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Amyloid-β: a potential link between epilepsy and cognitive decline

Abstract

People with epilepsy — in particular, late-onset epilepsy of unknown aetiology — have an elevated risk of dementia, and seizures have been detected in the early stages of Alzheimer disease (AD), supporting the concept of an epileptic AD prodrome. However, the relationship between epilepsy and cognitive decline remains controversial, with substantial uncertainties about whether epilepsy drives cognitive decline or vice versa, and whether shared pathways underlie both conditions. Here, we review evidence that amyloid-β (Aβ) forms part of a shared pathway between epilepsy and cognitive decline, particularly in the context of AD. People with epilepsy show an increased burden of Aβ pathology in the brain, and Aβ-mediated epileptogenic alterations have been demonstrated in experimental studies, with evidence suggesting that Aβ pathology might already be pro-epileptogenic at the soluble stage, long before plaque deposition. We discuss the hypothesis that Aβ mediates — or is at least a major determinant of — a continuum spanning epilepsy and cognitive decline. Serial cognitive testing and assessment of Aβ levels might be worthwhile to stratify the risk of developing dementia in people with late-onset epilepsy. If seizures are a clinical harbinger of dementia, people with late-onset epilepsy could be an ideal group in which to implement preventive or therapeutic strategies to slow cognitive decline.

Key points

  • Seizures and cognitive decline are interrelated: people with epilepsy have a threefold increased risk of dementia compared with the general population, and the risk is particularly high when the onset of epilepsy is in late adult life.

  • Around 25% of people who develop epilepsy in late adulthood have no defined cause for their seizures, leading to the diagnosis of late-onset epilepsy of unknown aetiology (LOEU).

  • People with LOEU have been shown to have amyloid pathology in the brain, with amyloid-β (Aβ) deposition increasing their risk of developing cognitive decline over the decades following seizure onset.

  • Experimental studies support a role for Aβ in promoting seizures: Aβ is pro-epileptogenic at the oligomer stage, long before plaque deposition, and its accumulation fosters network hyperexcitability.

  • Seizures can be a harbinger of dementia, and identification of people at high risk of cognitive decline at epilepsy onset might allow crucial interventions early in Aβ deposition, thereby preventing further neurodegeneration.

  • Neuropsychological and biomarker assessment should be used to stratify patients with LOEU at an early stage to enable personalized treatment and potential enrolment in disease-modifying drug trials.

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Fig. 1: Aβ at the interface of epileptogenesis and neuronal loss.
Fig. 2: Aβ accumulation, late-onset epilepsy and cognitive decline.
Fig. 3: Aβ pathology, LOEU and neurodegeneration.

References

  1. 1.

    The Lancet Neurology. Response to the growing dementia burden must be faster. Lancet Neurol. 17, 651 (2018).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Nichols, E. et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 88–106 (2019).

    Article  Google Scholar 

  3. 3.

    Lozano, R. et al. Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1250–1284 (2020).

    Article  Google Scholar 

  4. 4.

    Schneider, L. Alzheimer’s disease and other dementias: update on research. Lancet Neurol. 16, 4–5 (2017).

    PubMed  Article  Google Scholar 

  5. 5.

    Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Masters, C. L. et al. Alzheimer’s disease. Nat. Rev. Dis. Primers 1, 15056 (2015).

    PubMed  Article  Google Scholar 

  7. 7.

    Jack, C. R. et al. The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes. Brain 142, 3230–3242 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Polanco, J. C. et al. Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies. Nat. Rev. Neurol. 14, 22–40 (2018).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Jack, C. R. et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Bloom, G. S. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505–508 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Minkeviciene, R. et al. Amyloid-induced neuronal hyperexcitability triggers progressive epilepsy. J. Neurosci. 29, 3453–3462 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Costa, C. et al. Epilepsy, amyloid-β, and D1 dopamine receptors: a possible pathogenetic link? Neurobiol. Aging 48, 161–171 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Costa, C., Romoli, M. & Calabresi, P. Late onset epilepsy and Alzheimer’s disease: exploring the dual pathogenic role of amyloid-β. Brain 53, 467–472 (2018).

    Google Scholar 

  14. 14.

    Keret, O., Hoang, T. D., Xia, F., Rosen, H. J. & Yaffe, K. Association of late-onset unprovoked seizures of unknown etiology with the risk of developing dementia in older veterans. JAMA Neurol. 77, 710–715 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Palop, J. J. & Mucke, L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17, 777–792 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Nardi Cesarini, E. et al. Late-onset epilepsy with unknown etiology: a pilot study on neuropsychological profile, cerebrospinal fluid biomarkers, and quantitative EEG characteristics. Front. Neurol. 11, 199 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Ovsepian, S. V. & O’Leary, V. B. Neuronal activity and amyloid plaque pathology: an update. J. Alzheimers Dis. 49, 13–19 (2015).

