Neuropathologic Correlates of Seizures in Patients With Alzheimer Disease and Dementia With Lewy Bodies.

Abstract (English)

BACKGROUND AND OBJECTIVES: Seizures are a recognized comorbidity in dementia, with varying prevalence across Alzheimer disease (AD) and dementia with Lewy bodies (DLBs). Although previous studies have demonstrated an increased seizure risk in AD, the neuropathologic substrates underlying seizure susceptibility-particularly across dementia subtypes-remain incompletely understood. We aimed to identify distinct clinicopathologic correlates of clinically active seizures in AD and DLB using a large autopsy-confirmed cohort. METHODS: We conducted a retrospective cohort study using data from the National Alzheimer's Coordinating Center (2005-December 2022). Autopsy-confirmed AD and DLB cases were included. Individuals with a history of stroke or traumatic brain injury were excluded. The primary outcome was clinically active seizures, defined as seizures occurring within 3 years before or after the diagnosis of dementia. Neuropathologic exposures included Braak stage, cerebral amyloid angiopathy (CAA), frontotemporal lobar degeneration, and vascular pathologies. Multivariable logistic regression models were used to examine associations between pathologic features and seizure occurrence, adjusting for relevant demographic covariates. RESULTS: A total of 3,498 participants were included, comprising 3,040 with AD (mean age, 73.4 years; 48.5% female) and 458 with DLB (mean age, 75.1 years; 31.4% female). Active seizures were identified in 174 participants with AD (5.7%) and 13 with DLB (2.8%). In AD, Braak stage VI (vs V) was associated with higher odds of active seizures (adjusted odds ratio [OR], 1.81; 95% CI 1.20-2.82; <i>p</i> = 0.007), as was moderate to severe CAA (adjusted OR, 1.38; 95% CI 1.01-1.90; <i>p</i> = 0.045). In DLB, AD-related pathologic features were not associated with seizures. By contrast, vascular pathology was significantly associated with seizure occurrence, including microinfarcts (adjusted OR, 5.11; 95% CI 1.64-16.4; <i>p</i> = 0.005) and infarcts (adjusted OR, 4.11; 95% CI 1.27-12.9; <i>p</i> = 0.015). DISCUSSION: In this autopsy-confirmed cohort, seizure susceptibility was associated with advanced tau pathology and CAA in AD. In DLB, exploratory analyses suggested a possible association between vascular pathology and seizures; however, these findings should be interpreted cautiously. Overall, the results support potentially distinct pathologic contributions to seizure susceptibility across dementia subtypes. Limitations include the use of advanced-stage pathologic samples, which may limit generalizability to earlier disease stages.