Table 1.

Classes of antidiabetic compounds as potential therapies for Alzheimer’s disease.

Antidiabetic Drugs	Experimental Model	Findings	References
Insulin	rat model of intracerebroventricular streptozotocin (STZ) injection-induced cognitive dysfunction, intraventricular delivery of 0.5 units = 12 nmol of detemir	rescued STZ-induced cognitive decline	[79]
	patients with early AD or moderate cognitive impairment; intranasal delivery of 20 or 40 IU insulin	improved attention, verbal memory and functional status; modulation of Aβ peptide	[80,81,82,83]
	healthy volunteers, intranasal administration of 4 × 40 IU of insulin	improvement in memory and mood, increase regional cerebral blood flow in the putamen and the insular cortex	[84,85,86]
Metformin	neuronal cell lines under prolonged hyperinsulinemic conditions, various concentrations of metformin (0.4–3.2 mM)	insulin signaling resensitization, prevention of the molecular and pathological changes observed in AD neurons	[87]
	murine primary neurons (from tau transgenic mice and wild type), different concentration of metformin (2.5 mM or 10 nM)	reduction of tau phosphorylation	[88]
	transgenic mouse model of AD intraperitoneal delivery of 200 mg/kg metformin; or 350 mg/kg/day metformin delivered in drinking water for several months	amelioration of cognitive deficits, reduce Aβ plaque deposition attenuation of memory impairment	[73] [89]
	in older adults with an incident diagnosis of AD; 1–9, 10–29, 30–59, or ≥60 metformin prescriptions	more than 60 prescriptions were correlated with a slightly increased risk of developing AD	[72]
Thiazolidinediones	transgenic AD mouse model 0.03 mg/kg/day of leptin intranasal delivery + intraperitoneal administration of 10 mg/kg/day pioglitazone for 2 weeks	reduce brain Aβ levels and spatial memory impairments	[71]
	7 days gavage therapy with 40 mg/kg/day of pioglitazone	decrease glial inflammation and soluble Aβ1–42 peptide levels by 27%	[90]
	control trial in patients with AD and diabetes, doses of 15–30 mg pioglitazone for 6 months	cognitive deficits amelioration and stabilization of the disease in diabetics with AD	[91]
	pilot trial with AD patients without diabetes; daily 45 mg of pioglitazone	no important efficacy data were detected	[92]
	clinical trials; 2 to 8 mg of rosiglitazone, as adjunct therapy in AD patients	pro-cognitive effects	[93]
Glucagon-like peptide-1 receptor agonists	transgenic mouse model of AD intraperitoneal injection with 1 or 10 nmol/kg of lixisenatide for 10 weeks 10 nmol/kg lixisenatide for 60 days	prevented memory impairment, neuronal loss, and deterioration of synaptic plasticity reduction of amyloid plaques and neurofibrillary tangles	[94] [95]
	intraperitoneal injection with 2.5 or 25 nmol/kg of liraglutide for 10 weeks	reduce Aβ deposition by 40–50%, and decrease inflammatory response	[96]
	a pilot clinical trial in AD patients; daily subcutaneously injections of 0.6 mg liraglutide in the first week; hereafter 1.2 mg daily for another week before finally increasing to 1.8 mg daily (week 26)	brain glucose metabolism decline prevention; no important cognitive changes compared with placebo group	[97]
Dipeptidyl Peptidase-4 Inhibitors	transgenic mouse models of AD 20 mg/kg/day of sitagliptin for an 8-weeks period daily gavage of 5, 10 and 20 mg/kg sitagliptin for 12 weeks	pro-cognitive effects, reduction of Aβ deposits diminution of nitrosative stress and inflammation markers, reduction of Aβ deposition	[98] [99]
	daily oral administration of 5, 10, and 20 mg/kg linagliptin for 8 weeks	amelioration of cognitive deficits, diminution of Aβ42 levels, reduction of tau phosphorylation and neuroinflammation	[100]
	STZ-induced rat model of AD; 0.25, 0.5 and 1 mg/kg of saxagliptin in gavage delivery for 60 days	reduction of Aβ formation, a marked decrease of Aβ42 level and tau phosphorylation	[101]
	STZ- induced rat model of AD; daily orally doses of 2.5, 5 and 10 mg/kg vildagliptin for 30 days	attenuation of tau phosphorylation, Aβ and inflammatory markers	[102]
Sodium-glucose cotransporter 2 inhibitors	scopolamine-induced rat model of memory impairment; daily oral gavage of 10 mg/kg canagliflozin for 14 days	improvement of memory dysfunction	[103]

STZ, intracerebroventricular streptozotocin; AD, Alzheimer’s disease; Aβ, amyloid β.