Table 4.

Treatments that might suppress Alzheimer’s disease-associated network hyperexcitability

	Proposed mechanism	Phase of investigation in Alzheimer’s disease
Antiepileptic drug
Levetiracetam	Binds SV2A and prevents synaptic vesicle release,65 and increases glutamate transporter expression89	Animal model;6,70 case-control;58 phase 2 (NCT02002819);73 and phase 3 (registering in 2017)
Brivaracetam	Binds SV2A with higher affinity than levetiracetam90	Animal model76
Lamotrigine	Inhibits Na+ channel activity; more potent at inhibiting glutamate release than other antiepileptic drugs in this class66	Animal model;77 case-control58
Topiramate	Inhibits GSK-3β activation and histone deacetylase activity,70 inhibits Na+ and Ca2+ channels, enhances GABAA receptor function, and blocks AMPA and kainate receptors	Animal model70
Antineoplastic drug
Bexarotene	Retinoid X receptor agonist, alters gene expression	Animal model91
Cell-replacement therapies
GABAergic interneurons derived from stem cells	Increase local GABAergic interneuron populations (eg, somatostatin-positive interneurons in hilus of dentate gyrus)	Animal model57
Dietary therapies
Ketogenic diet	Increases mitochondrial biogenesis and oxidative phosphorylation, and enhances GABA levels92	Phase 2 (NCT02551419, NCT02709356, and NCT00142805);93 interventional placebo-controlled, single blind (NCT02521818); phase 4 (NCT00777010)
Taurine	Activates GABA receptors94	Animal model95
Gene therapy
Enhancing Nav1.1 expression	Improves function of parvalbumin-positive interneurons	Animal model37
Kinase inhibitors
Src family kinase inhibitor	Suppresses Fyn kinase phosphorylation of Tyr-1472 in NR2B subunit of NMDA receptors42	Phase 1 (AZD0530 [saracatinib], completed, NCT01864655);96 phase 2 (saracatinib, NCT02167256)
Tyrosine kinase inhibitor	Reduction in mast cell-mediated inflammation through c-Kit inhibition; Src family kinase inhibition, including Fyn kinase97	Phase 2 (masitinib, completed, NCT00976118);97 and phase 3 (masitinib, NCT01872598)
Tau reduction therapies
Salsalate	Inhibits tau acetylation, which enhances tau turnover98	Animal model; phase 1 for progressive supranuclear palsy (NCT02422485)
Antisense oligonucleotides	Reduces tau mRNA levels52	Animal model52
Methylene blue	Inhibits Hsp70 enzymatic activity99	Phase 2 (NCT02380573)

GSK-3β=glycogen synthase kinase 3β. SV2A=synaptic vesicle protein 2A.