Patient Information
The study population for this pilot randomized clinical trial consisted of 83 adults aged 60 years or older. All participants were diagnosed with Mild Cognitive Impairment (MCI), a clinical state representing an intermediate stage between the expected cognitive decline of normal aging and the more serious decline of dementia. The cohort was predominantly female (56%), with a mean age of approximately 72.9 years in the lithium group and 71.2 years in the placebo group. Participants were required to be free of major psychiatric or neurologic illnesses (such as major depressive disorder or Parkinson’s disease) and had no contraindications to lithium therapy, such as significant renal impairment or specific drug interactions.
Diagnosis
The primary diagnosis for all participants was Mild Cognitive Impairment (MCI). This diagnosis was established through comprehensive clinical assessments, including the California Verbal Learning Test-II (CVLT-II), which measures episodic memory. At baseline, the mean CVLT-II scores were 7.95 for the lithium cohort and 7.90 for the placebo group, reflecting characteristic memory impairment without fulfilling the criteria for clinical dementia. Participants also underwent neuroimaging to establish baseline hippocampal and cortical gray matter volumes.
Differential Diagnosis
During the screening of 170 individuals, differential diagnoses were carefully considered to ensure that cognitive deficits were attributable to MCI rather than other treatable or distinct conditions. Potential exclusions included:
- Major Depressive Disorder: Pseudo-dementia related to mood disorders was ruled out via psychiatric evaluation.
- Major Neurologic Illness: Conditions such as stroke-related vascular dementia, normal pressure hydrocephalus, or Parkinson’s disease were excluded.
- Metabolic or Nutritional Deficiencies: Standard clinical screens were utilized to ensure cognitive decline was not due to Vitamin B12 deficiency or thyroid dysfunction.
Treatment and Management
The intervention involved a 2-year, single-site, randomized, double-blind, placebo-controlled trial. Participants were randomized into two groups:
- Lithium Group (n=41): Received a daily low-dose of lithium carbonate. The rationale for low dosing was to maximize safety and tolerability while investigating the hypothesis that lithium deficiency contributes to Alzheimer’s disease pathogenesis.
- Placebo Group (n=39): Received a matching placebo.
Treatment was maintained for 24 months, with regular monitoring of plasma lithium levels, renal function (creatinine), and clinical status to ensure participant safety. The study design focused on the feasibility of long-term lithium administration in an older population with cognitive vulnerability.
Outcome and Prognosis
Over the 2-year follow-up, the study assessed six coprimary outcomes including memory recall, hippocampal volume, and brain-derived neurotrophic factor (BDNF).
Cognitive Results: The placebo group experienced an annual decline of 1.42 points on the CVLT-II delayed recall, whereas the lithium group declined by only 0.73 points per year. While the difference (0.69 points/year) reached a P-value of .05, it did not meet the rigorous prespecified significance threshold for this pilot.
Neuroimaging: Both groups showed a decline in hippocampal and cortical gray matter volumes over time, with no significant treatment-by-time interaction observed.
Safety: Lithium was generally well-tolerated. Serious adverse events (SAEs) occurred in 29% of the lithium group compared to 23% of the placebo group, but none were definitively linked to the medication. Common side effects in the lithium group included diarrhea (29%), tiredness (29%), and tremors (24%), though creatinine increases were similar between groups (29% vs 31%).
Discussion
This pilot trial is significant as it represents the first randomized clinical trial to examine the effects of lithium on cognition, neuroimaging, and biomarkers in patients with MCI. Although the primary endpoints did not achieve statistical significance, the study successfully demonstrated the feasibility and safety of using low-dose lithium in an older, cognitively impaired population.
The observed trend in the CVLT-II scores suggests that lithium might have a modest effect on slowing memory decline, which warrants further investigation in larger, adequately powered Phase III trials. The study provides critical effect size estimates that will inform the design of future studies. The lack of significant change in hippocampal volume suggests that if lithium is neuroprotective, its effects might be functional or molecular rather than purely structural over a 2-year period. This research supports the ongoing investigation of lithium as a potential low-cost, widely available intervention for delaying the progression of Alzheimer’s disease.
References
Gildengers AG, Ibrahim TS, Anderson SJ, et al. Low-Dose Lithium for Mild Cognitive Impairment: A Pilot Randomized Clinical Trial. JAMA Neurol. 2026; Published online March 2, 2026. doi:10.1001/jamaneurol.2026.0072
