Table 1.

Acute and long-term caffeine intake effects in different AD animal models.

Animal Model	Advantages of the Model	Drawbacks of the Model	Study Design	Main Results/Findings	Reference
APPswe mouse model	High concentration of Aβ even in young model (starting with 6–7 months of age) Replication of amyloidosis, vascular angiopathy, oxidative stress, and neuroinflammation	Absence of neurofibrillary tangles, no global neuronal or synaptic losses, no clear abnormalities in the brain structures associated with learning and memory	Administration of 1.5 mg p.o. caffeine for 2 weeks, every 12 h in 9.5-month-old mice in order to investigate the effects of caffeine on the signal transduction pathways in cognitively important areas of the mouse brain	Neuroprotective and antiapoptotic effect by stimulating PKA activity Increasing the level of phosphorylated CREB Decreasing JNK and ERK phosphorylation	Zeitlin et al., 2011 [33]
			Administration of 0.3 g/L p.o. caffeine in drinking water for 5.5 months, starting with 4-month-old mice in order to determine the neuroprotective effects of long-term dietary caffeine intake	Protective effect against cognitive impairment Reduction in Abeta levels in the hippocampus, restoration of brain adenosine levels No effect on A1R and A2AR hippocampal density and expression in the cerebral cortex and hippocampus	Arendash et al., 2006 [34]
			Administration of 0.75 mg/day or 1.5 mg/day p.o. of caffeine for 8 weeks in 12-month-old mice in order to investigate the effects of caffeine intake on the memory deficits, BDNF and TrkB expression	Increasing in spatial learning ability and memory capability Increasing in the expression of hippocampal BDNF and TrkB. Protective role against memory impairment	Han et al., 2013 [35]
			Acute administration regimen (single administration of 1.5 mg i.p. caffeine in 3- to 4-month-old; single administration of 1.5 mg i.p. or p.o. caffeine in 14-month-old) Long-term regimen (1.5 mg p.o. caffeine twice-daily for 7 days in 15- to 20-month-old; caffeine: 1.5 mg p.o. caffeine in two administrations on one day every 4th day for 2 months, 20-month-old)	Improvement of cognitive functions after long-term caffeine intake Reduction of Aβ interstitial fluid level after acute caffeine administration, but no effect on Aβ elimination Decreased Aβ plasma levels after single dose and chronic administration Reduction of soluble Aβ cortex and hippocampus level and insoluble Aβ hippocampus level after chronic caffeine administration	Cao et al., 2009 [36]
THY-Tau22 mouse model	Simulation of neurofibrillary tangle formation and pathological influence in AD Age-dependent neuropathological changes, which offer the possibility of study in different stages of the disease	No Aβ/senile plaques cerebral load	Administration of 0.3 g/L p.o. caffeine in drinking water for 10 months in 2-month-old male mice in order to study the effect of chronic caffeine intake on the development of hippocampal tau protein pathologies and spatial memory disorders	Prevention of spatial memory deficits Improvement of memory performance Reduction of neuroinflammation and decrease in the hippocampal level of hyperphosphorylated tau protein. Reduction of oxidative stress (reduced expression of MnSOD and EAAT3)	Laurent et al., 2014 [37]
			Chronic administration of 0.3 g/L p.o. caffeine in drinking water in female mice, starting of administration 2 weeks before mating and ending at 15th postnatal day in order to evaluate the effects of long-term caffeine exposure during pregnancy in offspring	Induction of physiological disorders and accelerated cognitive disorders Potential risk factor for early stages of AD.	Zappettini et al., 2019 [38]
3xTg mouse model	Neuropathological changes include both plaques and tangles Extracellular Aβ deposits are apparent as earlier as by six months in the frontal cortex Translates functional deficits such as synaptic dysfunction and LTP deficits	Tau pathology evident by 12 months	Chronic administration of 0.3 mg/mL caffeine in drinking water p.o. for 7 months, starting with 6-month-old male mice to investigate the effects of long-term caffeine administration on memory and learning	Reduction of motor activity, total horizontal activity, and emotionality in the behavioral tests Increasing of spontaneous motor activity (to a greater extent at night) Aggravation of BPSD-like behaviors, anxiety-related behaviors, or neophobia adversely affected possible beneficial effects	Baeta-Corral et al., 2018 [39]