    CAS  Article  Google Scholar 

  18. 18.

    Costa, C. et al. Alzheimer’s disease and late-onset epilepsy of unknown origin: two faces of beta amyloid pathology. Neurobiol. Aging 73, 61–67 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Sen, A., Jette, N., Husain, M. & Sander, J. W. Epilepsy in older people. Lancet 395, 735–748 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Cretin, B. et al. Epileptic prodromal Alzheimer’s disease, a retrospective study of 13 new cases: expanding the spectrum of Alzheimer’s disease to an epileptic variant? J. Alzheimers Dis. 52, 1125–1133 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Sen, A., Capelli, V. & Husain, M. Cognition and dementia in older patients with epilepsy. Brain 141, 1592–1608 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Stelzmann, R. A., Schnitzlein, H. N. & Murtagh, F. R. An English translation of Alzheimer’s 1907 paper “Über eine eigenartige Erkrankung der Hirnrinde”. Clin. Anat. 8, 429–431 (1995).

    PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Qiang, W., Yau, W.-M., Lu, J.-X., Collinge, J. & Tycko, R. Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes. Nature 541, 217–221 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Hardy, J. & Higgins, G. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Menéndez, M. Down syndrome, Alzheimer’s disease and seizures. Brain Dev. 27, 246–252 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Vossel, K. A., Tartaglia, M. C., Nygaard, H. B., Zeman, A. Z. & Miller, B. L. Epileptic activity in Alzheimer’s disease: causes and clinical relevance. Lancet Neurol. 16, 311–322 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    van der Kant, R., Goldstein, L. S. B. & Ossenkoppele, R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat. Rev. Neurosci. 21, 21–35 (2020).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  28. 28.

    Roberts, R. O. et al. Prevalence and outcomes of amyloid positivity among persons without dementia in a longitudinal, population-based setting. JAMA Neurol. 75, 970–979 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Palop, J. J. & Mucke, L. Amyloid-β-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat. Neurosci. 13, 812–818 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Hsiao, K. K. et al. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15, 1203–1218 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Leissring, M. A. et al. Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40, 1087–1093 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Chin, J. et al. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J. Neurosci. 24, 4692–4697 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Jankowsky, J. L. et al. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Hum. Mol. Genet. 13, 159–170 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Palop, J. J. et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55, 697–711 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Palop, J. J. & Mucke, L. Epilepsy and cognitive impairments in Alzheimer disease. Arch. Neurol. 66, 435–440 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Jankowsky, J. L. & Zheng, H. Practical considerations for choosing a mouse model of Alzheimer’s disease. Mol. Neurodegener. 12, 89 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Born, H. A. et al. Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of Alzheimer’s disease. J. Neurosci. 34, 3826–3840 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Gureviciene, I. et al. Characterization of epileptic spiking associated with brain amyloidosis in APP/PS1 mice. Front. Neurol. 10, 1151 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Jin, N., Lipponen, A., Koivisto, H., Gurevicius, K. & Tanila, H. Increased cortical beta power and spike-wave discharges in middle-aged APP/PS1 mice. Neurobiol. Aging 71, 127–141 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Busche, M. A. et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321, 1686–1689 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Reyes-Marin, K. E. & Nuñez, A. Seizure susceptibility in the APP/PS1 mouse model of Alzheimer’s disease and relationship with amyloid β plaques. Brain Res. 1677, 93–100 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Busche, M. A. et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 109, 8740–8745 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Tomiyama, T. et al. A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J. Neurosci. 30, 4845–4856 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Smith, L. M. & Strittmatter, S. M. Binding sites for amyloid-β oligomers and synaptic toxicity. Cold Spring Harb. Perspect. Med. 7, a024075 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Müller-Schiffmann, A. et al. Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity. Brain 139, 509–525 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Abramov, E. et al. Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses. Nat. Neurosci. 12, 1567–1576 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Knobloch, M., Konietzko, U., Krebs, D. C. & Nitsch, R. M. Intracellular Aβ and cognitive deficits precede β-amyloid deposition in transgenic arcAβ mice. Neurobiol. Aging 28, 1297–1306 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Ziyatdinova, S. et al. Increased epileptiform EEG activity and decreased seizure threshold in Arctic APP transgenic mouse model of Alzheimer’s disease. Curr. Alzheimer Res. 13, 817–830 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Orbán, G. et al. Different electrophysiological actions of 24- and 72-hour aggregated amyloid-beta oligomers on hippocampal field population spike in both anesthetized and awake rats. Brain Res. 1354, 227–235 (2010).

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Gavello, D. et al. Early alterations of hippocampal neuronal firing induced by Abeta42. Cereb. Cortex 28, 433–446 (2018).

    PubMed  Google Scholar 

  52. 52.

