{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T15:35:35Z","timestamp":1782228935924,"version":"3.54.5"},"reference-count":177,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Dement."],"abstract":"<jats:p>A long-standing theory for Alzheimer\u2019s disease (AD) has been that deterioration of synapses and depressed neuronal activity is a major contributing factor. We review the increasing evidence, in humans and in mouse models, that show that there is often neuronal hyperactivity at early stages rather than decreased activity. We discuss studies in mouse models showing that hyperexcitability can occur long before plaque deposition and memory impairment. In mouse models, a generator of the hyperactivity appears to be the dentate gyrus. We present evidence, based on mouse models, that inhibition of muscarinic cholinergic receptors or medial septal cholinergic neurons can prevent hyperactivity. Therefore, we hypothesize the novel idea that cholinergic neurons are overly active early in the disease, not depressed. In particular we suggest the medial septal cholinergic neurons are overly active and contribute to hyperexcitability. We further hypothesize that the high activity of cholinergic neurons at early ages ultimately leads to their decline in function later in the disease. We review the effects of a prenatal diet that increases choline, the precursor to acetylcholine and modulator of many other functions. In mouse models of AD, maternal choline supplementation (MCS) reduces medial septal cholinergic pathology, amyloid accumulation and hyperexcitability, especially in the dentate gyrus, and improves cognition.<\/jats:p>","DOI":"10.3389\/frdem.2025.1513144","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T05:28:00Z","timestamp":1750138080000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Evidence that cholinergic mechanisms contribute to hyperexcitability at early stages in Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"4","author":[{"given":"Helen E.","family":"Scharfman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korey","family":"Kam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ine M.","family":"Duffy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"LaFrancois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Leary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elissavet","family":"Chartampila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Ginsberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos Panagiotis","family":"Lisgaras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3389\/fnagi.2015.00030","article-title":"Regional and sub-regional differences in hippocampal GABAergic neuronal vulnerability in the TgCRND8 mouse model of Alzheimer's disease","volume":"7","author":"Albuquerque","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"105274","DOI":"10.1016\/j.nbd.2021.105274","article-title":"Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer's disease neuropathology and atypical effects of the cholinergic antagonist atropine","volume":"152","author":"Alcantara-Gonzalez","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/cne.23663","article-title":"Expression profile analysis of vulnerable CA1 pyramidal neurons in young-middle-aged Ts65Dn mice","volume":"523","author":"Alldred","year":"","journal-title":"J. Comp. Neurol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2983","DOI":"10.1007\/s00429-014-0839-0","article-title":"Expression profile analysis of hippocampal CA1 pyramidal neurons in aged Ts65Dn mice, a model of Down syndrome (DS) and Alzheimer's disease (AD)","volume":"220","author":"Alldred","year":"","journal-title":"Brain Struct. Funct."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"3715","DOI":"10.1007\/s00018-018-2886-9","article-title":"Memory corticalization triggered by REM sleep: mechanisms of cellular and systems consolidation","volume":"75","author":"Almeida-Filho","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.1016\/S0047-6374(01)00310-4","article-title":"Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches?","volume":"122","author":"Amenta","year":"2001","journal-title":"Mech. Ageing Dev."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/j.neuron.2012.03.023","article-title":"Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment","volume":"74","author":"Bakker","year":"2012","journal-title":"Neuron"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1002\/cne.902250304","article-title":"The distribution of acetylcholinesterase in the hippocampal formation of the monkey","volume":"225","author":"Bakst","year":"1984","journal-title":"J. Comp. Neurol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"2169","DOI":"10.1093\/brain\/awae126","article-title":"Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease and 5XFAD mice","volume":"147","author":"Barbour","year":"2024","journal-title":"Brain"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e0297289","DOI":"10.1371\/journal.pone.0297289","article-title":"Perinatal choline supplementation prevents learning and memory deficits and reduces brain amyloid A\u03b242 deposition in APPNL-G-F Alzheimer's disease model mice","volume":"19","author":"Bellio","year":"2024","journal-title":"PLoS One"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1038\/nn.2801","article-title":"Neuronal activity regulates the regional vulnerability to amyloid-\u03b2 deposition","volume":"14","author":"Bero","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e0119910","DOI":"10.1371\/journal.pone.0119910","article-title":"Early onset of hypersynchronous network activity and expression of a marker of chronic seizures in the Tg2576 mouse model of Alzheimer's disease","volume":"10","author":"Bezzina","year":"2015","journal-title":"PLoS One"},{"key":"ref13","first-page":"229","article-title":"Characteristics of familial Alzheimer's disease in nine kindreds of Volga german ancestry","volume":"317","author":"Bird","year":"1989","journal-title":"Prog. Clin. Biol. Res."