Table 2.

Summary of the human epidemiological studies and the in vitro and in vivo animal studies investigating the effect of caffeine on Alzheimer's disease (AD)

Alzheimer's disease (AD)—human epidemiological studies
Reference	Participants	Duration	Main results	Conclusion
van Gelder et al., 2007	676 healthy men from Finland, Italy and the Netherlands 75‐77 y	10 y Mini‐mental state examination to assess global cognitive function	Coffee: ↓ cognitive decline (54%) Without coffee: 2.6 points of cognitive decline, 1 cup: 1.4 point of cognitive decline 2 cups: 1.3 points of cognitive decline 3 cups: 0.6 points of cognitive decline 4 cups: 1.6 points of cognitive decline Cognitive decline was not reduced for men who consumed >4 cups.	Consuming coffee was associated with slower cognitive decline in men. Consumption of 3 cups/d was most beneficial.
Eskelinen et al., 2009	1409 healthy participants 875 women 534 men Midlife: 50.4 y Later in life: 70.1 y	21 y	3‐5 cups of coffee: ↓ 65%‐70% risk of dementia and ↓ 62‐64% risk of AD vs 0‐2 cups 3‐5 cups/d of coffee: ↓ risk of dementia in men (OR=0.27, CI=0.08‐0.89) and women (OR=0.51, CI=0.17‐1.52) vs 0‐2 cups/d. In men, >5 cups: ↓ risk of dementia vs low coffee consumption (OR=0.36, CI=0.13‐0.97).	Moderate coffee consumption at midlife may decrease the risk of developing AD and dementia later in life.
Maia & Mendoca, 2002	54 patients with probable AD 26 women 28 men 71.2 y 54 healthy controls 26 women 28 men 70.4 y	20 y preceding diagnosis	AD patients: average caffeine intake of 74±98 mg Healthy controls: average caffeine intake 199±136 mg Caffeine exposure: ↓ 60% risk of AD (OR=0.40, CI=0.25‐0.67)	There is an inverse association between caffeine intake and AD
Lindsay et al., 2002	10 263 Canadian women and men >65 y	5 y	Daily coffee consumption: ↓ 31% risk of AD (OR=0.69, CI=0.5‐0.96)	Coffee consumption is associated with lower risk of AD in Canadian population.
Kim et al., 2015	31 479 participants		RR of Caffeine intake from coffee or tea for cognitive disorders (dementia, AD, cognitive impairment, and cognitive decline) was 0.82 (CI=0.67‐1.01)	Meta‐analysis found that caffeine intake from coffee or tea was not associated with the risk of cognitive disorders. May be due to type II error.

