The Crossroads Between Alzheimer's Disease Pathophysiology and Epilepsy

Association of Plasma Aβ42/Aβ40 Ratio and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study Johnson EL, Sullivan KJ, Schneider ALC, Simino J, Mosley TH, Kucharska-Newton A, Knopman DS, Gottesman RF. Neurology . 2023 Sep 26;101(13):e1319-e1327. doi: 10.1212/WNL.0000000000207635 . Epub 2023 Aug 4. PMID: 37541842 Background and Objectives: The objective of this study was to determine the relationship between plasma β-amyloid (Aβ), specifically the ratio of 2 Aβ peptides (the Aβ 42 /Aβ 40 ratio, which correlates with increased accumulation of Aβ in the central nervous system [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 1424 Black and White men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study cohort. The Aβ 42 /Aβ 40 ratio was calculated from plasma samples collected from ARIC participants from 1993 to 1995 (age 50-71 years) and 2011 to 2013 (age 67-90 years). We used survival analysis accounting for the competing risk of death to determine the relationship between late-life plasma Aβ 42 /Aβ 40 , 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 Aβ 42 /Aβ 40 ratio, correlates with low CSF Aβ 42 /Aβ 40 and with increased accumulation of Aβ in the CNS. Results: A decrease in plasma Aβ 42 /Aβ 40 ratio from midlife to late life, but not an isolated measurement of Aβ 42 /Aβ 40 , was associated with the development of epilepsy in later life. For every 50% reduction in Aβ 42 /Aβ 40 , there was a 2-fold increase in the risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI: 1.27-4.17). Discussion: A reduction in plasma Aβ 42 /Aβ 40 is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aβ, hyperexcitable states, and LOE. Similar Brain Proteomic Signatures in Alzheimer's Disease and Epilepsy Leitner D, Pires G, Kavanagh T, Kanshin E, Askenazi M, Ueberheide B, Devinsky O, Wisniewski T, Drummond E. Acta Neuropathol . 2024 Jan 30;147(1):27. doi: 10.1007/s00401-024-02683-4 . PMID: 38289539 The prevalence of epilepsy is increased among Alzheimer's disease (AD) patients and cognitive impairment is common among people with epilepsy. Epilepsy and AD are linked but the shared pathophysiological changes remain poorly defined. We aim to identify protein differences associated with epilepsy and AD using published proteomics datasets. We observed a highly significant overlap in protein differences in epilepsy and AD: 89% (689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the same direction, while 216 proteins were altered in the opposite direction. Synapse and mitochondrial proteins were markedly decreased in epilepsy and AD, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Notably, many of the proteins altered in epilepsy interact with tau or are regulated by tau expression. This suggests that tau likely mediates common protein changes in epilepsy and AD. Immunohistochemistry for Aβ and multiple phosphorylated tau species (pTau396/404, pTau217, and pTau231) showed a trend for increased intraneuronal pTau217 and pTau231 but no phosphorylated tau aggregates or amyloid plaques in epilepsy hippocampal sections. Our results provide insights into common mechanisms in epilepsy and AD and highlight the potential role of tau in mediating common pathological protein changes in epilepsy and AD.

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