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"82","DOI":"10.2174\/187152412800792706","article-title":"Choline nutrition programs brain development via DNA and histone methylation","volume":"12","author":"Blusztajn","year":"2012","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"815","DOI":"10.3390\/nu9080815","article-title":"Neuroprotective actions of dietary choline","volume":"9","author":"Blusztajn","year":"2017","journal-title":"Nutrients"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"107990","DOI":"10.1016\/j.neuropharm.2020.107990","article-title":"Rescue of ethanol-induced FASD-like phenotypes via prenatal co-administration of choline","volume":"168","author":"Bottom","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1404022","DOI":"10.3389\/fnmol.2024.1404022","article-title":"Microglia and infiltrating macrophages in ictogenesis and epileptogenesis","volume":"17","author":"Broer","year":"2024","journal-title":"Front. Mol. Neurosci."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.nurt.2009.01.019","article-title":"Alteration of epileptogenesis genes","volume":"6","author":"Brooks-Kayal","year":"2009","journal-title":"Neurotherapeutics"},{"key":"ref9001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1523\/ENEURO.0426-17.2018","article-title":"Circadian and brain state modulation of network Hyperexcitability in Alzheimer\u2019s disease","volume":"5","author":"Brown","year":"2018","journal-title":"eNeuro."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1002\/hipo.450020403","article-title":"Mossy cell axonal projections to the dentate gyrus molecular layer in the rat hippocampal slice","volume":"2","author":"Buckmaster","year":"1992","journal-title":"Hippocampus"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1002\/(sici)1096-9861(19960304)366:2<270::aid-cne7>3.0.co;2-2","article-title":"Axon arbors and synaptic connections of hippocampal mossy cells in the rat in vivo","volume":"366","author":"Buckmaster","year":"1996","journal-title":"J. Comp. Neurol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1002\/1531-8249(200007)48:1<126::AID-ANA21>3.0.CO;2-N","article-title":"FTDP-17: phenotypical heterogeneity within P301S","volume":"48","author":"Bugiani","year":"2000","journal-title":"Ann. Neurol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.brainresbull.2016.04.019","article-title":"Physiological and pathological roles of the \u03b3-secretase complex","volume":"126","author":"Carroll","year":"2016","journal-title":"Brain Res. Bull."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1002\/cne.902600205","article-title":"Somatostatin immunoreactive neurons in the human hippocampus and cortex shown by immunogold\/silver intensification on vibratome sections: coexistence with neuropeptide Y neurons, and effects in Alzheimer-type dementia","volume":"260","author":"Chan-Palay","year":"1987","journal-title":"J. Comp. Neurol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1002\/cne.902480307","article-title":"Distribution of altered hippocampal neurons and axons immunoreactive with antisera against neuropeptide Y in Alzheimer's-type dementia","volume":"248","author":"Chan-Palay","year":"1986","journal-title":"J. Comp. Neurol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e89884","DOI":"10.7554\/eLife.89889.4","article-title":"Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer's disease","volume":"12","author":"Chartampila","year":"2024","journal-title":"eLife"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.neuron.2005.10.028","article-title":"Synaptic activity regulates interstitial fluid amyloid-\u03b2 levels in vivo","volume":"48","author":"Cirrito","year":"2005","journal-title":"Neuron"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1523\/JNEUROSCI.2699-07.2008","article-title":"P75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate","volume":"28","author":"Coulson","year":"2008","journal-title":"J. Neurosci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1177\/1073858408331376","article-title":"The role of the p75 neurotrophin receptor in cholinergic dysfunction in Alzheimer's disease","volume":"15","author":"Coulson","year":"2009","journal-title":"Neuroscientist"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"ENEURO.0192-23.2023","DOI":"10.1523\/ENEURO.0192-23.2023","article-title":"Dentate gyrus granule cells show stability of BDNF protein expression in mossy fiber axons with age, and resistance to Alzheimer\u2019s disease neuropathology in a mouse model","volume":"11","author":"Criscuolo","year":"2024","journal-title":"eNeuro"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1111\/jnc.13167","article-title":"Differential regulation of the high-affinity choline transporter by wild-type and swedish mutant amyloid precursor protein","volume":"134","author":"Cuddy","year":"2015","journal-title":"J. Neurochem."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"102713","DOI":"10.1016\/j.arr.2025.102713","article-title":"Mitochondrial dysfunction in Alzheimer's disease","volume":"107","author":"D'Alessandro","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1001\/jama.281.15.1433","article-title":"Challenging the cholinergic hypothesis in Alzheimer disease","volume":"281","author":"Davies","year":"1999","journal-title":"JAMA"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1016\/s0140-6736(76)91936-x","article-title":"Selective loss of central cholinergic neurons in Alzheimer's disease","volume":"2","author":"Davies","year":"1976","journal-title":"Lancet"},{"key":"ref34","first-page":"263","article-title":"Segmental trisomy of murine chromosome 16: a new model system for studying down syndrome","volume":"360","author":"Davisson","year":"1990","journal-title":"Prog. Clin. Biol. Res."},{"key":"ref9002","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1002\/ana.10069","article-title":"Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment","volume":"51","author":"DeKosky","year":"2002","journal-title":"Ann Neurol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1002\/(SICI)1098-1063(1999)9:3<314::AID-HIPO10>3.0.CO;2-7","article-title":"Cholinergic innervation of mossy cells in the rat fascia dentata","volume":"9","author":"Deller","year":"1999","journal-title":"Hippocampus"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.3390\/nu12061731","article-title":"Choline, neurological development and brain function: a systematic review focusing on the first 1000 days","volume":"12","author":"Derbyshire","year":"2020","journal-title":"Nutrients"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.neurobiolaging.2014.07.001","article-title":"Entorhinal cortical defects in Tg2576 mice are present as early as 2-4 months of age","volume":"36","author":"Duffy","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.expneurol.2011.03.008","article-title":"A selective role for ARMS\/kidins220 scaffold protein in spatial memory and trophic support of entorhinal and frontal cortical neurons","volume":"229","author":"Duffy","year":"2011","journal-title":"Exp. Neurol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.yebeh.2011.04.056","article-title":"Sudden unexpected death in epilepsy","volume":"21","author":"Duncan","year":"2011","journal-title":"Epilepsy Behav."