Alzheimer's disease—in vitro and in vivo animal studies
Reference	Subjects	Treatment	Main results	Conclusion
Arendash et al., 2006	APPsw mice n=41 transgenic mice n=16 NT mice Females and males 4‐9 mo	1.5 mg/d (human equivalence of 500 mg/d) of caffeine 5.5 mo of treatment	Caffeine: complete protection in all cognitive tasks Caffeine: ↓ soluble Aβ1‐40 (37%) and insoluble Aβ1‐42 (32%) in the hippocampus Caffeine: normalized PS‐1 levels and ↓ 50% in BACE levels	Daily caffeine intake may reduce or delay the risk of developing AD.
Arendash et al., 2009	APPsw mice n=6 transgenic‐caffeine‐treated n=7 transgenic control n=8 NT control Females and males 18‐19 mo	1.5 mg/d (human equivalence of 500 mg/d) of caffeine 2 mo of treatment	Caffeine: ↑ memory vs control (4 wk: ~217%, 5 wk: ~198%) Caffeine: ↓ Aβ deposition in the hippocampus (40%) and the entorhinal cortex (46%) Caffeine: ↓ Aβ1‐42 in cortex (51%) and hippocampus (59%) Caffeine: ↓ Aβ1‐40 in the cortex (25%) and the hippocampus (37%) Caffeine: ↑ PKA levels, and ↓ c‐Raf‐1, NF‐kB pathway activation and BACE‐1 production	Even with pre‐existing Aβ in APPsw mice, caffeine administration restored memory function and reversed AD pathology, suggesting a therapeutic role of caffeine in well‐established cases of AD.
Chu et al. 2012	J20 mice n=17 wild type n=14 APP‐control n=9 APP‐CC n=11 APP‐caffeine Males 3 mo	1.84 mg/d of crude caffeine (CC) or pure caffeine 2 mo of treatment	Pure caffeine and CC: enhance Morris maze performance CC: ↓ Aβ1‐42 (52%) and plaque number (67%) Aβ with 0.5, 5 and 50 ng/mL CC: 57%, 68%, and 77% ↑ ATP levels vs controls Aβ with pure caffeine and CC: ↓ number of caspase‐3 positive neurons 43% and 48%, respectively	Pure and crude caffeine can protect against cell death and memory impairment in male mice.
Qosa et al., 2012	C57BL/6 mice Males n=4 per group 7‐8 wk	0.8 mg/d of caffeine 3 wk of treatment Plasma concentration: 103±28 μmol/L	Caffeine: ↑ 20% Aβ clearance	Caffeine enhanced Aβ clearance from the brain of mice, partially explaining the protective effects of caffeine in AD.
Dragicevic et al., 2012	APPsw mice n=3 transgenic and caffeine n=4 transgenic control n=2 NT and caffeine n=2 NT control Sex not identified 11‐12 mo	0.6 mg/d of caffeine 1 mo of treatment	Caffeine: ↑ hippocampal mitochondrial respiration (25%) and ATP levels (46%) Caffeine: ↑ hippocampal mitochondrial membrane potential (78%) and ↓ ROS production (100%).	Caffeine increases mitochondrial function in APPsw mice.
Han et al., 2013	APPsw mice n=8 per group Sex not identified 24 mo	0.75 mg/d or 1.5 mg/d of caffeine 8 wk of treatment	Caffeine: ↓ escape time (46%‐62%) and ↑ time spent in the target quadrant (32‐46%). Caffeine (0.75 mg/d and 1.5 mg/d): ↑ brain‐derived neurotrophic factors (BDNF) and its receptors (TrkB)	Chronic caffeine treatment may reverse memory impairment in APPsw mice, and BDNF and its receptor TrkB may be partially responsible.
Prasanthi et al., 2011	New Zealand white rabbits Male 1.5‐2 y	Treatment with 0.5 or 30 mg caffeine/d and 2% cholesterol‐enriched diet	Caffeine (0.5 and 30 mg): ↓ cholesterol‐induced increase in Aβ polypeptide and ↑ cholesterol‐induced decrease in A1R Caffeine (30 mg): ↓ cholesterol‐induced increase in BACE1, tau phosphorylation, ROS generation, and glutathione depletion	The protective effect of caffeine was dose dependent, and associated with increases in A1R, not decrease in cholesterol levels.
Zeitlin et al., 2011	APPsw mice n=5‐8 per experimental group Sex not identified 9.5 mo	1.5 mg/d of caffeine 2 wk of treatment	Caffeine: ↑ PKA activity in the striatum and ↑ CREB levels by 126% Caffeine: ↓ pERK (striatum: 70%, cortex: 59%) and PJNK (striatum:60%, cortex: 54%)	Caffeine stimulates pro‐survival pathways and inhibits pro‐apoptotic pathways in the striatum and the cortex.
Giunta et al., 2014	Human neuroblastoma cells	Pretreatment with 10 μmol/L of caffeine Treatment with AlCl3	Caffeine: ↓ phosphorylated IκBα and NF‐κB levels and nuclear translocation of NF‐κB back Caffeine: ↓ ROS production (51%), ↑ SOD (50%) and ↓ MDA (50%) Caffeine: ↓ pro‐apoptotic Bax and ↑ anti‐apoptotic Bcl‐2 levels	Caffeine has a potential beneficial role in preventing AD in those exposed to aluminum.