Alzheimer’s disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied neurodegenerative disorder yet incurable to date. While its main postmortem brain hallmarks are the presence of amyloid-
Alzheimer’s disease (AD), the most common neurodegenerative disorder, as well as dementia type, is characterized by extracellular senile beta-amyloid protein (A
Mitochondria are essential yet independent organelles contained in eukaryotic cells, and they are responsible for numerous functional activities within the cells. However, they are not always an intrinsic structure of eukaryotic cells. They occur through the endosymbiosis of an alpha-proteobacterium into a prokaryotic progenitor, and this is why they contain their own DNA, namely, the mitochondrial DNA (mtDNA) [
Mitochondria have obtained the title of “powerhouse of the cell” due to their ability of producing the energy, mainly through OXPHOS, required for the survival and functioning of the cell. Actually, they are more than just a “powerhouse” as they are the ultimate multitaskers which define the cell fate. Apart from the production of energy in the form of ATP, mitochondria are the key modulators of brain cell survival and death by controlling calcium (Ca2+) and redox equilibrium (which in turn affects neurotransmitter release and neuronal plasticity), by producing reactive oxygen species (ROS), and by controlling cell apoptosis [
However, while mitochondria regulate the functions of healthy neurons, they are also largely affected during aging and pathological states such as age-related neurodegenerative diseases. Mitochondria are not only the regulators of energy metabolism but are also the main ROS generators. ROS are immensely reactive species which are produced in mitochondria mainly by complexes I and III of the ETC when there is a leak of electrons. They are chemical species including hydroxyl radical (∙OH), superoxide anion (O2-), and hydrogen peroxide (H2O2) which can interact with and damage DNA and proteins and lipids which can compromise cell survival leading to aging and to vulnerability to several diseases [
Intense oxidative stress and decreased brain energy metabolism are common characteristics of both normal aging and AD, although to different extents [
The current mitochondrial cascade hypothesis postulates mitochondrial dysfunction as a central pathomechanism in age-related degenerative disorders [
Many drugs including whole plant extracts and single compounds originate from natural and botanical sources. Two single compound AD drugs are derived from plants: (i) the acetylcholine-esterase inhibitor, galanthamine, derived from the
Common mitochondria-related targets of natural substances in neuroprotection. In AD, the precursor of amyloid protein APP is cleaved sequentially by
The effects of A
Neuroprotective effects of resveratrol in AD. The precursor of amyloid protein APP is cleaved sequentially by
In detail, the administration of GBE restored CREB phosphorylation in the hippocampus of TgAPP/PS1 mice [
Standardized
Apart from the preclinical studies, the extract has been largely investigated in clinical trials in a range of age-associated cognitive conditions from SMI and MCI to dementia and AD. GBE has been suggested for both the symptomatic treatment and prevention of those cognitive decline-related diseases. The standardized GBE is considered a phytopharmacon, and the dose of 240 mg/day is recommended as the most effective by the guidelines for biological treatment of dementias [
Clinical trials on the effects of GBE.