    Zott, B. et al. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science 365, 559–565 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Zott, B., Busche, M. A., Sperling, R. A. & Konnerth, A. What happens with the circuit in Alzheimer’s disease in mice and humans? Annu. Rev. Neurosci. 41, 277–297 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Cuevas, M. E. et al. Soluble Aβ1-40 peptide increases excitatory neurotransmission and induces epileptiform activity in hippocampal neurons. J. Alzheimers Dis. 23, 673–687 (2011).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Lei, M. et al. Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance. Neurobiol. Dis. 85, 111–121 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Alcantara-Gonzalez, D., Villasana-Salazar, B. & Peña-Ortega, F. Single amyloid-beta injection exacerbates 4-aminopyridine-induced seizures and changes synaptic coupling in the hippocampus. Hippocampus 29, 1150–1164 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    D’Amelio, M. et al. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat. Neurosci. 14, 69–79 (2011).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  58. 58.

    Westmark, C. J., Westmark, P. R., Beard, A. M., Hildebrandt, S. M. & Malter, J. S. Seizure susceptibility and mortality in mice that over-express amyloid precursor protein. Int. J. Clin. Exp. Pathol. 1, 157–168 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Kam, K., Duffy, Á. M., Moretto, J., LaFrancois, J. J. & Scharfman, H. E. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of β-amyloid neuropathology. Sci. Rep. 6, 20119 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Jacobsen, J. S. et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 103, 5161–5166 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Korzhova, V., Marinković, P., Goltstein, P. M., Herms, J. & Liebscher, S. Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease. Preprint at bioRxiv https://doi.org/10.1101/801902 (2019).

    Article  Google Scholar 

  62. 62.

    Harris, S. S., Wolf, F., De Strooper, B. & Busche, M. A. Tipping the scales: peptide-dependent dysregulation of neural circuit dynamics in Alzheimer’s disease. Neuron 107, 417–435 (2020).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Kamenetz, F. et al. APP processing and synaptic function. Neuron 37, 925–937 (2003).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Sima, X., Xu, J., Li, J., Zhong, W. & You, C. Expression of β-amyloid precursor protein in refractory epilepsy. Mol. Med. Rep. 9, 1242–1248 (2014).

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Busche, M. A. et al. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat. Neurosci. 22, 57–64 (2019).

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Busche, M. A. & Hyman, B. T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat. Neurosci. 23, 1183–1193 (2020).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Johnson, E. C. B. et al. Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1. Mol. Neurodegener. 15, 53 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Bakker, A. et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74, 467–474 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Sarkis, R. A., Willment, K. C., Pennell, P. B. & Marshall, G. Late-onset unexplained epilepsy: what are we missing? Epilepsy Behav. 99, 106478 (2019).

    PubMed  Article  Google Scholar 

  71. 71.

    Garg, N., Joshi, R. & Medhi, B. Cracking novel shared targets between epilepsy and Alzheimer’s disease: need of the hour. Rev. Neurosci. 29, 425–442 (2018).

    PubMed  Article  Google Scholar 

  72. 72.

    Born, H. A. Seizures in Alzheimer’s disease. Neuroscience 286, 251–263 (2015).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Kazim, S. F. et al. Early-onset network hyperexcitability in presymptomatic Alzheimer’s disease transgenic mice is suppressed by passive immunization with anti-human APP/Aβ antibody and by mGluR5 blockade. Front. Aging Neurosci. 9, 71 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Nygaard, H. B. et al. Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer’s disease mouse model. Alzheimers Res. Ther. 7, 25 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Zhang, M. Y. et al. Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice. Neurobiol. Aging 35, 2713–2725 (2014).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Ziyatdinova, S. et al. Spontaneous epileptiform discharges in a mouse model of Alzheimer’s disease are suppressed by antiepileptic drugs that block sodium channels. Epilepsy Res. 94, 75–85 (2011).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Sanchez, P. E. et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc. Natl Acad. Sci. USA 109, E2895–E2903 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Verret, L. et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in alzheimer model. Cell 149, 708–721 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Ziyatdinova, S., Viswanathan, J., Hiltunen, M., Tanila, H. & Pitkänen, A. Reduction of epileptiform activity by valproic acid in a mouse model of Alzheimer’s disease is not long-lasting after treatment discontinuation. Epilepsy Res. 112, 43–55 (2015).

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Toniolo, S., Sen, A. & Husain, M. Modulation of brain hyperexcitability: potential new therapeutic approaches in Alzheimer’s disease. Int. J. Mol. Sci. 21, 1–37 (2020).

    Article  CAS  Google Scholar 

  81. 81.

