Table 4.

Main in vivo and in vitro studies of beer and its compounds’ activity on neurodegenerative diseases.

Compound	Species and Trial Mode	Formulation and Doses	Results	Reference
Beer	Clinical trial in humans with 125 males of the Helsinki Sudden Death autopsy	Total life consumption	Neuroprotective effect by a possible depletion of Aβ aggregation in brain	Kok et al. [111]
Beer	Cohort study with 360 patients in early AD, biannually evaluation up to 19–28 years.	Heavy drinkers (≥8 alcoholic drinks/week); mild-moderate drinkers (1–7 alcoholic drinks/week); abstainers	Increasing standard drinks of hard liquor, but not beer or wine, was associated with a faster rate of cognitive decline, such as AD	Heymann et al [114]
Beer	Cardiovascular Health Study, cohort study with 5888 men and women aged ≥65 years and 5–7 years follow up.	12oz of beer with later magnetic resonance imaging of the brain and cognitive capacity evaluation.	Limited beer consumption resulted in a decreased risk of dementia or AD	Mukamal et al. [115]
Beer	Cohort study with 980 community-dwelling individuals aged ≥65 years without dementia at baseline, annually evaluation.	Light drinkers (1 serving/month to 6 servings/week); moderate drinkers (1–3 servings/day); heavy drinkers (≥4 servings/day)	Light to moderate alcohol intake was associated with a lower risk of dementia and AD, whereas intake of beer and liquor was not associated with incident dementia.	Luchsinger et al. [116]
Beer	Review of the observational studies, trials, reviews, and meta-analyses in humans	Review from 45 reports since the early 1990’s	More than half of the papers indicate that low consumption of beer reduced the risk of dementia. While a minority suggests the risk of neurodegeneration due to its ethanol content	Collins et al. [112]
Beer	Immune response evaluation in human peripheral blood mononuclear cells with 48-h treatment	Different beer types with 2%–4% (v/v) ethanol	Beer reduces the production of neopterin and the tryptophan degradation. Its immunosuppressive capacity seems related to its anti-inflammatory mechanisms.	Winkler et al. [117]
Beer	In vitro experiments of pure samples	Electron paramagnetic resonance spectroscopy and antioxidant activity of different types of beer	Beers exhibit antioxidant properties	Polak et al. [118]
Alcohol	Review of the human, rodents and cell culture neuroprotection evaluations and epidemiological studies	Wine, beer, and liquor administration and consumption	Alcohol-dependent neuroprotected state appears linked to an activation of signal transduction processes of reactive oxygen species. The alcohol intake ameliorates inflammatory pathways and increases hippocampal acetylcholine release. Alcohol exposure is inversely associated with dementia through protective changes in cerebral vasculature	Collins et al. [112]
Beer/silicon	Human intake with 6-h bioavailability evaluation of silicon-enriched beer	0.6 L beer containing 22.5 mg Si and 4.6% (v/v) ethanol	Silicon in beer in monomeric form, is readily bioavailable in healthy volunteers	Sripanyakorn et al. [119]
Beer/silicic acid	Acute three-day study with male NMRI mice	Equivalent to moderate-high consumption in humans (1 L/day; 55 g alcohol/day).	Beer, mainly associated with its silicon content, reduces dietary aluminum toxicokinetics and bioavailability through a reduction of aluminum uptake in the digestive tract and by increasing its fecal excretion	Peña et al. [120]
Beer/silicon	Male NMRI mice on 3-month trial with neuroprotective evaluation	2.5 mL beer/per week (5.5% (v/v)), and 40 mg silicon/L/day	Silicon appears to be effective in preventing aluminum accumulation in mouse’s brain. Nonetheless, silicon could act either as neuroprotector or neurotoxic	Granero et al. [121]
Beer/silicic acid	Male NMRI mice on 3-month evaluation	450 mg of aluminum nitrate,0.5 mL beer* (5.5% (v/v))/day, and 9 µg silicon/day *equivalent to moderate to high consumption in humans (1 L/day)	Beer consumption, and its content on bioavailable silicon, reduces the accumulation of aluminum in the body and brain tissue, the lipid peroxidation, and protected against the neurotoxic effects through the regulation of antioxidant enzymes	González-Muñoz et al. [48,122]