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1212\/WNL.52.3.566","article-title":"A presenilin 1 mutation (ser169pro) associated with early-onset AD and myoclonic seizures","volume":"52","author":"Ezquerra","year":"1999","journal-title":"Neurology"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"909669","DOI":"10.3389\/fnins.2022.909669","article-title":"Rodent modeling of Alzheimer's disease in Down syndrome: in vivo and ex vivo approaches","volume":"16","author":"Farrell","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref42","author":"Festing","year":"1998"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/336170a0","article-title":"GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus","volume":"336","author":"Freund","year":"1988","journal-title":"Nature"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1002\/cne.902390210","article-title":"Cholinergic innervation of the rat hippocampus as revealed by choline acetyltransferase immunocytochemistry: a combined light and electron microscopic study","volume":"239","author":"Frotscher","year":"1985","journal-title":"J. Comp. Neurol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1034\/j.1601-183X.2003.00024.x","article-title":"Understanding mental retardation in Down's syndrome using trisomy 16 mouse models","volume":"2","author":"Galdzicki","year":"2003","journal-title":"Genes Brain Behav."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"106332","DOI":"10.1016\/j.nbd.2023.106332","article-title":"Maternal choline supplementation protects against age-associated cholinergic and GABAergic basal forebrain neuron degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease","volume":"188","author":"Gautier","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.neurobiolaging.2024.09.002","article-title":"Maternal choline supplementation rescues early endosome pathology in basal forebrain cholinergic neurons in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease","volume":"144","author":"Gautier","year":"2024","journal-title":"Neurobiol. Aging"},{"key":"ref9004","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1523\/JNEUROSCI.0876-20.2020","article-title":"Implications of oligomeric amyloid-beta (oA\u03b242) signaling through \u03b17\u03b22-nicotinic acetylcholine receptors (nAChRs) on basal forebrain cholinergic neuronal intrinsic excitability and cognitive decline","volume":"41","author":"George","year":"2021","journal-title":"J Neurosci."},{"key":"ref48","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1159\/000114073","article-title":"Myoclonus and photic-induced seizures in Alzheimer's disease","volume":"5","author":"Gimenez-Roldan","year":"1971","journal-title":"Eur. Neurol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1002\/cne.902730405","article-title":"Acetylcholinesterase fiber staining in the human hippocampus and parahippocampal gyrus","volume":"273","author":"Green","year":"1988","journal-title":"J. Comp. Neurol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"745","DOI":"10.3390\/biomedicines10040745","article-title":"Cholinergic regulation of hippocampal theta rhythm","volume":"10","author":"Gu","year":"2022","journal-title":"Biomedicines"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/978-3-030-42667-5_8","article-title":"Early diagnosis and targeted treatment strategy for improved therapeutic outcomes in Alzheimer's disease","volume":"1260","author":"Guest","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/S0006-8993(98)00792-6","article-title":"Selective in vivo fluorescence labelling of cholinergic neurons containing p75(NTR) in the rat basal forebrain","volume":"808","author":"Hartig","year":"1998","journal-title":"Brain Res."},{"key":"ref53","first-page":"313","article-title":"Epidemiology of epilepsy","volume":"19","author":"Hauser","year":"1978","journal-title":"Adv. Neurol."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1528-1157.1975.tb04721.x","article-title":"The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967","volume":"16","author":"Hauser","year":"1975","journal-title":"Epilepsia"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1212\/WNL.36.9.1226","article-title":"Seizures and myoclonus in patients with Alzheimer's disease","volume":"36","author":"Hauser","year":"1986","journal-title":"Neurology"},{"key":"ref56","first-page":"353","article-title":"Alzheimer's disease in down syndrome","volume":"1","author":"Head","year":"2012","journal-title":"Eur. J. Neurodegener. Dis."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1177\/1073858419882619","article-title":"Amyloid, APP, and electrical activity of the brain","volume":"26","author":"Hefter","year":"2020","journal-title":"Neuroscientist"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1242\/dmm.029728","article-title":"Rodent models in Down syndrome research: impact and future opportunities","volume":"10","author":"Herault","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0301-0082(96)00021-4","article-title":"Activation of c-fos in the brain","volume":"50","author":"Herrera","year":"1996","journal-title":"Prog. Neurobiol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.brainres.2010.01.011","article-title":"Muscarinic receptor activation modulates the excitability of hilar mossy cells through the induction of an afterdepolarization","volume":"1318","author":"Hofmann","year":"2010","journal-title":"Brain Res."