Natural Products from Plants and Algae for Treatment of Alzheimer’s Disease: A Review

Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet available. The recent approval of sodium oligomannate (GV-971) for AD treatment in China emphasized the potential value of natural products for the treatment of neurodegenerative disorders. Many current clinical studies include the administration of a natural compound as a single and combination treatment. The most prominent mechanisms of action are anti-inflammatory and anti-oxidative activities, thus preserving cellular survival. Here, we review current natural products that are either approved or are in testing for a treatment of neurodegeneration in AD. In addition to the most important compounds of plant origin, we also put special emphasis on compounds from algae, given their neuroprotective activity and their underlying mechanisms of neuroprotection.


Introduction
Neurodegenerative diseases are a group of disorders in which neuronal function and survival are seriously affected. Many of these diseases, including Parkinson's, Huntington's and Alzheimer's Disease (AD), are caused by structural changes and the deposition of proteins; therefore, they are also assigned to the group of protein misfolding diseases or amyloidoses [1][2][3]. AD is by far the most common cause of neurodegeneration and dementia. It is estimated that AD currently affects 55 million people worldwide (World-Alzheimer-Report-2021. Available online: https://www.alzint.org/u/World-Alzheimer-Report-2021.pdf, accessed on 4 February 2022). Characteristic symptoms of the disease are progressive memory loss, impaired cognitive function and paranoia. The histopathological hallmarks of AD, extracellular amyloid deposits ("amyloid plaques"), which mainly consist of the peptide Aβ, and intraneuronal neurofibrillary tangles of the hyperphosphorylated protein tau, mainly affect the cerebral cortex and the hippocampus [4,5]. Numerous studies suggest that the disease is initiated by the deposition of Aβ, which starts presumably years or decades before the first symptomatic changes [6]. The slow Aβ deposition triggers a downstream cascade (the amyloid cascade), which involves pathologic tau formation and hyperphosphorylation, widespread neuroinflammation and, finally, neuronal death [7,8]. Although the intense research during the last decades enabled a much better understanding of the crucial events in AD pathogenesis, a curative therapy that halts the progression of the disease is not yet available. Most of the so-called disease-modifying experimental drugs are targeting events of the amyloid cascade such as the generation and aggregation of Aβ and the phosphorylation of tau or the cellular metabolism and energy homeostasis [9]. The drug development in AD is faced with several challenges which has resulted in numerous setbacks in recent years [10]. For instance, the enzymes responsible for Aβ formation also have physiological substrates and functions. This complicates the suppression of amyloid peptide formation without interfering with other proteolytical degradation processes. Prominent examples are the γ-secretase complex and the β-secretase BACE1, which play a role in the formation of Aβ peptides [11][12][13]. Moreover, several reports suggest that Aβ1-40/42 and tau also have physiological functions, which leads one to question whether these represent druggable targets [14][15][16][17]. Also, many of the amyloidogenic proteins are localized in the cell nucleus or cytosol, which makes an effective suppression of the aggregation or the breakdown of the conglomerates, e.g., by antibodies, even more difficult [18]. Third, the efficient passage of the blood-brain barrier is needed and thus the pharmaceuticals are required to meet various physicochemical parameters [19,20]. Hence, methods are currently being examined (e.g., focused ultrasound) to make the blood-brain barrier more permeable [21].
Finally, major factors hampering the development and testing of new drugs are based on the clinical presentation of dementia and the currently available diagnostic biomarkers. AD patients frequently also show the presence of Lewy bodies and thus, significant pathological overlap with patients with dementia with Lewy bodies (DLB). As a result, the clinical testing of new active ingredients does not take place in "pure" Alzheimer's patient populations. Accordingly, attempts are being made (using imaging methods and genetic analyses, among others) to conduct clinical studies in narrowly defined patient populations at an early stage of the disease [22][23][24]. Previously, numerous approaches were therefore undertaken in patients with a possibly too advanced a disease stage [23,25]. In addition, the available diagnostic biomarkers often do not specifically reflect the neurodegenerative disease or provide enough correlation with the clinical status of the patients. These imponderables could be responsible for the failure of different therapeutic approaches in the clinical phase. As mentioned above, alterations in biomarkers precede the symptoms of the disease [6,26], i.e., the measured value of a biomarker cannot be directly correlated with an effect on cognition. An example of this is the antibody bapineuzumab, which caused a significant change in phospho-tau in CSF in phase 2, but missed clinical endpoints [27].
All of these factors finally led to the numerous failures of disease-modifying drugs in AD clinical trials. The very recent accelerated approval of Aducanumab to treat AD may thus represent a first sign of success. However, the complexity also triggered the intense investigations of other fields, such as drugs from natural sources and nutraceuticals (Table 1). One potential reason is that food supplements may have the status as being generally regarded as safe (GRAS) and thus can be quickly applied in clinical testing, and eventually in combination with experimental drugs. Most of these substances are addressing protective mechanisms to cells by, e.g., anti-oxidative effects. However, there are also compounds in testing which are dedicated to disease-modification by, for example, their influence on immune cells. A prominent example is represented by oligomannate from red algae, which obtained approval for AD therapy in China and is currently being tested in additional clinical trials. Due to the emerging role in clinical testing, this review focuses on the current treatment strategies which are based on natural products. We will review drugs which are currently approved but will put a special emphasis on natural products from algae.
This review is based on the personal databases and knowledge of the authors. The work was completed by a substantial amount of literature search using the databases PubMed, Google scholar and SciFinder. The database search was performed until end of February 2022. Only articles in which an active compound was isolated were considered. The date of publication was not an exclusion criterion. neuroinflammation modulators, microbiome modulators, amyloid beta-protein inhibitors; reconditioning the dysbiosis of gut microbiota, preventing peripheral immune cells from invading the brain, inhibiting the inflammatory response in the brain targeting protein folding errors in the brain tissue improve the cognitive function of patients with mild to moderate AD Recruiting NCT05058040 IV Sodium oligomannte capsules (GV-971) neuroinflammation modulators, microbiome modulators, amyloid beta-protein inhibitors; reconditioning the dysbiosis of gut microbiota, preventing peripheral immune cells from invading the brain, inhibiting the inflammatory response in the brain targeting protein folding errors in the brain tissue improve the cognitive function of patients with mild to moderate AD Recruiting NCT05181475 IV Ginkgo biloba metabolism and bioenergetics; plant extract with antioxidant properties Improve brain blood flow and mitochondrial function (cognitive enhancer) Recruiting NCT03090516 III Sodium oligomannate (GV-971) reconditioning the dysbiosis of gut microbiota, preventing peripheral immune cells from invading the brain, inhibiting the inflammatory response in the brain targeting protein folding errors in the brain tissue improve the cognitive function of patients with mild to moderate AD; evaluate safety, tolerability and efficacy of GV-971

