncture; serum lithium also collected for correlation. Feasibility and tolerability supported by caregiver adherence tools Safety monitoring at each visit with renal and thyroid laboratory assessments; The selected LiO dose (target 720 mg/day) reflects upper limit safely used as a supplement (30mg elemental Li). Randomized, double-blind, placebo-controlled design with identical schedules across arms.
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 mirror tolerability adjustments in the active arm Key distinguishing and blinding-maintenance features: Randomized, double-blind, placebo-controlled administration with identical visit schedules, counseling, adherence supports. Study staff, participants, caregivers, and outcome assessors remain blinded. Safety monitoring (including renal and thyroid labs) and adverse event assessments occur at the same frequency as the active arm without revealing assignment.
Sponsors
Johns Hopkins University
National Institutes of Health (NIH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility (Recruitment, Retention) | Baseline up to Week 9 | Proportion of eligible participants enrolled; proportion completing Week 9 procedures; |
| Feasibility (Visit Completion) | Baseline up to Week 9 | Proportion of scheduled visits completed |
| Feasibility (Adherence) | Baseline up to Week 9 | Medication adherence defined as percent of prescribed doses taken (target ≥80%) |
| Safety (Frequency of Adverse Events) | Baseline up to Week 11 (includes Safety Follow-up) | Frequency of adverse events collected at each visit |
| Safety (Adverse Events Relatedness) | Baseline through Week 11 (includes Safety Follow-up) | Relatedness of adverse event to intervention as determined by study physician (definitely related, possibly related, not related) |
| Safety (Adverse Events Severity) | Baseline through Week 11 (includes Safety Follow-up) | Severity of adverse events as judged by study physician (mild, moderate, severe) |
| Safety (Renal function) | Baseline through Week 11 (includes Safety Follow-up) | Renal function will be assessed by measuring creatinine levels in mg/dL |
| Safety (Thyroid functioning) | Baseline through Week 11 (includes Safety Follow-up) | Thyroid functioning with be measured using thyroid stimulating hormone measured in mclU/mL |
| Tolerability (Dose Modifications) | Baseline up to Week 9 | Rates of dose reductions |
| Tolerability (Discontinuations) | Baseline to Week 9 | Rates of discontinuation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Central Nervous System Target Engagement (CSF Lithium Change) | Baseline up to Week 9 | Change in cerebrospinal fluid (CSF) lithium concentration from baseline to post-treatment, comparing lithium orotate vs. placebo (mEq/L) |
| Change in neurofilament light chain (NfL) | Baseline up to Week 9 | Change from baseline in CSF NfL measured in pg/mL |
| Neuropsychiatric Symptoms (NPI-Q) | Baseline up to Week 9 | Change in Neuropsychiatric Inventory Questionnaire (NPI-Q) total score from baseline to post-treatment; between-group comparisons at Week 9. Scored 0-36 with a higher score representing more severe symptoms. |
| Delayed Recall | Baseline up to Week 9 | Change in Hopkins Verbal Learning Test-Revised score from baseline to post-treatment; between-group comparisons at Week 9. Scored from 0-36 with a higher score representing better cognitive performance. |
Contacts
CONTACTChristopher Morrow, MD, MHS
PRINCIPAL_INVESTIGATORChristopher Morrow, MD, MHS
Johns Hopkins University
Outcome results
None listed