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/s41419-024-06815-2","article-title":"Tau(P301L) disengages from the proteosome core complex and neurogranin coincident with enhanced neuronal network excitability","volume":"15","author":"Hole","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1126\/science.274.5284.99","article-title":"Correlative memory deficits, A\u03b2 elevation, and amyloid plaques in transgenic mice","volume":"274","author":"Hsiao","year":"1996","journal-title":"Science"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"e2204306119","DOI":"10.1073\/pnas.2204306119","article-title":"Early death in a mouse model of Alzheimer's disease exacerbated by microglial loss of TAM receptor signaling","volume":"119","author":"Huang","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.brainres.2012.05.048","article-title":"Emergence of a seizure phenotype in aged apolipoprotein \u03b54 targeted replacement mice","volume":"1467","author":"Hunter","year":"2012","journal-title":"Brain Res."},{"key":"ref65","article-title":"Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B(6), folate, vitamin B(12), pantothenic acid, biotin, and choline","year":"1998"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1097\/00005072-199709000-00002","article-title":"APPSw transgenic mice develop age-related A\u03b2 deposits and neuropil abnormalities, but no neuronal loss in CA1","volume":"56","author":"Irizarry","year":"1997","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"5161","DOI":"10.1073\/pnas.0600948103","article-title":"Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease","volume":"103","author":"Jacobsen","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"102635","DOI":"10.1016\/j.arr.2024.102635","article-title":"Beyond the blur: scopolamine's utility and limits in modeling cognitive disorders across sexes - narrative review","volume":"104","author":"Jagielska","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref9003","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1152\/jn.2001.86.3.1312","article-title":"Cellular mechanisms for amyloid beta-protein activation of rat cholinergic basal forebrain neurons","volume":"86","author":"Jhamandas","year":"2001","journal-title":"J Neurophysiol."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s13024-020-00393-5","article-title":"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","volume":"15","author":"Johnson","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1007\/s00401-023-02616-7","article-title":"Inflammation and the pathological progression of Alzheimer's disease are associated with low circulating choline levels","volume":"146","author":"Judd","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"20119","DOI":"10.1038\/srep20119","article-title":"Interictal spikes during sleep are an early defect in the Tg2576 mouse model of \u03b2-amyloid neuropathology","volume":"6","author":"Kam","year":"2016","journal-title":"Sci. Rep."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/S0896-6273(03)00124-7","article-title":"APP processing and synaptic function","volume":"37","author":"Kamenetz","year":"2003","journal-title":"Neuron"},{"key":"ref9005","first-page":"427","article-title":"Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer\u2019s disease","volume":"29","author":"Kar","year":"2004","journal-title":"J Psychiatry Neurosci."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"84","DOI":"10.2174\/1567205012666150921100515","article-title":"Effects of maternal choline supplementation on the septohippocampal cholinergic system in the Ts65Dn mouse model of Down syndrome","volume":"13","author":"Kelley","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1093\/brain\/116.2.309","article-title":"Familial Alzheimer's disease. A pedigree with a mis-sense mutation in the amyloid precursor protein gene (amyloid precursor protein 717 valine-->glycine)","volume":"116","author":"Kennedy","year":"1993","journal-title":"Brain"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1002\/ana.21896","article-title":"Hippocampal interictal spikes disrupt cognition in rats","volume":"67","author":"Kleen","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1212\/WNL.0b013e318297ee50","article-title":"Hippocampal interictal epileptiform activity disrupts cognition in humans","volume":"81","author":"Kleen","year":"2013","journal-title":"Neurology"},{"key":"ref77","doi-asserted-by":"crossref","DOI":"10.1093\/med\/9780199746545.003.0072","article-title":"Cognitive and behavioral co-morbidities of epilepsy","volume-title":"Jasper's basic mechanisms of the epilepsies","author":"Kleen","year":"2012"},{"key":"ref78","doi-asserted-by":"publisher","first-page":"734001","DOI":"10.3389\/fnins.2021.734001","article-title":"Astrocytic and neuronal apolipoprotein e isoforms differentially affect neuronal excitability","volume":"15","author":"Konings","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"327","DOI":"10.3389\/fnmol.2018.00327","article-title":"Soluble A\u03b242 acts as allosteric activator of the core cholinergic enzyme choline acetyltransferase","volume":"11","author":"Kumar","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"105999","DOI":"10.1016\/j.nbd.2023.105999","article-title":"Diverse nature of interictal oscillations: EEG-based biomarkers in epilepsy","volume":"177","author":"Lai","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/S0928-4257(99)80007-2","article-title":"Medical management of organophosphate-induced seizures","volume":"92","author":"Lallement","year":"1998","journal-title":"J. Physiol. Paris"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/nm.4330","article-title":"Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease","volume":"23","author":"Lam","year":"2017","journal-title":"Nat. Med."},{"key":"ref83","doi-asserted-by":"publisher","first-page":"e2259","DOI":"10.1212\/WNL.0000000000010612","article-title":"Association of epileptiform abnormalities and seizures in Alzheimer disease","volume":"95","author":"Lam","year":"2020","journal-title":"Neurology"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"656521","DOI":"10.3389\/fcell.2021.656521","article-title":"Apoe4 promotes tonic-clonic seizures, an effect modified by familial Alzheimer's disease mutations","volume":"9","author":"Lamoureux","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"687","DOI":"10.3390\/neurosci3040050","article-title":"Current opinion on the use of c-Fos in neuroscience","volume":"3","author":"Lara","year":"2022","journal-title":"NeuroSci"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0079-6123(07)63004-0","article-title":"Extrinsic afferent systems to the dentate gyrus","volume":"163","author":"Leranth","year":"2007","journal-title":"Prog. Brain Res."