Study design | GBE dose/preparation | Duration | Subjects | Purpose | Main results | References |
---|---|---|---|---|---|---|
Patients with memory complaints, SMI, and MCI | ||||||
R, DB, PC | 240 mg of GBE once daily or placebo | (61) |
Test the effect of GBE on cognitive functions associated with prefrontal dopamine | GBE caused a mild increase in prefrontal dopamine; there were indications for enhanced cognitive flexibility and for ameliorated response inhibition results | Beck et al., 2016 [ | |
R, DB, PC | 240 mg of GBE once daily or placebo | 12 weeks | (300) |
Evaluate the effects of GBE on cognition and quality of life in patients with very mild cognitive impairment | GBE improved the cognitive ability and quality of life of patients | Grass-Kapanke, 2011 [ |
R, PC, DB, MC | 240 mg of GBE once daily or placebo | 24 weeks | (160) |
Test the effect of GBE on NPS and cognition in patients with MCI | GBE improved NPS and cognition; the extract was safe and well tolerated | Gavrilova et al., 2014 [ |
Patients with dementia | ||||||
R, DB, PC | 240 mg of GBE once daily | 22 weeks | (400) |
Test the efficacy of GBE on NPS of dementia | GBE statistically superior to placebo in ameliorating NPS (e.g., irritability, apathy, and anxiety) | Scripnikov et al., 2007 [ |
Systematic review | 240 mg of GBE once daily | 22 weeks | (1628) |
Demonstrate efficacy of GBE in dementia with BPSD | Improvements of quality of life, cognition, and BPSD activities of daily living clinical global impression | Von Gunten et al., 2016 [ |
Meta-analysis and systematic review | Different dosages of GBE | Not available | Demented patients | Test the efficacy of GBE in ameliorating symptoms of demented patients | GBE improved cognitive function and activities of everyday life in patients with dementia | Brondino et al., 2013 [ |
Meta-analysis of randomized placebo controlled trials | 120 mg or 240 mg of GBE per day or placebo | 22-26 weeks | (2684) |
Evaluate evidence for efficacy of GBE in dementia | Confirmation of efficacy of GBE and good tolerability | Gauthier and Schlaefke, 2014 [ |
Systematic review and meta-analysis of randomized controlled trials | 240 mg of GBE once daily | 22-26 weeks | (2561) |
Evaluate the clinical efficacy and adverse effects of GBE in dementia and cognitive decline | GBE was found more effective than placebo in decelerating cognition deficits and in improving daily life activities and NPS in dementia | Tan et al., 2015 [ |
Meta-analysis of randomized controlled clinical trials | 240 mg/day | 22 or 24 weeks | Old patients aged over 60 years | Effects of GBE on anxiety, dementia, and depression in aging patients | Improvements in dementia, anxiety, and depression | Kasper, 2015 [ |
Meta-analysis of randomized controlled trials | 240 mg of GBE once daily | 22 or 24 weeks | (1628) |
Test the effects of GBE on BPSD of demented patients | Significant superiority of GBE to placebo in improving BPSD and therefore caregiver experience | Savaskan et al., 2017 [ |
Bivariate meta-analysis | Different dosages of GBE | Approximately 6 months | Demented patients | Evaluate baseline risk on the treatment effect and assess the efficacy of GBE on cognitive symptoms of dementia | GBE was effective at improving cognitive functions in dementia after 6 months of treatment | Wang et al., 2010 [ |
R, DB, PC, PG, MC | 160 mg or 240 mg of GBE daily | 24 weeks | (214) |
To assess the efficacy of GBE in aged demented patients or patients with age-related memory loss | No beneficial effect of GBE for demented or age-related memory-impaired patients | Van Dongen, 2000 [ |
R, DB, PC, PG | 120 mg of GBE daily | 6 months | 176 mildly to moderately demented patients | Assess the efficacy and safety of GBE for treating dementia in early stages | GBE not beneficial in mild to moderate dementia after a 6-month treatment | McCarney et al., 2008 [ |
Cochrane analysis of R, DB, PC trials | Different GBE doses ranging from low to high | Different treatment periods | Aging with dementia or cognitive impairment | Assess the efficacy and safety of GBE in dementia and cognitive impairment | GBE displays unreliable and inconsistent evidence in being beneficial for demented people | Birks and Evans, 2009 [ |
