Association of Plasma Aβ₄₂/Aβ₄₀ Ratio and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study

Background and ObjectivesThe objective of this study was to determine the relationship between plasma β-amyloid (Aβ), specifically the ratio of 2 Aβ peptides (the Aβ₄₂/Aβ₄₀ ratio, which correlates with increased accumulation of Aβ in the CNS), and late-onset epilepsy (LOE).MethodsWe used Medicare fee-for-service claims codes from 1991 to 2018 to identify cases of LOE among 1,424 Black and White men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study cohort. The Aβ₄₂/Aβ₄₀ ratio was calculated from plasma samples collected from ARIC participants in 1993-1995 (age 50-71 years) and 2011-2013 (age 67-90 years). We used survival analysis accounting for the competing risk of death to determine the relationship between late-life plasma Aβ₄₂/Aβ₄₀, and its change from midlife to late life, and the subsequent development of epilepsy. We adjusted for demographics, the apolipoprotein e4 genotype, and comorbidities, including stroke, dementia, and head injury. A low plasma ratio of 2 Aβ peptides, the Aβ₄₂/Aβ₄₀ ratio, correlates with low CSF Aβ₄₂/Aβ₄₀ and with increased accumulation of Aβ in the CNS.ResultsDecrease in plasma Aβ₄₂/Aβ₄₀ ratio from midlife to late life, but not an isolated measurement of Aβ₄₂/Aβ₄₀, was associated with development of epilepsy in later life. For every 50% reduction in Aβ₄₂/Aβ₄₀, there was a 2-fold increase in risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI 1.27-4.17).DiscussionA reduction in plasma Aβ₄₂/Aβ₄₀ is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aβ, hyperexcitable states, and LOE.