    Romoli, M. et al. Synaptic vesicle protein 2A tumoral expression predicts levetiracetam adverse events. J. Neurol. 266, 2273–2276 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Chakroborty, S., Kim, J., Schneider, C., West, A. R. & Stutzmann, G. E. Nitric oxide signaling is recruited as a compensatory mechanism for sustaining synaptic plasticity in Alzheimer’s disease mice. J. Neurosci. 35, 6893–6902 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Demuro, A., Parker, I. & Stutzmann, G. E. Calcium signaling and amyloid toxicity in Alzheimer disease. J. Biol. Chem. 285, 12463–12468 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Bezprozvanny, I. & Mattson, M. P. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci. 31, 454–463 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Leal, S. L., Landau, S. M., Bell, R. K. & Jagust, W. J. Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline. eLife 6, e22978 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Shi, J. Q. et al. Antiepileptics topiramate and levetiracetam alleviate behavioral deficits and reduce neuropathology in APPswe/PS1dE9 transgenic mice. CNS Neurosci. Ther. 19, 871–881 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. 87.

    Sendrowski, K., Sobaniec, W., Stasiak-Barmuta, A., Sobaniec, P. & Popko, J. Study of the protective effects of nootropic agents against neuronal damage induced by amyloid-beta (fragment 25-35) in cultured hippocampal neurons. Pharmacol. Rep. 67, 326–331 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Sanz-Blasco, S., Piña-Crespo, J. C., Zhang, X., McKercher, S. R. & Lipton, S. A. Levetiracetam inhibits oligomeric Aβ-induced glutamate release from human astrocytes. Neuroreport 27, 705–709 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Williams, R. S. B. & Bate, C. Valproic acid and its congener propylisopropylacetic acid reduced the amount of soluble amyloid-β oligomers released from 7PA2 cells. Neuropharmacology 128, 54–62 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Wu, H. et al. Lamotrigine reduces β-site AβPP-cleaving enzyme 1 protein levels through induction of autophagy. J. Alzheimers Dis. 46, 863–876 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91.

    Li, L. et al. Autophagy enhancer carbamazepine alleviates memory deficits and cerebral amyloid-β pathology in a mouse model of Alzheimer’s disease. Curr. Alzheimer Res. 10, 433–441 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Mark, R. J., Ashford, J. W., Goodman, Y. & Mattson, M. P. Anticonvulsants attenuate amyloid β-peptide neurotoxicity, Ca2+ deregulation and cytoskeletal pathology. Neurobiol. Aging 16, 187–198 (1995).

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    French, J. A. & Perucca, E. Time to start calling things by their own names? The case for antiseizure medicines. Epilepsy Curr. 20, 69–72 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Cirrito, J. R. et al. Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo. Neuron 58, 42–51 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Bero, A. W. et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14, 750–756 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Yamamoto, K. et al. Chronic optogenetic activation augments aβ pathology in a mouse model of Alzheimer disease. Cell Rep. 11, 859–865 (2015).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Naegele, J. R. Neuroprotective strategies to avert seizure-induced neurodegeneration in epilepsy. Epilepsia 48, 107–117 (2007).

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Sen, A. & Romoli, M. Pathological brain ageing in epilepsy and dementia: two sides of the same coin? Brain 144, 9–11 (2021).

    PubMed  Article  Google Scholar 

  99. 99.

    Mendez, M. F. & Lim, G. T. H. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging 20, 791–803 (2003).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Hauser, W. A., Morris, M. L., Heston, L. L. & Anderson, V. E. Seizures and myoclonus in patients with Alzheimer’s disease. Neurology 36, 1226–1226 (1986).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Romanelli, M. F., Morris, J. C., Ashkin, K. & Coben, L. A. Advanced Alzheimer’s disease is a risk factor for late-onset seizures. Arch. Neurol. 47, 847–850 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

    Volicer, L., Smith, S. & Volicer, B. J. Effect of seizures on progression of dementia of the Alzheimer type. Dementia 6, 258–263 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    McAreavey, M. J., Ballinger, B. R. & Fenton, G. W. Epileptic seizures in elderly patients with dementia. Epilepsia 33, 657–660 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. 104.

    Amatniek, J. C. et al. Incidence and predictors of seizures in patients with Alzheimer’s disease. Epilepsia 47, 867–872 (2006).

    Article  Google Scholar 

  105. 105.

    Cheng, C.-H. et al. Incidence and risk of seizures in Alzheimer’s disease: a nationwide population-based cohort study. Epilepsy Res. 115, 63–66 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Larner, A. J. Epileptic seizures in AD patients. Neuromolecular Med. 12, 71–77 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Subota, A. et al. The association between dementia and epilepsy: a systematic review and meta-analysis. Epilepsia 58, 962–972 (2017).

    Article  Google Scholar 

  108. 108.

    Cortini, F., Cantoni, C. & Villa, C. Epileptic seizures in autosomal dominant forms of Alzheimer’s disease. Seizure 61, 4–7 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Larner, A. J. & Doran, M. Clinical phenotypic heterogeneity of Alzheimer’s disease associated with mutations of the presenilin-1 gene. J. Neurol. 253, 139–158 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    Zarea, A. et al. Seizures in dominantly inherited Alzheimer disease. Neurology 87, 912–919 (2016).