},{"key":"ref87","doi-asserted-by":"publisher","first-page":"830","DOI":"10.2174\/1570159X17666181127124803","article-title":"Evolving mechanistic concepts of epileptiform synchronization and their relevance in curing focal epileptic disorders","volume":"17","author":"Levesque","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref88","doi-asserted-by":"publisher","first-page":"106065","DOI":"10.1016\/j.nbd.2023.106065","article-title":"Evolution of interictal activity in models of mesial temporal lobe epilepsy","volume":"180","author":"Levesque","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref89","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/jnr.20354","article-title":"Characterization of the neuronal marker NeuN as a multiply phosphorylated antigen with discrete subcellular localization","volume":"79","author":"Lind","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"106294","DOI":"10.1016\/j.nbd.2023.106294","article-title":"Interictal spikes in Alzheimer's disease: preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum","volume":"187","author":"Lisgaras","year":"","journal-title":"Neurobiol. Dis."},{"key":"ref91","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1111\/epi.17462","article-title":"High-frequency oscillations (250-500 Hz) in animal models of Alzheimer's disease and two animal models of epilepsy","volume":"64","author":"Lisgaras","year":"","journal-title":"Epilepsia"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"e136","DOI":"10.1111\/epi.13847","article-title":"Accelerated kindling epileptogenesis in Tg4510 tau transgenic mice, but not in tau knockout mice","volume":"58","author":"Liu","year":"2017","journal-title":"Epilepsia"},{"key":"ref93","doi-asserted-by":"publisher","first-page":"114062","DOI":"10.1016\/j.ejmech.2021.114062","article-title":"Dyrk1a inhibitors for disease therapy: current status and perspectives","volume":"229","author":"Liu","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref94","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.nbd.2012.03.011","article-title":"Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy","volume":"47","author":"Loreth","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref95","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s00429-010-0244-2","article-title":"Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models","volume":"214","author":"Luebke","year":"2010","journal-title":"Brain Struct. Funct."},{"key":"ref96","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/j.1600-0404.1995.tb05835.x","article-title":"Early onset Alzheimer's disease in a south american pedigree from Argentina","volume":"91","author":"Mangone","year":"1995","journal-title":"Acta Neurol. Scand."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/BF00165140","article-title":"Differential increases in brain levels of neuropeptide Y and vasoactive intestinal polypeptide after kainic acid-induced seizures in the rat","volume":"339","author":"Marksteiner","year":"1989","journal-title":"Naunyn Schmiedeberg's Arch. Pharmacol."},{"key":"ref98","doi-asserted-by":"publisher","first-page":"703876","DOI":"10.3389\/fnagi.2021.703876","article-title":"Basal forebrain cholinergic neurons: linking down syndrome and Alzheimer's disease","volume":"13","author":"Martinez","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref99","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.neuron.2018.02.029","article-title":"Nav1.1-overexpressing interneuron transplants restore brain rhythms and cognition in a mouse model of Alzheimer's disease","volume":"98","author":"Martinez-Losa","year":"2018","journal-title":"Neuron"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1152\/physrev.1997.77.4.1081","article-title":"Cellular actions of \u03b2-amyloid precursor protein and its soluble and fibrillogenic derivatives","volume":"77","author":"Mattson","year":"1997","journal-title":"Physiol. Rev."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.molbrainres.2004.05.014","article-title":"\u0394Fosb: a molecular switch for long-term adaptation in the brain","volume":"132","author":"McClung","year":"2004","journal-title":"Mol. Brain Res."},{"key":"ref102","doi-asserted-by":"publisher","first-page":"12821","DOI":"10.1074\/jbc.M115.708297","article-title":"Presenilin 1 and presenilin 2 target \u03b3-secretase complexes to distinct cellular compartments","volume":"291","author":"Meckler","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref103","doi-asserted-by":"publisher","first-page":"e0170450","DOI":"10.1371\/journal.pone.0170450","article-title":"Perinatal choline supplementation reduces amyloidosis and increases choline acetyltransferase expression in the hippocampus of the APPSwePS1de9 Alzheimer's disease model mice","volume":"12","author":"Mellott","year":"2017","journal-title":"PLoS One"},{"key":"ref104","doi-asserted-by":"publisher","first-page":"791","DOI":"10.2165\/00002512-200320110-00001","article-title":"Seizures in elderly patients with dementia: epidemiology and management","volume":"20","author":"Mendez","year":"2003","journal-title":"Drugs Aging"},{"key":"ref105","doi-asserted-by":"publisher","first-page":"3453","DOI":"10.1523\/JNEUROSCI.5215-08.2009","article-title":"Amyloid \u03b2-induced neuronal hyperexcitability triggers progressive epilepsy","volume":"29","author":"Minkeviciene","year":"2009","journal-title":"J. Neurosci."},{"key":"ref106","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.neures.2022.12.019","article-title":"Fast network oscillations during non-REM sleep support memory consolidation","volume":"189","author":"Mizuseki","year":"2023","journal-title":"Neurosci. Res."},{"key":"ref107","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1037\/a0019590","article-title":"Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome","volume":"124","author":"Moon","year":"2010","journal-title":"Behav. Neurosci."},{"key":"ref108","doi-asserted-by":"publisher","first-page":"4050","DOI":"10.1523\/JNEUROSCI.20-11-04050.2000","article-title":"High-level neuronal expression of A\u03b2 1-42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation","volume":"20","author":"Mucke","year":"2000","journal-title":"J. Neurosci."