Lithium therapy and delayed progression of Alzheimer’s disease and related dementias in patients with bipolar disorder and mild neurocognitive disorders

Recent mechanistic evidence identifies lithium deficiency as a driver of Alzheimer's disease and related dementias (ADRD) pathogenesis. To evaluate this hypothesis in a population-based setting, we emulated a target trial comparing ADRD progression after initiation of lithium versus antiepileptic mood stabilizers among adults ≥55 years with bipolar disorder and mild neurocognitive disorder, using US Medicare claims with replication in two commercial databases. Lithium initiation was associated with a lower 5-year risk of progression to advanced ADRD (risk ratio 0.87; 95% CI 0.78-0.99) and long-term care stay with ADRD (0.75; 0.56-0.97). Lower risks were most pronounced in patients with later stages of mild cognitive impairment. Results were consistent across sensitivity analyses and replications. Validations using linked cognitive assessments from standardized instruments strengthened confidence in findings. While results may be susceptible to residual bias, this study supports investigating lithium's potential to delay ADRD progression with randomized trials of optimized lithium formulations.