    Article  Google Scholar 

  111. 111.

    Cabrejo, L. et al. Phenotype associated with APP duplication in five families. Brain 129, 2966–2976 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Edwards-Lee, T. et al. An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology 64, 377–379 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Lindquist, S. G. et al. Atypical early-onset Alzheimer’s disease caused by the Iranian APP mutation. J. Neurol. Sci. 268, 124–130 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Lott, I. T. et al. Down syndrome and dementia: seizures and cognitive decline. J. Alzheimers Dis. 29, 177–185 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Ryan, N. S. et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 15, 1326–1335 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Jayadev, S. et al. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 133, 1143–1154 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Liu, J. et al. Diagnostic approach of early-onset dementia with negative family history: implications from two cases of early-onset Alzheimer’s disease with de novo PSEN1 mutation. J. Alzheimers Dis. 68, 551–558 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118.

    Mucke, L. & Selkoe, D. J. Neurotoxicity of Amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb. Perspect. Med. 2, a006338 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 119.

    McKhann, G. et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–939 (1984).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Samson, W. N., van Duijn, C. M., Hop, W. C. J. & Hofman, A. Clinical features and mortality in patients with early-onset Alzheimer’s disease. Eur. Neurol. 36, 103–106 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Lozsadi, D. A. & Larner, A. J. Prevalence and causes of seizures at the time of diagnosis of probable Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 22, 121–124 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Scarmeas, N. et al. Seizures in Alzheimer disease: who, when, and how common? Arch. Neurol. 66, 992–997 (2009).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Rao, S. C., Dove, G., Cascino, G. D. & Petersen, R. C. Recurrent seizures in patients with dementia: frequency, seizure types, and treatment outcome. Epilepsy Behav. 14, 118–120 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  124. 124.

    Vossel, K. A. et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 70, 1158–1166 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Sarkis, R. A., Willment, K. C., Gale, S. A. & Dworetzky, B. A. Recurrent epileptic auras as a presenting symptom of Alzheimer’s disease. Front. Neurol. 8, 360 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Difrancesco, J. C. et al. Adult-onset epilepsy in presymptomatic Alzheimer’s disease: a retrospective study. J. Alzheimers Dis. 60, 1267–1274 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. 127.

    Sarkis, R. A., Dickerson, B. C., Cole, A. J. & Chemali, Z. N. Clinical and neurophysiologic characteristics of unprovoked seizures in patients diagnosed with dementia. J. Neuropsychiatry Clin. Neurosci. 28, 56–61 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Vossel, K. A. et al. Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease. Ann. Neurol. 80, 858–870 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Horváth, A., Szcs, A., Barcs, G. & Kamondi, A. Sleep EEG detects epileptiform activity in Alzheimer’s disease with high sensitivity. J. Alzheimers Dis. 56, 1175–1183 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  130. 130.

    Sen, A. & Husain, M. Reply: Late onset epilepsy and Alzheimer’s disease: exploring the dual pathogenic role of amyloid-β. Brain 141, e61–e61 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  131. 131.

    Breteler, M. M. et al. Medical history and the risk of Alzheimer’s disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int. J. Epidemiol. 20 (Suppl. 2), S36–S42 (1991).

    PubMed  Article  PubMed Central  Google Scholar 

  132. 132.

    Breteler, M. M. B., De Groot, R. R. M., Van Romunde, L. K. J. & Hofman, A. Risk of dementia in patients with Parkinson’s disease, epilepsy, and severe head trauma: a register-based follow-up study. Am. J. Epidemiol. 142, 1300–1305 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    French, L. R. et al. A case-control study of dementia of the Alzheimer type. Am. J. Epidemiol. 121, 414–421 (1985).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    Broe, G. A. et al. A case-control study of Alzheimer’s disease in Australia. Neurology 40, 1698–1698 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. 135.

    Shalat, S. L., Seltzer, B., Pidcock, C. & Baker, E. L. Risk factors for Alzheimer’s disease: a case-control study. Neurology 37, 1630–1633 (1987).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Hofman, A. et al. History of dementia and Parkinson’s disease in 1st-degree relatives of patients with Alzheimer’s disease. Neurology 39, 1589–1592 (1989).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137.

    Kokmen, E. et al. Clinical risk factors for Alzheimer’s disease: a population-based case-control study. Neurology 41, 1393–1397 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  138. 138.

    Tsai, Z.-R. et al. Late-onset epilepsy and subsequent increased risk of dementia. Aging 13, 3573–3587 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Johnson, E. L. et al. Dementia in late-onset epilepsy: the Atherosclerosis Risk in Communities study. Neurology 95, e3248–e3256 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Piazzini, A., Canevini, M. P., Turner, K., Chifari, R. & Canger, R. Elderly people and epilepsy: cognitive function. Epilepsia 47, 82–84 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  141. 141.