C57BL/6N mouse	Most used breed in clinical studies Different modifications possible (lipopolysaccharide—LPS, genetics)	More susceptible to morphine addiction, atherosclerosis, and age-related hearing loss	Chronic caffeine administration of 30 mg/kg/day i.p. for 6 weeks in C57BL/6N male mice treated with LPS in order to examine caffeine effect on LPS-induced oxidative stress, neuroinflammation, apoptotic cell death, neurodegeneration, and synaptic impairment	Reduction of LPS-induced oxidative stress, neuroinflammation, and synaptic dysfunctions	Badshah et al., 2019 [40]
Adult CF1 male mice	Multipurpose model Suited for safety and efficacy testing		Single and chronic administration of caffeine in order to assess its effect on cognitive impairment in AD induced CF1 mouse model by i.c.v. A25–35 administration	Prevention of cognitive impairment, neurodegeneration, and brain destruction	Dall’Igna et al., 2007 [41]
Adult male Sprague–Dawley rats with accelerated aging	Multipurpose model Calmness Ease of handling Fast growing	Increased (and very variable) rate of tumor growth	Chronic caffeine administration (3 mg/kg/day i.p. for 60 days) impact on neurodegeneration induced by D-galactose-aging rat model	Reduction of oxidative stress, neuroinflammation, neuronal cell apoptosis, neurodegeneration, synaptic dysfunction and memory deficits	Ullah et al., 2015 [42]
			Chronic administration of instant decaffeinated coffee (p.o.) at 120 or 240 mg/kg for 2 weeks	Inhibition of scopolamine-induced memory impairment Suppression of TNF-α and NF-κB pathway at hippocampus level	Jang et al., 2013 [43]
Adult male Wistar rats	One of the most popular rat models used worldwide (first rat model) More active than other rat models High survival rate	Very high spontaneous incidences of foci of altered hepatocytes (FAH) Affected by vascular tumors	Chronic caffeine administration (20 mg/kg i.p. for 30 days) in adult male Wistar rats treated with AlCl3 (100 mg/kg p.o. for 30 days)	Antioxidant and anticholinesterase activity against AlCl3-induced neurotoxicity Reduction of oxidative stress parameters (NO level) Decrease of AChE and Na+/K+-ATPase activity in the cerebral cortex and hippocampus Anti-inflammatory properties—reduction of TNF-α levels in the hippocampus and striatum	Hosny et al., 2019 [44]
Fischer-344 male rats	Excellent model for aging research Extensive research (more than 5 decades) in carcinogenicity studies	High prevalence of severe nephropathy at advanced ages	Chronic administration of caffeine for 2 or 4 weeks to young rats and for 2 weeks to aged rats in order to assess caffeine effect on neuroinflammation	Potential protective effect against LPS-induced neuroinflammation	Brothers et al., 2010 [45]
New Zealand white rabbit cholesterol-induced AD model	Preferred in laboratory testing because of their docility and good health Small size, easy and low-cost maintenance, high availability		Chronic caffeine administration (3 mg/day in 50 mL of drinking water for 12 weeks) in order to investigate the effects on blood–brain barrier leakage in rabbits fed with cholesterol-enriched diet	Prevention of BBB dysfunction Reduction of astrocytes activation Reduction in microglia density	Chen et al., 2008 [46]
Caenorhabditis elegans (nematode model)	Possesses homologs of about two-thirds of all human disease genes Useful model for aging research Ease of maintenance	Lack of certain anatomical structures of mammals (BBB, blood transport system) Lack of long-range transcriptional regulation	Administration of 10% coffee extract (3.6 mM caffeine) in the agar medium in order to assess the effects of caffeine on the Aβ-induced toxicity in Caenorhabditis elegans	Prevention of Aβ-induced toxicity Delay in the paralysis progression No reduction in Aβ expression, Aβ aggregation or distribution	Dostal et al., 2010 [47]