LATTICE
(2026)Objective
To evaluate whether low-dose lithium carbonate (150–300 mg daily) over 2 years reduces cognitive decline and preserves neurobiological markers in mild cognitive impairment (MCI).
Study Summary
• CVLT-II verbal memory showed nominal benefit: decline 0.73 pts/year (lithium) vs 1.42 pts/year (placebo), difference 0.69 pts/year (95% CI 0.01–1.37, P=0.05).
• Hippocampal volume loss was numerically attenuated with lithium (59 mm³/year less loss, P=0.09) but not significant.
• In amyloid-positive participants, effect sizes were larger for verbal memory (Hedges g=0.74) and hippocampal volume (g=0.82), suggesting a potential disease-modification signal in this subgroup.
Intervention
Low-dose lithium carbonate 150–300 mg daily vs placebo for 2 years
Inclusion Criteria
Adults aged 60 years or older with mild cognitive impairment (MCI)
Study Design
Arms: Lithium carbonate 150–300 mg daily (n=41) vs Placebo (n=39)
Patients per Arm: 41 lithium, 39 placebo (80 started treatment, 83 randomized)
Outcome
• CVLT-II verbal memory: nominally significant (P=0.05) but below prespecified threshold; lithium group declined 0.73 pts/year vs 1.42 pts/year with placebo.
• SAEs: 29% lithium vs 23% placebo; none considered definitely treatment-related.
Bottom Line
Low-dose lithium (150-300 mg daily) did not meet any of its 6 coprimary endpoints over 2 years in adults with MCI. A nominally significant verbal memory benefit (P=0.05) and a numerical trend toward hippocampal preservation were observed but fell short of the prespecified threshold. Larger effects in amyloid-positive participants warrant further investigation in enriched populations.
Major Points
- None of the 6 coprimary endpoints reached the prespecified P<0.01 significance threshold -- the trial's primary result is negative.
- CVLT-II verbal memory showed the strongest signal: lithium reduced annual decline by ~49% (0.73 vs 1.42 pts/year, diff 0.69, 95% CI 0.01-1.37, P=0.05) -- nominally significant but below threshold.
- Hippocampal volume loss was numerically less with lithium (59 mm3/year difference, P=0.09) -- a trend without significance.
- Amyloid-positive subgroup showed larger effect sizes: Hedges g=0.74 for verbal memory and g=0.82 for hippocampal volume, suggesting potential benefit in those with underlying Alzheimer pathology.
- SAEs occurred in 29% lithium vs 23% placebo; none were considered definitely treatment-related, supporting tolerability of low-dose lithium.
- As a single-site pilot trial (n=80), the study was underpowered -- results are hypothesis-generating and should not change clinical practice.
- Findings support a larger RCT enriched for amyloid-positive MCI participants to adequately test lithium as a disease-modifying agent.
Study Design
- Study Type
- Single-center, randomized, double-blind, placebo-controlled pilot trial
- Randomization
- Yes
- Blinding
- Double-blind (participants and investigators blinded to treatment assignment)
- Sample Size
- 83
- Follow-up
- 2 years
- Centers
- 1
- Countries
- USA
Primary Outcome
Definition: 6 coprimary outcomes at 2 years: (1) CVLT-II delayed recall (verbal memory), (2) BVMT-R delayed recall (visual memory), (3) PACC (global cognitive composite), (4) hippocampal volume, (5) cortical gray matter volume, (6) plasma BDNF -- assessed via linear mixed-effects trajectory models
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| None of 6 outcomes met threshold | None of 6 outcomes met threshold | - | All P>0.01 |
Limitations & Criticisms
- Single-site pilot trial with limited statistical power and generalizability
- 6 coprimary endpoints tested at prespecified P<0.01 threshold to address multiple comparisons; still susceptible to false-positive risk in exploratory analyses
- Small sample size (n=80) means most individual endpoints are severely underpowered
- Sample predominantly amyloid-negative (~68%), likely diluting any true disease-modifying effect
- Amyloid subgroup analysis was exploratory with small subgroup sizes -- highly susceptible to type I error
- 36% overall medication discontinuation may limit interpretation
- The 2-year follow-up may be insufficient to detect disease modification effects in MCI
- Conducted during COVID-19 pandemic which affected assessments and possibly retention
Citation
JAMA Neurol. 2026;83(4):310-319