Patients with AD and vascular dementia | ||||||
R, DB, PC | 120 mg of GBE, 60 mg of GBE, or placebo | 6 months | (90) |
Evaluate the efficacy and safety of GBE in vascular demented patients | GBE slowed down the cognitive deterioration in vascular demented patients, effect shown in only one of the four neuropsychological tests | Demarin et al., 2017 [ |
Review of R, PC | 120 mg of GBE twice daily or 240 mg of GBE once daily | 22 or 24 weeks | (1294) |
Test the efficacy of GBE in older patients with AD/vascular dementia with NPS | Confirmation of efficacy of GBE and good tolerability | Ihl, 2013 [ |
Systematic review and meta-analysis | GBE extract | 12-52 weeks | (2372) |
Evaluate the effects of GBE in AD and vascular and mixed dementias | Superiority of GBE to placebo in improving everyday life activities in mainly the AD type of dementia | Weinmann et al., 2010 [ |
Systematic review and meta-analysis | 240 mg and 120 mg of GBE daily | 24 weeks | Patients with MCI or AD | Assess the effectiveness and safety of GBE in treating MCI and AD | There is an indication for the beneficial effect of GBE in MCI and AD but the results were inconsistent | Yang et al., 2016 [ |
Systematic review of randomized controlled trials | 240 mg of GBE daily | Patients with mildly to moderately severe and severe AD | Assess the beneficial effect of GBE in AD | Evidence of beneficial effects of GBE in amelioration cognition, every day activities, and psychopathological symptoms but great heterogeneity among the results | Janssen et al., 2010 [ | |
Prevention | ||||||
R, DB, PC, PG | 120 mg of GBE twice daily | 5 years | Adults 70 years or older with occasional memory problems | Efficacy of long-term use of GBE for the prevention of AD in aging with memory complaints | GBE did not reduce the incidence of AD compared to placebo | GuidAge study, Vellas et al., 2012 [ |
R, DB, PC | 120 mg of GBE twice daily | Every 6 months from 2000 to 2008 | (3069) |
Test whether GBE delays or prevents global or domain-specific cognitive impairment in aging | GBE did not prevent cognitive decline in aging | Snitz et al., 2009 [ |
R, DB, PC | 120 mg of GBE twice daily | 5 years | (3000) |
Assess the ability of GBE in the prevention of dementia in normal aging or those with MCI | GBE does not prevent dementia | GEM study, DeKosky et al., 2006 [ |
Systematic review and meta-analysis | 240 mg of GBE daily | Not available | Nondemented patients aged 70 years or older | Evaluate the efficacy of GBE for the prevention of dementia in nondemented adults | GBE is not able to prevent the development of dementia | Charemboon and Jaisin, 2015 [ |
SMI, subjective memory impairment; MCI, mild cognitive impairments; AD, Alzheimer’s disease; VaD, vascular dementia; R, randomized; DB, double blind; PC, placebo controlled; MC, multicenter; PG, parallel group; BPSD, behavioural psychological symptoms; VCI: vascular cognitive impairment. The number of patients involved in the trials is indicated in parentheses.
Based on the included studies, GBE has been reported in only a few studies that show no effect. The majority of the recent studies demonstrated that the treatment with doses up to 240 mg/day was safe, well-tolerated, and efficacious against age-related disorders.
In summary, GBE has been proven more effective in patients with cognitive impairment at baseline than preventing the onset of cognitive impairment in healthy aged subjects. As mentioned before (see Introduction), mitochondrial dysfunction is more profound in cognitive disorders than in normal aging. Similarly, GBE shows increasing promising effects with increasing cognitive impairment. This, again, represents an indicator that GBE exerts its effects clinically by acting on mitochondria [
Resveratrol, known as a polyphenol from white hellebore (
In a study using A
Only eight clinical trials and four ongoing trials on resveratrol aim at evaluating the effects of this compound on cognitive function in humans [
Clinical trials on the effects of resveratrol. Ongoing trials are italicized.