    Griffith, H. R., Martin, R. C., Bambara, J. K., Marson, D. C. & Faught, E. Older adults with epilepsy demonstrate cognitive impairments compared with patients with amnestic mild cognitive impairment. Epilepsy Behav. 8, 161–168 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  142. 142.

    Martin, R. C. et al. Cognitive functioning in community dwelling older adults with chronic partial epilepsy. Epilepsia 46, 298–303 (2005).

    PubMed  Article  Google Scholar 

  143. 143.

    Acharya, J. & Acharya, V. Epilepsy in the elderly: special considerations and challenges. Ann. Indian Acad. Neurol. 17, S18–S26 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Johnson, E. L. et al. Association between midlife risk factors and late-onset epilepsy: results from the Atherosclerosis Risk in Communities study. JAMA Neurol. 75, 1375–1382 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Johnson, E. L. et al. Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy. Neurology 92, E988–E995 (2019).

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Kawakami, O. et al. Incidence of dementia in patients with adult-onset epilepsy of unknown causes. J. Neurol. Sci. 395, 71–76 (2018).

    PubMed  Article  Google Scholar 

  147. 147.

    Witt, J. A. et al. Cognitive-behavioral screening in elderly patients with new-onset epilepsy before treatment. Acta Neurol. Scand. 130, 172–177 (2014).

    PubMed  Article  Google Scholar 

  148. 148.

    Babiloni, C. et al. Cortical sources of resting state EEG rhythms are sensitive to the progression of early stage Alzheimer’s disease. J. Alzheimers Dis. 34, 1015–1035 (2013).

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Kawakami, O. et al. Is adult onset epilepsy of unknown cause a predictor of Alzheimer disease? [abstract]. J. Neurol. Sci. 381 (Suppl.), 545 (2017).

    Article  Google Scholar 

  150. 150.

    Joutsa, J. et al. Association between childhood-onset epilepsy and amyloid burden 5 decades later. JAMA Neurol. 74, 583–590 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Joutsa, J. et al. Brain glucose metabolism and its relation to amyloid load in middle-aged adults with childhood-onset epilepsy. Epilepsy Res. 137, 69–72 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  152. 152.

    Carter, M. D., Weaver, D. F., Joudrey, H. R., Carter, A. O. & Rockwood, K. Epilepsy and antiepileptic drug use in elderly people as risk factors for dementia. J. Neurol. Sci. 252, 169–172 (2007).

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Tariot, P. N. et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch. Gen. Psychiatry 68, 853–861 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Fleisher, A. S., Truran, D., Langbaum, J. B. S., Weiner, M. W. & Schneider, L. S. Chronic divalproex sodium use and brain atrophy in Alzheimer disease. Neurology 77, 1263–1272 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Liguori, C. et al. Cognitive performances in patients affected by late-onset epilepsy with unknown etiology: a 12-month follow-up study. Epilepsy Behav. 101, 106592 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  156. 156.

    De Groot, M. et al. Levetiracetam improves verbal memory in high-grade glioma patients. Neuro Oncol. 15, 216–223 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  157. 157.

    Kern, D. M., Cepeda, M. S., Lovestone, S. & Seabrook, G. R. Aiding the discovery of new treatments for dementia by uncovering unknown benefits of existing medications. Alzheimers Dement. 5, 862–870 (2019).

    Article  Google Scholar 

  158. 158.

    Cumbo, E. & Ligori, L. D. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav. 17, 461–466 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  159. 159.

    Bakker, A., Albert, M. S., Krauss, G., Speck, C. L. & Gallagher, M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 7, 688–698 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Tambasco, N., Romoli, M. & Calabresi, P. Selective basal ganglia vulnerability to energy deprivation: experimental and clinical evidences. Prog. Neurobiol. 169, 55–75 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  161. 161.

    Hamilton, L. K. et al. Widespread deficits in adult neurogenesis precede plaque and tangle formation in the 3xTg mouse model of Alzheimer’s disease. Eur. J. Neurosci. 32, 905–920 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  162. 162.

    Griffith, H. R. et al. Cognitive functioning over 3 years in community dwelling older adults with chronic partial epilepsy. Epilepsy Res. 74, 91–96 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  163. 163.

    Miller, L. A. et al. Cognitive impairment in older adults with epilepsy: characterization and risk factor analysis. Epilepsy Behav. 56, 113–117 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  164. 164.

    Kasai, T. et al. Aβ levels in the jugular vein and high molecular weight Aβ oligomer levels in CSF can be used as biomarkers to indicate the anti-amyloid effect of IVIg for Alzheimer’s disease. PLoS ONE 12, e0174630 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. 165.

    Lewczuk, P. et al. Validation of the Erlangen Score algorithm for the prediction of the development of dementia due to Alzheimer’s disease in pre-dementia subjects. J. Alzheimers Dis. 48, 433–441 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Selkoe, D. J. Alzheimer disease and aducanumab: adjusting our approach. Nat. Rev. Neurol. 15, 365–366 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  167. 167.