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/S0891-0618(03)00068-1","article-title":"Human cholinergic basal forebrain: Chemoanatomy and neurologic dysfunction","volume":"26","author":"Mufson","year":"2003","journal-title":"J. Chem. Neuroanat."},{"key":"ref110","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.bbr.2016.05.030","article-title":"Molecular and cellular pathophysiology of preclinical Alzheimer's disease","volume":"311","author":"Mufson","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref111","doi-asserted-by":"publisher","first-page":"383796","DOI":"10.1155\/2012\/383796","article-title":"The Alzheimer's amyloid-degrading peptidase, neprilysin: can we control it?","volume":"2012","author":"Nalivaeva","year":"2012","journal-title":"Int. J. Alzheimers Dis."},{"key":"ref112","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1126\/science.abb8739","article-title":"Glymphatic failure as a final common pathway to dementia","volume":"370","author":"Nedergaard","year":"2020","journal-title":"Science"},{"key":"ref113","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1021\/cn500105p","article-title":"New mouse model of Alzheimer's","volume":"5","author":"Nilsson","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref114","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1038\/s41580-024-00757-5","article-title":"Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases","volume":"25","author":"Nixon","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref115","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1097\/00000433-199609000-00013","article-title":"Cerebral amyloid angiopathy. A review","volume":"17","author":"Opeskin","year":"1996","journal-title":"Am J Forensic Med Pathol"},{"key":"ref116","doi-asserted-by":"publisher","first-page":"825157","DOI":"10.1155\/2015\/825157","article-title":"Limited effects of an eif2aS51a allele on neurological impairments in the 5xFAD mouse model of Alzheimer's disease","volume":"2015","author":"Paesler","year":"2015","journal-title":"Neural Plast."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.neuron.2007.07.025","article-title":"Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease","volume":"55","author":"Palop","year":"2007","journal-title":"Neuron"},{"key":"ref118","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1001\/archneurol.2009.15","article-title":"Epilepsy and cognitive impairments in Alzheimer disease","volume":"66","author":"Palop","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref119","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/978-1-60761-744-0_17","article-title":"Quantifying biomarkers of cognitive dysfunction and neuronal network hyperexcitability in mouse models of Alzheimer's disease: depletion of calcium-dependent proteins and inhibitory hippocampal remodeling","volume":"670","author":"Palop","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref120","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.bbr.2014.07.046","article-title":"Interactions between A\u03b2 oligomers and presynaptic cholinergic signaling: age-dependent effects on attentional capacities","volume":"274","author":"Parikh","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref121","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1152\/physiol.00025.2008","article-title":"Engineered GPCRs as tools to modulate signal transduction","volume":"23","author":"Pei","year":"2008","journal-title":"Physiology (Bethesda)"},{"key":"ref122","doi-asserted-by":"publisher","first-page":"166793","DOI":"10.1016\/j.bbadis.2023.166793","article-title":"Apolipoprotein E \u03b54 triggers neurotoxicity via cholesterol accumulation, acetylcholine dyshomeostasis, and PKC\u03b5 mislocalization in cholinergic neuronal cells","volume":"1869","author":"Piccarducci","year":"2023","journal-title":"Biochim. Biophys. Acta Mol. basis Dis."},{"key":"ref123","doi-asserted-by":"publisher","first-page":"723046","DOI":"10.3389\/fnagi.2021.723046","article-title":"Maternal choline supplementation as a potential therapy for Down syndrome: assessment of effects throughout the lifespan","volume":"13","author":"Powers","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref124","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1111\/j.1749-6632.1982.tb26850.x","article-title":"Alzheimer's disease and Down's syndrome","volume":"396","author":"Price","year":"1982","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref125","first-page":"5","article-title":"The paroxysmal depolarizing shift: the first cellular marker of focal epileptogenesis","volume-title":"Jasper's basic mechanisms of the epilepsies","author":"Prince","year":"2024"},{"key":"ref126","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1177\/089198879400700106","article-title":"A new italian pedigree with early-onset Alzheimer's disease","volume":"7","author":"Rainero","year":"1994","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref127","doi-asserted-by":"publisher","first-page":"975","DOI":"10.3233\/JAD-160612","article-title":"Amyloid-\u03b2 and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer's disease neurons","volume":"57","author":"Rajmohan","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref128","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1016\/j.neurobiolaging.2005.09.022","article-title":"Early neuropathology of somatostatin\/npy GABAergic cells in the hippocampus of a PS1xAPP transgenic model of Alzheimer's disease","volume":"27","author":"Ramos","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref129","doi-asserted-by":"publisher","first-page":"109533","DOI":"10.1016\/j.jnutbio.2023.109533","article-title":"Maternal methyl donor supplementation: a potential therapy for metabolic disorder in offspring","volume":"124","author":"Ren","year":"2024","journal-title":"J. Nutr. Biochem."},{"key":"ref130","doi-asserted-by":"publisher","first-page":"798335","DOI":"10.15252\/embj.201798335","article-title":"Distinct in vivo roles of secreted APP ectodomain variants apps\u03b1 and APPs\u03b2 in regulation of spine density, synaptic plasticity, and cognition","volume":"37","author":"Richter","year":"2018","journal-title":"EMBO J."