Beer/silicic acid	Male NMRI mice on 3-month trial	450 mg of aluminum nitrate,0.5 mL beer* (5.5% (v/v))/day, and 9 µg silicon/day *equivalent to moderate to high consumption in humans (1 L/day)	Silicic acid and beer block the metal imbalance, inflammation, and antioxidant defense impairment induced by aluminum intoxication in the brain	González-Muñoz et al. [43]
Non-alcoholic beer/hops extract/organic silicon (Silicium organique G57™)	Male Wistar rats on 3-month trial with behavioral, organs, and in vitro studies of neurodegeneration	450 µg aluminum nitrate/kg/day; 2 mg hops extract/day; 250 µg silicon/day; 5 mL NA-beer/day* *equivalent to moderate/high consumption in humans (1 L/day)	NA-beer, hops, and silicon ameliorated behavioral modifications, blocked the negative effect on the in vivo and in vitro antioxidant status, and reduced the inflammation markers in brain induced by aluminum intoxication	Merino et al. [123]
Hops extract	Homozygous transgenic mice (V717F) and heterozygous transgenic mice (V717F/P267S) on a 2-, 6-, 11-, and 18-month trial, and HEK293A cell culture	Hops extract added to drinking water at a dose of 2 g extract/L	Hops extract reduced Alzheimer’s phenotypes in mice and prevented the emotional disturbance at the 18 months AD-mice. The extract significantly reduced Aβ production in cultured cells and presented γ-secretase inhibitory activity	Sasaoka et al. [124]
Hops pellets	Hops pellets to obtain its chemical characterization	Chemical and quantitative determination of hops compounds	The presence of resveratrol in hops highlights the potential health-promoting effect of moderate beer consumption	Callemien et al. [125]
Silicon	Human trial in 7598 women ≥75 years for evaluation of cognitive function and neuroprotective effect	Silica content in drinking water	Silicon in drinking water might reduce the risk of AD	Gillette-Guyonnet et al. [126]
Silicon	Review from human trials that evaluate the neuroprotective effect of silica in drinking water	Reviews from tidies of silica in drinking water	Aluminum in water seems to have a deleterious effect when the silica concentrations were low, while the risk of AD was reduced in subjects who had higher daily silica intake	Gillette-Guyonnet et al. [127]
Silicon	Male Wistar rats on a 12-week trial	0.5 mg aluminum/kg/day, and 2 mg silicon/kg/day	Silicon is considered an important protector against lipid peroxidation induced by aluminum intake	Noremberg et al. [18]
Silicon	SH-5HSY neuroblastoma cells line with a 24-h treatment	Ladder concentration of 50–250 ng silicon/mL	Silicon treatment reduced TBARS levels, it also may act as neuroprotector by inducing antiapoptotic effects at low doses and may act as neurotoxic by regulating necrosis and apoptosis mechanisms at high doses.	Garcimartín et al. [128]
Beer/melatonin	Human trial with healthy volunteers (4 men and 3 women) aged 20 to 30 years.	Different beer brands with diverse ethanol content	Melatonin contained in beer showed antioxidant, oncostatic, and immune enhancer activities	Maldonado et al. [129]
Melatonin	Review of the main effects on AD pathology	Main research publications on the melatonin pathological mechanisms related to AD through different approaches	Prevention of amyloid overproduction, reduction of tau phosphorylation, antioxidant ability, modulates inflammation, anticholinesterase agent, prevents mitochondrial damage and apoptosis.	Rosales-Corral et al. [130]
Melatonin	Transgenic mice Tg2576 on an 8-, 9.5-, 11-, and 15.5-month survival study trial to evaluate neuroprotective effect	0.5 mg/mL melatonin administration to obtain Aβ measurements in brain, quantitative immunoblots of APP levels, and nitrotyrosine measurements	The melatonin administration proved a reduction of major AD markers and brain Aβ levels	Matsubara et al. [131]