    Insel, P. S. et al. Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology. Neurology 86, 1887–1896 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Harrington, K. D. et al. Amyloid β-associated cognitive decline in the absence of clinical disease progression and systemic illness. Alzheimers Dement. 8, 156–164 (2017).

    Google Scholar 

  169. 169.

    Hanseeuw, B. J. et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 76, 915–924 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  170. 170.

    Insel, P. S., Hansson, O., Mackin, R. S., Weiner, M. & Mattsson, N. Amyloid pathology in the progression to mild cognitive impairment. Neurobiol. Aging 64, 76–84 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  171. 171.

    Lim, E. W. et al. Amyloid-β and Parkinson’s disease. J. Neurol. 266, 2605–2619 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  172. 172.

    Siderowf, A. et al. CSF amyloid β 1-42 predicts cognitive decline in Parkinson disease. Neurology 75, 1055–1061 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Parnetti, L. et al. Cerebrospinal fluid biomarkers in Parkinson’s disease with dementia and dementia with Lewy bodies. Biol. Psychiatry 64, 850–855 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  174. 174.

    Blennow, K., Biscetti, L., Eusebi, P. & Parnetti, L. Cerebrospinal fluid biomarkers in Alzheimer’s and Parkinson’s diseases — from pathophysiology to clinical practice. Mov. Disord. 31, 836–847 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  175. 175.

    Edison, P. et al. Amyloid load in Parkinson’s disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J. Neurol. Neurosurg. Psychiatry 79, 1331–1338 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  176. 176.

    Calabresi, P., Picconi, B., Parnetti, L. & Di Filippo, M. A convergent model for cognitive dysfunctions in Parkinson’s disease: the critical dopamine-acetylcholine synaptic balance. Lancet Neurol. 5, 974–983 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 177.

    Nedelska, Z. et al. Association of longitudinal β-amyloid accumulation determined by positron emission tomography with clinical and cognitive decline in adults with probable Lewy body dementia. JAMA Netw. Open 2, e1916439 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Zwan, M. D. et al. Subjective memory complaints in APOE ε4 carriers are associated with high amyloid-β burden. J. Alzheimers Dis. 49, 1115–1122 (2015).

    Article  CAS  Google Scholar 

  179. 179.

    Perrotin, A., Mormino, E. P., Madison, C. M., Hayenga, A. O. & Jagusr, W. J. Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals. Arch. Neurol. 69, 223–229 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Rodrigue, K. M. et al. β-Amyloid burden in healthy aging: regional distribution and cognitive consequences. Neurology 78, 387–395 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Svenningsson, A. L. et al. β-Amyloid pathology and hippocampal atrophy are independently associated with memory function in cognitively healthy elderly. Sci. Rep. 9, 11180 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  182. 182.

    van Oijen, M., Hofman, A., Soares, H. D., Koudstaal, P. J. & Breteler, M. M. Plasma Aβ1-40 and Aβ1-42 and the risk of dementia: a prospective case-cohort study. Lancet Neurol. 5, 655–660 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  183. 183.

    Keskin, A. D. et al. BACE inhibition-dependent repair of Alzheimer’s pathophysiology. Proc. Natl Acad. Sci. USA 114, 8631–8636 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Das, M. et al. Neuronal levels and sequence of tau modulate the power of brain rhythms. Neurobiol. Dis. 117, 181–188 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  185. 185.

    Gourmaud, S. et al. Alzheimer-like amyloid and tau alterations associated with cognitive deficit in temporal lobe epilepsy. Brain 143, 191–209 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  186. 186.

    Tai, X. Y. et al. Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections. Brain 139, 2441–2455 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  187. 187.

    Kaestner, E. et al. Atrophy and cognitive profiles in older adults with temporal lobe epilepsy are similar to mild cognitive impairment. Brain 144, 236–250 (2021).

    PubMed  Article  PubMed Central  Google Scholar 

  188. 188.

    Roberson, E. D. et al. Amyloid-/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J. Neurosci. 31, 700–711 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Angulo, S. L. et al. Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit. Neurobiol. Dis. 108, 261–276 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  190. 190.

    Vossel, K. A. et al. Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β. J. Cell Biol. 209, 419–433 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Chabrier, M. A., Cheng, D., Castello, N. A., Green, K. N. & LaFerla, F. M. Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease. Neurobiol. Dis. 64, 107–117 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W. & Strittmatter, S. M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457, 1128–1132 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  193. 193.

    Um, J. W. et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron 79, 887–902 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    Um, J. W. et al. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15, 1227–1235 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. 195.

    Romoli, M., Perucca, E. & Sen, A. Pyridoxine supplementation for levetiracetam-related neuropsychiatric adverse events: a systematic review. Epilepsy Behav. 103, 106861 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  196. 196.