Plant Natural Products with Antioxidant and Anti-Inflammatory Efficacy
Ginseng. Extracts of the rhizome of the plant Panax ginseng have been used in Asia for thousands of years to treat different diseases including neurological disorders [67].The extract of the plant has several active compounds, ginsenosides, ginseng polysaccharides, volatile oils, peptides and amino acids [68,69]. There are several ginsenosides identified as useful in the treatment of neurodegenerative disease such as AD, PD and HD. The ginsenoside Rb1, Rg1, Rg2, Rg3, Re and Rh2 and Gintonin showed a beneficial effect on AD symptomatology; Rg1, Re and Rd in PD and Ginseng total saponins and Ginsenosides in HD [70][71][72]. The ginsenosides are classified in two groups: the 20(S)-protopanaxadiol (PPD) group and the 20(S)-protopanaxtriol (PPT) group. Rb1, Rc, Rb2, Rd and Rg3 belong to the 20(S)-protopanaxadiol group, while Rg1, Re, Rg2 and Rh1 belong to the 20(S)-protopanaxtriol group [73]. The chemical structure of the ginsenosides is shown in Table 3. Ginsenosides prevent neuroinflammation and oxidative stress. They also have a positive influence on the brain function by apparently diverse mechanisms [74][75][76][77].
For instance, the ginsenoside Rb1 and Rg1 protects spinal cord neurons from oxidative stress induced by H2O2 and excitotoxicity induced by glutamate and kainic acid with an optimal dose of 20-40 µ M [67]. In an AD mouse model, Rg1 showed neuroprotective effects through improved cognition and amyloid pathology, modulation of the amyloid precursor protein process and activation of the hippocampal-dependent protein kinase/hippocampal-respond element-binding protein (PKA/CREB) signalling [78]. The Galanthus nivalis reversible, competitive AChE inhibitor, allosteric modulator of nicotinic acetylcholine receptors, modulates α4β2 and α7 nicotinic receptors [40][41][42][43] huperzine A and phenserine were synthesized to improve the short half-life and to prevent side effects.
Only phenserine was tested in clinical studies [66].