},{"key":"ref131","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1097\/00002093-199040400-00003","article-title":"Myoclonus, seizures, and paratonia in Alzheimer disease","volume":"4","author":"Risse","year":"1990","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref132","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1126\/science.1141736","article-title":"Reducing endogenous tau ameliorates amyloid \u03b2-induced deficits in an Alzheimer's disease mouse model","volume":"316","author":"Roberson","year":"2007","journal-title":"Science"},{"key":"ref133","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1001\/archneur.1990.00530080029006","article-title":"Advanced Alzheimer's disease is a risk factor for late-onset seizures","volume":"47","author":"Romanelli","year":"1990","journal-title":"Arch. Neurol."},{"key":"ref134","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3390\/cells10020204","article-title":"Calcium signaling and mitochondrial function in presenilin 2 knock-out mice: looking for any loss-of-function phenotype related to Alzheimer's disease","volume":"10","author":"Rossi","year":"2021","journal-title":"Cells"},{"key":"ref135","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/0304-3940(80)90177-9","article-title":"Reduced amounts of immunoreactive somatostatin in the temporal cortex in senile dementia of Alzheimer type","volume":"20","author":"Rossor","year":"1980","journal-title":"Neurosci. Lett."},{"key":"ref136","doi-asserted-by":"publisher","first-page":"e00291","DOI":"10.1016\/j.neurot.2023.10.001","article-title":"Development of small-molecule tau-SH3 interaction inhibitors that prevent amyloid-\u03b2 toxicity and network hyperexcitability","volume":"21","author":"Roth","year":"2024","journal-title":"Neurotherapeutics"},{"key":"ref137","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1002\/(SICI)1096-9861(19970414)380:3<382::AID-CNE7>3.0.CO;2-Z","article-title":"Muscarinic acetylcholine receptor immunoreactivity after hippocampal commissural\/associational pathway lesions: evidence for multiple presynaptic receptor subtypes","volume":"380","author":"Rouse","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"ref138","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nn.3697","article-title":"Single APP knock-in mouse models of Alzheimer's disease","volume":"17","author":"Saito","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref139","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2174\/1567205012999151021102914","article-title":"The link between Alzheimer's disease and Down syndrome. A historical perspective","volume":"13","author":"Salehi","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"ref140","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.3390\/ijms19041092","article-title":"Tau-induced pathology in epilepsy and dementia: notions from patients and animal models","volume":"19","author":"Sanchez","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"ref141","doi-asserted-by":"publisher","first-page":"459","DOI":"10.3389\/fpsyg.2019.00459","article-title":"The functional role of dreaming in emotional processes","volume":"10","author":"Scarpelli","year":"2019","journal-title":"Front. Psychol."},{"key":"ref142","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1038\/nrn.2016.87","article-title":"The enigmatic mossy cell of the dentate gyrus","volume":"17","author":"Scharfman","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref143","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.bbr.2010.11.058","article-title":"The cholinergic system in aging and neuronal degeneration","volume":"221","author":"Schliebs","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref144","doi-asserted-by":"publisher","first-page":"eabm5527","DOI":"10.1126\/scitranslmed.abm5527","article-title":"Tau ablation in excitatory neurons and postnatal tau knockdown reduce epilepsy, sudep, and autism behaviors in a Dravet syndrome model","volume":"14","author":"Shao","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref145","doi-asserted-by":"publisher","first-page":"781731","DOI":"10.1155\/2015\/781731","article-title":"Altered theta oscillations and aberrant cortical excitatory activity in the 5XFAD model of Alzheimer's disease","volume":"2015","author":"Siwek","year":"2015","journal-title":"Neural Plast."},{"key":"ref146","doi-asserted-by":"publisher","first-page":"678","DOI":"10.3390\/nu16050678","article-title":"Epigenetic genome modifications during pregnancy: the impact of essential nutritional supplements on DNA methylation","volume":"16","author":"Socha","year":"2024","journal-title":"Nutrients"},{"key":"ref147","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1002\/1531-8249(199911)46:5<708::AID-ANA5>3.0.CO;2-K","article-title":"FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation","volume":"46","author":"Sperfeld","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref148","doi-asserted-by":"publisher","first-page":"545","DOI":"10.2217\/bmm.11.72","article-title":"High-frequency oscillations and other electrophysiological biomarkers of epilepsy: underlying mechanisms","volume":"5","author":"Staba","year":"2011","journal-title":"Biomark. Med"},{"key":"ref149","doi-asserted-by":"publisher","first-page":"2442","DOI":"10.1016\/j.neuropsychologia.2012.12.014","article-title":"A task to assess behavioral pattern separation (bps) in humans: data from healthy aging and mild cognitive impairment","volume":"51","author":"Stark","year":"2013","journal-title":"Neuropsychologia"},{"key":"ref150","doi-asserted-by":"publisher","first-page":"97","DOI":"10.2174\/1567205012666150921100311","article-title":"Maternal choline supplementation: a potential prenatal treatment for down syndrome and Alzheimer's disease","volume":"13","author":"Strupp","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"ref151","doi-asserted-by":"publisher","first-page":"925546","DOI":"10.3389\/fnsyn.2022.925546","article-title":"Rtg(tau(P301L))4510 mice exhibit increased vGLUT1 in hippocampal presynaptic glutamatergic vesicles and increased extracellular glutamate release","volume":"14","author":"Taipala","year":"2022","journal-title":"Front. Synaptic Neurosci."