Melatonin	Male swiss albino mice in a 5-day neuroprotective effect evaluation experiment	50 mg melatonin/kg body weight and 5µg Aβ42-1 intracerebroventricularly administrated	The treatment reduced Aβ-induced oxidative stress, related to ROS and proinflammatory cytokines IL6 and IL1-β, and the intracellular calcium levels and acetylcholinesterase activity in the neocortex and hippocampus regions	Masilamoni et al. [132]
Melatonin	Review of the in vivo and in vitro studies	Reviews about the effects on the prevention of neurodegenerative diseases and their molecular mechanism	Melatonin is significantly decreased in elderly AD individuals and associated with the emergence of AD, it exhibits a protective effect on the cholinergic system and protects brain neurons from damage and death by increasing viability in hippocampal neurons and glial cells	Hornedo-Ortega et al. [133]
Phenolic compounds from beer	In vitro anti-AChE and anti-BChE activities of simple phenolic acids	Phenolic solutions at their beer concentration. IC50 values at 336 and 160 mM calculated for AChE and BChE, respectively	Phenolic acids from beer can play a role in neuroprotection by through an inhibition of cholinesterases	Szwajgier [134]
Phenolic compounds from malt	In vitro studies of the phenolic fraction profile from several malt types.	Phenolic solution at different concentrations to inhibit AChE and BChE enzymes (~0.38–1 mM/L)	The main phenolic compounds from malt (ferulic acid, p-coumaric, 4-hydroxybenzoic, and sinapic acids). Among them, the ferulic and p-coumaric acids showed a high neuroprotective role and can be considered as possible anti-AD agents	Szwajgier and Borowiec [135]
Phenolic compounds from beer	Female Tg2576 mice on a 14 months trial to evaluate the pathology of AD	Different diets including 0.5% phenolic compounds evaluated through immunohistochemistry and morphometry of Aβ deposits	The extracted phenolic compounds prevent AD pathology development through the regulation of Aβ aggregation pathway	Hamaguchi et al. [136]
Xanthohumol	Wild-type murine neuroblastoma Neuro2a cells (N2a/WT) and N2a stably transfected with human APP Swedish mutant (N2a/APP) on a 24-h treatment	0–25 μM Xanthohumol in cell culture and later comparative proteomics, immunocytochemistry of Aβ1-40 and Aβ1-42	Xanthohumol suppresses Aβ production and tau hyperphosphorylation via APP processing and the GSK-3β pathway. Thus, it may have potential effects for the treatment of AD	Huang et al. [137]
Iso-α-acids	Alzheimer’s model in 5xFAD mice on a three-month period to evaluate cognitive function in the progression of dementia	0.05% (w/w) of the iso-α-acids	The iso-α-acids suppressed the neuroinflammation markers IL-1β and chemokine, and improve cognitive function	Ano et al. [138]
Iso-α-acids	Male Crl:CD1(ICR) mice, vagotomized male ICR mice, and Sprague-Dawley (SD) rats on a 3-month period to evaluate cognitive function test, especially hippocampus-dependent memory	1 mg/kg iso-α-acids	Iso-α-acids activate dopamine D1 receptor-signaling in the hippocampus and improves spatial and object recognition memory functions	Ano et al. [139,140]
Iso-α-acids	Male C57BL/6J mice treated for 3 months	Dietary intake of 0.05% (w/w) iso-α-acids to evaluate episodic and spatial memory and microglia analysis	Reduced inflammation in the brain and prevent the cognitive impairment associated with normal aging	Ano et al. [140]
Iso-α-acids	Male C57BL/6J mice on an AD model (5xFAD transgenic) on a 7-day trial	1 mg/kg iso-α-acids and later transcriptome analysis	Reduced Aβ in the brain and increased the expression of transthyretin in the hippocampus, thus displayed protective effects AD pathologies	Fukuda et al. [141]
Beer/iso-α-acids from hops extract	Male C57BL/6J mice on a long-term cognitive evaluation trial	1 mg extract/kg equivalent to 4.8 mg/day in humans (60 kg body weight) or 0.17–0.3 L/day of beers	Iso-α-acids could improve working memory in dementia and visual/reversal discrimination learning, which are considered high-order cognitive functions.	Ayabe et al. [142]

AChE, acetyl cholinesterase; AD, Alzheimer’s disease; Aβ, amyloid-β; Al, aluminum; BChE, butylcholinesterase; ChAT, choline acetyltransferase; HDL, high density lipoproteins; ROS, reactive oxygen species; Si, silicon; TNFα, tumor necrosis factor alpha.