Association of Plasma Aß42/Aß40 Ratio and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

ABSTRACT

BACKGROUND AND OBJECTIVES: The objective of this study was to determine the relationship between plasma ß-amyloid (Aß), specifically the ratio of 2 Aß peptides (the Aß42/Aß40 ratio, which correlates with increased accumulation of Aß in the CNS), and late-onset epilepsy (LOE). METHODS: We 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 Aß42/Aß40 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 Aß42/Aß40, 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 Aß peptides, the Aß42/Aß40 ratio, correlates with low CSF Aß42/Aß40 and with increased accumulation of Aß in the CNS. RESULTS: Decrease in plasma Aß42/Aß40 ratio from midlife to late life, but not an isolated measurement of Aß42/Aß40, was associated with development of epilepsy in later life. For every 50% reduction in Aß42/Aß40, there was a 2-fold increase in risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI 1.27-4.17). DISCUSSION: A reduction in plasma Aß42/Aß40 is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aß, hyperexcitable states, and LOE.