Study design | Resveratrol dose/preparation | Duration | Subjects | Purpose | Main results | References |
---|---|---|---|---|---|---|
Young and aged healthy individuals | ||||||
R, DB, PC, CO | 21 days | (24) |
Ability to increase cerebral blood flow and modulate mental function | Increase in cerebral flow, no effect in cognitive function | Kennedy et al., 2010 [ | |
R, DB, PC, CO | 21 days | (23) |
Effect of piperine on the efficacy and bioavailability of resveratrol | Piperine enhances the effect of resveratrol on cerebral blood flow but no effect on bioavailability and cognition | Wightman et al., 2014 [ | |
Study in older adults | 200 mg of resveratrol per day | 26 weeks | (46) |
Test whether resveratrol would improve memory performance in older adults | Resveratrol ameliorates memory performance in combination with improved glucose metabolism and increased hippocampal functional connectivity in healthy overweight old people | Witte et al., 2014 [ |
Patients with cognitive decline and postmenopausal women | ||||||
R, DB, PC | 72 g of active grape formulation | 6 months | (10) Adults with mild cognitive decline with mean age of 72.2 years | Evaluate the effects of grapes on regional cerebral metabolism | Grapes could possess a protective effect against early pathologic metabolic decline | Lee et al., 2017 [ |
R, PC, intervention trial | 75 mg twice daily of |
14 weeks | (80) Postmenopausal women between 45 and 85 years old | Test the effects of resveratrol on cognition, mood, and cerebrovascular function in postmenopausal women | Resveratrol was well tolerated and able to improve cognition which was related to the improvement of cerebrovascular function. Mood was improved but not significantly. | Evans et al., 2017 [ |
Patients with MCI | ||||||
R, DB, interventional study | 200 mg of resveratrol per day | 26 weeks | (40) |
Assess if resveratrol improves long-term glucose control, resting-state functional connectivity of the hippocampus, and memory function in patients with MCI | Resveratrol supplementation decreased glycated hemoglobin A1c, preserved hippocampus volume, and improved hippocampus RSFC in patients with MCI | Koebe et al., 2017 [ |
R, DB |
Bioactive dietary polyphenol preparation (BDPP) at low, moderate, and high doses | 4 months | (48) |
Safety and efficacy in treating mild cognitive impairment | — | |
R, DB, PC |
Resveratrol or omega-3 supplementation or caloric restriction | 6 months | (330) |
Effects on brain function | — | |
Patients with mild to moderate AD | ||||||
R, DB, PC, MC |
Resveratrol 500 mg/day with escalation by 500 mg increments ending with 2 g/day | 52 weeks | (119) |
Assess efficacy and safety | No effect on cognitive score, decrease of CSF and plasma A |
Turner et al., 2015 [ |
R, DB, PC Phase 2 | Resveratrol 500 mg daily (orally) with a dose elevation by 500 mg every 13 weeks until a final dose of 1000 mg twice daily was reached for the final 13 weeks. | 52 weeks | (119) |
Evaluation of safety and tolerability of resveratrol and its effects on AD biomarkers and also on clinical outcomes | Resveratrol was well tolerated and safe, it was detected in the cerebrospinal fluid (nM), it changed the AD biomarker paths, it modified the CNS immune response, and it maintained the BBB integrity; however, more research is needed | |
R, DB, PC |
Longevinex brand resveratrol supplement (resveratrol 250 mg/day) | 52 weeks | (50) |
Effects on cognitive and global functioning | — | |
R, DB, PC |
Resveratrol with malate and glucose | 12 months | (27) |
Ability to slow the progression of AD | — |
MCI, mild cognitive impairment; AD, Alzheimer’s disease; R, randomized; DB, double blind; PC, placebo controlled; CO, cross over; MC, multicenter; CSF, cerebrospinal fluid. The number of patients involved in the trials is indicated in parentheses.
Clinical studies are underway to explore the beneficial effect of resveratrol on MCI. In the ongoing trials, one four-month resveratrol supplementation study in phase 1 aims at evaluating the efficacy and safety of bioactive dietary preparation (BDPP) at low, moderate, and high doses in treating mild cognitive impairment on 48 MCI subjects (55-85 years) [
On the basis of the results from the very few clinical trials in MCI and AD, no conclusion about the efficacy of resveratrol on cognition can be drawn at the current time, but promising trials are underway.
