Lithium vs. Valproate on Dementia Risk

Lithium lowers dementia risk compared with valproate

STUDY: Pan C-S et al, Journal of Affective Disorders 2026

STUDY TYPE: Retrospective, active-comparator, new-user cohort study with propensity score matching

FUNDING: Independent

Background

Lithium may protect the brain by inhibiting an enzyme linked to amyloid and tau buildup, while valproate’s mitochondrial effects raise neurotoxicity concerns. Several earlier studies show a lower risk with lithium, and low-dose lithium may prevent dementia in healthy adults.

This study is the first to focus on the differential risk of early-onset dementia, before age 65.

The Study

• Adults 18 to 60 with bipolar disorder starting lithium or valproate, drawn from the TriNetX real-world database.
• Propensity matching balanced the groups on comorbidities and kidney function, yielding 41,086 patients per arm.
• Primary outcome: new dementia diagnosis within 5 years.

Results

Lithium carried an 18% lower dementia risk than valproate (hazard ratio of 0.82).

The finding held across a 10-year follow-up, a complete-case analysis, and after accounting for death as a competing risk.

Those who benefited most: Women, patients without diabetes or with preserved kidney function.

Limitations

Since this is observational, not randomized, part of the difference could reflect frailty in patients steered toward valproate rather than lithium’s effect alone.

Practice Implications

1. This adds to the long-term medical benefits with lithium, and the shift in thinking about its risks in older age.