},{"key":"ref152","doi-asserted-by":"publisher","first-page":"reviews3014","DOI":"10.1186\/gb-2002-3-11-reviews3014","article-title":"The presenilins","volume":"3","author":"Tandon","year":"2002","journal-title":"Genome Biol."},{"key":"ref153","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.eplepsyres.2012.04.014","article-title":"Characterization of status epilepticus induced by two organophosphates in rats","volume":"101","author":"Todorovic","year":"2012","journal-title":"Epilepsy Res."},{"key":"ref154","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.semcdb.2008.10.007","article-title":"Structure and function of \u03b3-secretase","volume":"20","author":"Tolia","year":"2009","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref155","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/0166-4328(83)90136-5","article-title":"Limbic seizures produced by pilocarpine in rats: Behavioural, electroencephalographic and neuropathological study","volume":"9","author":"Turski","year":"","journal-title":"Behav. Brain Res."},{"key":"ref156","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/0166-4328(83)90026-8","article-title":"Intrahippocampal bethanechol in rats: Behavioural, electroencephalographic and neuropathological correlates","volume":"7","author":"Turski","year":"","journal-title":"Behav. Brain Res."},{"key":"ref157","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.brainres.2004.04.032","article-title":"Loss of NeuN immunoreactivity after cerebral ischemia does not indicate neuronal cell loss: a cautionary note","volume":"1015","author":"Unal-Cevik","year":"2004","journal-title":"Brain Res."},{"key":"ref158","doi-asserted-by":"publisher","first-page":"2703","DOI":"10.1111\/epi.17355","article-title":"Higher susceptibility to 6 Hz corneal kindling and lower responsiveness to antiseizure drugs in mouse models of Alzheimer's disease","volume":"63","author":"Vande Vyver","year":"2022","journal-title":"Epilepsia"},{"key":"ref159","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1038\/s41380-018-0322-z","article-title":"Maternal choline supplementation ameliorates Alzheimer's disease pathology by reducing brain homocysteine levels across multiple generations","volume":"25","author":"Velazquez","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref160","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.cell.2012.02.046","article-title":"Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model","volume":"149","author":"Verret","year":"2012","journal-title":"Cell"},{"key":"ref161","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1159\/000106956","article-title":"Effect of seizures on progression of dementia of the Alzheimer type","volume":"6","author":"Volicer","year":"1995","journal-title":"Dementia"},{"key":"ref162","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1001\/jamaneurol.2013.136","article-title":"Seizures and epileptiform activity in the early stages of Alzheimer disease","volume":"70","author":"Vossel","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref164","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1002\/ana.24794","article-title":"Incidence and impact of subclinical epileptiform activity in Alzheimer's disease","volume":"80","author":"Vossel","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref163","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1001\/jamaneurol.2021.3310","article-title":"Effect of levetiracetam on cognition in patients with Alzheimer disease with and without epileptiform activity: a randomized clinical trial","volume":"78","author":"Vossel","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref165","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/j.jsmc.2010.08.003","article-title":"Neuropharmacology of sleep and wakefulness","volume":"5","author":"Watson","year":"2010","journal-title":"Sleep Med. Clin."},{"key":"ref166","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1007\/978-94-017-8914-1_14","article-title":"Does brain inflammation mediate pathological outcomes in epilepsy?","volume":"813","author":"Wilcox","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref167","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.semcdb.2008.12.011","article-title":"\u03b3-secretase in biology and medicine","volume":"20","author":"Wolfe","year":"2009","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref168","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1021\/acs.biochem.4c00830","article-title":"Presenilin, \u03b3-secretase, and the search for pathogenic triggers of Alzheimer's disease","volume":"64","author":"Wolfe","year":"2025","journal-title":"Biochemistry"},{"key":"ref169","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1007\/s12035-014-8994-0","article-title":"The binding receptors of A\u03b2: an alternative therapeutic target for Alzheimer's disease","volume":"53","author":"Xia","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref170","doi-asserted-by":"publisher","first-page":"529","DOI":"10.3233\/JAD-215186","article-title":"Hyperphosphorylated tau relates to improved cognitive performance and reduced hippocampal excitability in the young rTg4510 mouse model of tauopathy","volume":"87","author":"Xolalpa-Cueva","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"ref171","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1111\/j.1753-4887.2009.00246.x","article-title":"Choline: an essential nutrient for public health","volume":"67","author":"Zeisel","year":"2009","journal-title":"Nutr. Rev."},{"key":"ref172","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1007\/s11011-021-00733-4","article-title":"Recent advances in pre-clinical diagnosis of Alzheimer's disease","volume":"37","author":"Zhou","year":"2022","journal-title":"Metab. Brain Dis."}],"container-title":["Frontiers in Dementia"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/frdem.2025.1513144\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T05:28:03Z","timestamp":1750138083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/frdem.2025.1513144\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,17]]},"references-count":177,"alternative-id":["10.3389\/frdem.2025.1513144"],"URL":"https:\/\/doi.org\/10.3389\/frdem.2025.1513144","relation":{},"ISSN":["2813-3919"],"issn-type":[{"value":"2813-3919","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,17]]},"article-number":"1513144"}}