Neurosteroids offer therapeutic opportunities through their pleiotropic effects on the nervous system. They are a subcategory of steroids synthetized de novo from cholesterol in the central nervous system independently of supply by peripheral steroidogenic glands [
Neuroprotective effects of allopregnanolone (AP) in AD. AP has been proven to reduce A
Ongoing clinical trial on the effects of allopregnanolone in MCI and mild AD.
Study design | Allopregnanolone dose/preparation | Duration | Subjects | Purpose | Main results | References |
---|---|---|---|---|---|---|
R, DB, parallel assignment |
Allopregnanolone 2, 4, or 6 mg intravenous injection once per week or placebo intravenous injection once per week | 12 weeks | (8) For each dose group, 55 years and older, both genders |
Determine the maximally tolerated dose, safety and tolerability, pharmacokinetic profile, and effects on cognitive function | Not available | NCT02221622 [ |
The number of patients involved in the trials is indicated in parentheses.
The natural neurosteroid allopregnanolone appears to be a promising therapeutic tool with specific regard to its neurogenic properties besides its mitochondria-directed effects. However, more trials are urgently needed to prove that.
Phytoestrogens are the most bioactive molecules of soy and present structural similarity to the 17
Modulation of mitochondrial function by estrogen and phytoestrogen. Less evidence is provided for the direct effects of phytoestrogen on mitochondria compared to estrogen, but antioxidant properties were demonstrated.
Until today, no clinical trials in MCI and AD were performed. Thus, currently there is no clinical evidence.
Clinical trials on the effects of phytoestrogens.
Study design | Phytoestrogens dose/preparation | Duration | Subjects | Purpose | Main results | References |
---|---|---|---|---|---|---|
Healthy individuals and postmenopausal women | ||||||
Randomized control trial | High soya (100 mg total isoflavones/day) or a low soya (0.5 mg total isoflavones/day) diet | 10 weeks | (27) |
Effects on memory, attention, and frontal lobe function | Improvements in short-term memory, long-term memory and mental flexibility | File et al., 2015 [ |
DB, CO, PC | 4 capsules/day containing soya isoflavones (116 mg isoflavone equivalents/day: 68 mg daidzein, 12 mg genistein, and 36 mg glycitin) or placebo | 6 weeks | (34) |
Effects on cognitive function | Improvements of spatial working memory but no effect on auditory and episodic memory and executive function and visual-spatial processing | Thorp et al., 2009 [ |
18 |
Isoflavone supplementation 60 mg/day or placebo | 6 months | (78) |
Effects of soy isoflavones on mood and cognitive function in postmenopausal women | Improvements in mental flexibility, attention, mood, and lower depressive symptoms | Casini et al., 2006 [ |
R, DB, PC | 100 mg/day soy isoflavones (glycoside weight) or matching placebo tablets | 6 months | Older nondemented men and women (age 62-89 years) | Examination of safety, feasibility, and cognitive efficacy of soy isoflavone administration | Improvements of visual-spatial memory and construction of verbal fluency and speeded dexterity | Gleason et al., 2009 [ |
R, DB, PC | 20 g of soy protein containing 160 mg of total isoflavones | 12 weeks | (93) |
Effect of a high-dose isoflavones on cognition, quality of life, lipoproteins, and androgen status in postmenopausal women | Significant improvement in the quality of life versus placebo. No significant effects in cognition. The testosterone and HDL levels were significantly lower at the end of the study. | Basaria et al., 2009 [ |
The number of patients involved in the trials is indicated in parentheses.
