Association of Lithium Exposure With Alzheimer's Disease: A Propensity Score-Matched Cohort Study

Lithium has been widely studied for its potential neuroprotective effects through mechanisms implicated in Alzheimer's disease (AD), yet evidence from large real-world populations remains inconsistent. Clarifying the association between lithium exposure and AD risk in routine clinical practice is important given lithium's widespread use in mood disorders.

This study aims to examine the association between lithium exposure and the incidence and time to diagnosis of AD among adults with bipolar disorder or recurrent major depressive disorder.

We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults aged 50 years or older with bipolar disorder or recurrent major depressive disorder and no prior diagnosis of dementia or neurodegenerative disease were identified. Patients with documented lithium exposure for at least one year were propensity score-matched 1:1 to patients without lithium exposure on demographic and clinical covariates. Follow-up began one year after cohort entry. The primary outcome was incident AD, identified using the International Classification of Diseases, 10th Revision, code G30. Cumulative risk measures, Kaplan-Meier survival analysis, and Cox proportional hazards models were used to assess associations.

The matched cohorts included 67,020 patients each. Incident AD occurred in 34 patients in the lithium cohort and 69 patients in the no lithium cohort. Lithium exposure was associated with a lower recorded risk of AD, with a risk ratio of 0.49 (95% confidence interval (CI) = 0.33-0.74) and an odds ratio of 0.49 (95% CI = 0.33-0.74). Time-to-event analysis demonstrated a lower hazard of AD diagnosis among lithium-exposed patients (hazard ratio = 0.48; 95% CI = 0.32-0.73; log rank p < 0.001). Among patients who developed AD, the number of AD-coded encounters did not differ significantly between the cohorts.

In this large real-world cohort of older adults with mood disorders, lithium exposure was associated with a lower recorded incidence and hazard of AD. Although absolute event rates were low, the consistency of findings across analytic approaches supports a potential protective association and highlights the need for prospective studies with detailed exposure and cognitive assessments.