Epilepsy and subsequent dementia in adults with down syndrome: a propensity score–matched cohort study using federated electronic health records

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PURPOSE: Epilepsy and early-onset Alzheimer disease (AD) are both common in adults with Down syndrome (DS), and their temporal relationship remains unclear. We examined whether a recorded diagnosis of epilepsy was associated with higher subsequent recording of all-cause dementia, AD, non-Alzheimer dementia, and mortality among adults with DS aged 40 years or older. METHODS: Retrospective cohort study using deidentified electronic health records from the TriNetX Global Collaborative Network. Adults with DS (ICD-10-CM Q90; age ≥40 years; 2010-2025) were classified as having epilepsy (G40 recorded before any dementia code) or not; secondary seizures were excluded. Cohorts were balanced by 1:1 propensity score matching. Outcomes were assessed from 90 to 730 days after the index date using hazard ratios (HRs) and Kaplan-Meier analyses. RESULTS: After matching, 1812 patients per cohort were retained (mean [SD] age, 54.3 [7.0] vs 54.2 [7.4] years). Epilepsy was associated with higher subsequent recording of all-cause dementia (12.9%vs 6.5%; HR, 2.03 [95% CI, 1.59-2.60]), AD (6.1%vs 3.2%; HR, 1.97 [1.41-2.76]), non-Alzheimer dementia (12.9%vs 6.3%; HR, 2.08 [1.63-2.65]), and mortality (12.8%vs 5.1%; HR, 2.55 [2.00-3.24]). Estimates were similar by age and sex, and when exposure required an antiseizure medication prescription alongside the diagnostic code. CONCLUSION: Epilepsy was associated with higher subsequent recording of dementia and mortality over 2 years. No biomarker, neuroimaging, or neuropathological measure was available; the estimates describe the order in which diagnoses were documented and do not establish that epilepsy marks the underlying neurodegenerative process. Differential ascertainment and residual confounding remain plausible contributors.