Inconclusive findings have also been reported from randomized controlled trials and observational studies in humans. In fact, these discrepant data could have several possible reasons. Investigation in European cohorts showed that a low dietary consumption of phytoestrogens had a significant effect on the improvement of the quality of life but no effect on cognition [
Mediating variables in the characteristics of the study population such as gender, age, ethnicity, and menopausal status appears to play an important role [
Globally, the effects of phytoestrogens can be dependent upon a window of opportunity for treatment and can affect males differentially than females due to the diminished presence of ER-mediated protective mechanisms and the tyrosine kinase activity with a potentially deleterious outcome of the supplements [
In this article, the efficacy of standardized
Regarding clinical trials, there is a different level of evidence for the four phytochemicals. Standardized GBE, resveratrol, allopregnanolone, and phytoestrogens appear in a descending order according to the level of existing clinical evidence. According to the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines, GBE has been classified in category B and grade 3 in terms of the outcome of existing studies. Therefore, there is sufficient and good clinical evidence for the efficacy of GBE. There is increasing and promising clinical evidence for resveratrol, but more studies of larger sample size are definitively needed. Lastly, there are no clinical trials indicating the beneficial effect of allopregnanolone and phytoestrogen in age-related cognitive decline disorders. There is only promising evidence from preclinical data regarding allopregnanolone and phytoestrogen. Notably, the four entities follow the same descending order regarding the existing level of clinical evidence and their mitochondria-improving properties. All in all, the effect on mitochondria goes hand in hand with the clinical effect and this highlights one more time the importance of these organelles not only in the pathogenesis of AD but also in aging in general.
Estradiol
Catalytic subunit of protein phosphatase
Triple transgenic mouse model of AD
Alzheimer’s disease
Protein kinase B
5
Amyloid precursor protein
Adenosine triphosphate
beta-Amyloid protein
Apoptotic regulator
Blood-brain barrier
Anti-B-cell lymphoma 2
Brain-derived neurotrophic factor
Bioactive dietary preparation
Calcium
Cerebral metabolic rates of glucose
Cyclooxygenase-2
Cyclic AMP response element-binding protein
Cerebrospinal fluid
Untreated SH-SY5Y cells
Dopamine transporters
Estrogen
Endoplasmic reticulum
Estrogen replacement therapies
Electron transport chain
Familial Alzheimer’s disease
Forkhead box O
Glutathione peroxidase 1
Glycogen synthase kinase 3 beta
Human neural stem cells
Heme oxigenase 1
Transient potassium channel
Ibotenic acid
Inhibitory kappa B kinase
Inner mitochondrial membrane
Human neuroblastoma cells
Nitric oxide synthase
Janus kinases/extracellular signal-regulated kinases/signal transducers and activators of transcription
c-Jun N-terminal kinase
Liver-X-receptor
Mild cognitive impairment
Malondialdehyde
Mitochondrial membrane potential
Manganese superoxide dismutase
Mitochondrial permeability transition pore
Magnetic resonance imaging
Multitarget-directed ligands
Mitochondrial DNA
Nuclear factor kappa-light-chain-enhancer of activated B cells
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4
Neuropsychiatric symptoms
Nuclear factor erythroid 2-related factor 2
Nuclear receptors
Ovarectomized
Oxidative phosphorylation
Tumor protein
Cytochrome cholesterol side-chain cleavage enzyme
Platelet-activating factor-acetylhydrolase-1
Peroxisome proliferator-activated receptor
Pheochromocytoma cells
Pyruvate dehydrogenase
Protein kinase C delta
Peroxisome proliferator-activated receptor gamma
Synapse-associated protein
Pregnane xenobiotic receptor
Reactive nitrogen species
Reactive oxygen species
Resting-state functional connectivity
Sporadic Alzheimer’s disease
Senescence-accelerated mice
Subgranular zone
Human neuroblastoma cells
Sirtuin1
Subjective memory impairment
Superoxide dismutase
Superoxide dismutase 1
Tyrosine hydroxylase
Tumor necrosis factor alpha
Tropomyosin receptor kinase A
Tropomyosin receptor kinase B
The translocator protein
Tyrosyl tRNA synthetase-poly(ADP-ribose) polymerase 1
Vascular dementia
A terpene trilactone-enhanced GBE.
AE has served as a consultant or on advisory boards for Vifor Pharma and Schwabe.
With the relevance to this review, there is no direct conflict of interest to declare.
AE has received grant/research support from Schwabe and Vifor Pharma.