    Foster, E. et al. Antiepileptic drugs are not independently associated with cognitive dysfunction. Neurology 94, e1051–e1061 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  197. 197.

    Romoli, M. et al. Antiepileptic drugs in migraine and epilepsy: who is at increased risk of adverse events? Cephalalgia 38, 274–282 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  198. 198.

    Belcastro, V. et al. Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Eur. J. Neurol. 14, 1176–1178 (2007).

    CAS  PubMed  Article  Google Scholar 

  199. 199.

    Liu, J., Wang, L. N., Wu, L. Y. & Wang, Y. P. Treatment of epilepsy for people with Alzheimer’s disease. Cochrane Database Syst. Rev. 12, CD011922 (2018).

    PubMed  Google Scholar 

  200. 200.

    Lezaic, N. et al. The medical treatment of epilepsy in the elderly: a systematic review and meta-analysis. Epilepsia 60, 1325–1340 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  201. 201.

    Romoli, M. et al. Valproic acid and epilepsy: from molecular mechanisms to clinical evidences. Curr. Neuropharmacol. 17, 926–946 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    Perucca, E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 16, 695–714 (2002).

    CAS  Article  Google Scholar 

  203. 203.

    Read, C. L. et al. Cognitive effects of anticonvulsant monotherapy in elderly patients: a placebo-controlled study. Seizure 7, 159–162 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  204. 204.

    Romoli, M. et al. Liverpool Adverse Events Profile: Italian validation and predictive value for dropout from antiepileptic treatment in people with epilepsy. Epilepsy Behav. 81, 111–114 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Panelli, R. J. et al. The Liverpool Adverse Events Profile: relation to AED use and mood. Epilepsia 48, 456–463 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

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Acknowledgements

A.S. is supported by the NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.

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M.R., A.S. and C.C. researched data for the article and drafted the paper. All authors contributed substantially to discussion of the article content and to the writing, review and editing of the manuscript before submission.

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Correspondence to Cinzia Costa.

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Competing interests

P.C. receives research support from Preston and Zambon to perform preclinical investigation on drugs that are not discussed in the text. A.S. has received research funding, speaker fees and/or honoraria from Bial Limited, Eisai Europe, GW Pharma, Livanova and Eisai. He is lead investigator on the Investigation of Levetiracetam in Alzheimer’s Disease Study (ILiAD), which is currently active but no data are yet available. M.R., C.C. and L.P. declare no competing interests.

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Review criteria

We selected references by searching PubMed, EMBASE and Cochrane CENTRAL for articles published in English before 1 February 2021, the main search string being “Alzheimer disease” or “cognitive decline”, and “late onset epilepsy”. Assorted combinations of the following terms were used to retrieve all papers: “epilepsy”, “late onset epilepsy”, “seizures”, “epileptiform activity”, “network hyperexcitability”, “epileptogenesis”, “epileptogenic”, “antiepileptic drugs”, “antiseizure medications”, “anticonvulsants”, “dementia”, “amyloid”, “amyloid precursor protein” or “APP”, “presenilin” or “PSEN”. We reviewed reference lists within original research and review articles for additional references through backward citation search. We finalized the reference list on the basis of originality and relevance to the scope of this Review. We focused on scientific literature in the English language published from 1990 onwards, but also included older publications of high value, merit or originality.

Glossary

Aβ-facilitated tauopathy

The hypothesis that Alzheimer disease (AD) is the trigger for the accumulation and spread of tau pathology, leading to overt neurodegeneration.

Late-onset epilepsy

Epilepsy that develops in late adult life. Cerebrovascular events, such as ischaemic or haemorrhagic stroke, are the main cause, but late-onset epilepsy might also arise from metabolic, infectious or structural (for example, neoplastic) disorders or dementia.

Aβ plaques

Aggregates of amyloid-β (Aβ) protein, which accumulate to form neuritic plaques during the course of Alzheimer disease (AD).

Late-onset epilepsy of unknown aetiology

(LOEU). Epilepsy that develops in late adult life in the absence of vascular, metabolic, infectious, structural or neurocognitive causes. Up to 20% of adults who develop epilepsy in late adulthood have an unknown cause; amyloid-β pathology might contribute to epilepsy and cognitive decline in these patients.

Epileptic prodromal AD

Retrospective definition denoting patients with an Alzheimer disease (AD) diagnosis preceded by seizures in adulthood.

Quantitative EEG analysis

Analysis of cortical connectivity and neuronal synchronization of rhythmic oscillations at various frequencies. Abnormalities in cortical connectivity can be used to detect patients with mild cognitive impairment and predict evolution to Alzheimer disease (AD).

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Romoli, M., Sen, A., Parnetti, L. et al. Amyloid-β: a potential link between epilepsy and cognitive decline. Nat Rev Neurol 17, 469–485 (2021). https://doi.org/10.1038/s41582-021-00505-9

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