Plant Natural Products with Antioxidant and Anti-Inflammatory Efficacy
Ginseng. Extracts of the rhizome of the plant Panax ginseng have been used in Asia for thousands of years to treat different diseases including neurological disorders [67].The extract of the plant has several active compounds, ginsenosides, ginseng polysaccharides, volatile oils, peptides and amino acids [68,69]. There are several ginsenosides identified as useful in the treatment of neurodegenerative disease such as AD, PD and HD. The ginsenoside Rb1, Rg1, Rg2, Rg3, Re and Rh2 and Gintonin showed a beneficial effect on AD symptomatology; Rg1, Re and Rd in PD and Ginseng total saponins and Ginsenosides in HD [70][71][72]. The ginsenosides are classified in two groups: the 20(S)-protopanaxadiol (PPD) group and the 20(S)-protopanaxtriol (PPT) group. Rb1, Rc, Rb2, Rd and Rg3 belong to the 20(S)-protopanaxadiol group, while Rg1, Re, Rg2 and Rh1 belong to the 20(S)-protopanaxtriol group [73]. The chemical structure of the ginsenosides is shown in Table 3. Ginsenosides prevent neuroinflammation and oxidative stress. They also have a positive influence on the brain function by apparently diverse mechanisms [74][75][76][77].
For instance, the ginsenoside Rb1 and Rg1 protects spinal cord neurons from oxidative stress induced by H2O2 and excitotoxicity induced by glutamate and kainic acid with an optimal dose of 20-40 µ M [67]. In an AD mouse model, Rg1 showed neuroprotective effects through improved cognition and amyloid pathology, modulation of the amyloid precursor protein process and activation of the hippocampal-dependent protein kinase/hippocampal-respond element-binding protein (PKA/CREB) signalling [78]. The Huperzia serrata specific and reversible AChE inhibitor, protects cells against hydrogen peroxide, β-amyloid toxicity, glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis [45][46][47][48]51] physostigmine Biomolecules 2022, 12, x FOR PEER REVIEW 6 of 27 and phenserine were synthesized to improve the short half-life and to prevent side effects.
Only phenserine was tested in clinical studies [66].

Plant Natural Products with Antioxidant and Anti-Inflammatory Efficacy
Ginseng. Extracts of the rhizome of the plant Panax ginseng have been used in Asia for thousands of years to treat different diseases including neurological disorders [67].The extract of the plant has several active compounds, ginsenosides, ginseng polysaccharides, volatile oils, peptides and amino acids [68,69]. There are several ginsenosides identified as useful in the treatment of neurodegenerative disease such as AD, PD and HD. The ginsenoside Rb1, Rg1, Rg2, Rg3, Re and Rh2 and Gintonin showed a beneficial effect on AD symptomatology; Rg1, Re and Rd in PD and Ginseng total saponins and Ginsenosides in HD [70][71][72]. The ginsenosides are classified in two groups: the 20(S)-protopanaxadiol (PPD) group and the 20(S)-protopanaxtriol (PPT) group. Rb1, Rc, Rb2, Rd and Rg3 belong to the 20(S)-protopanaxadiol group, while Rg1, Re, Rg2 and Rh1 belong to the 20(S)-protopanaxtriol group [73]. The chemical structure of the ginsenosides is shown in Table 3. Ginsenosides prevent neuroinflammation and oxidative stress. They also have a positive influence on the brain function by apparently diverse mechanisms [74][75][76][77].
For instance, the ginsenoside Rb1 and Rg1 protects spinal cord neurons from oxidative stress induced by H2O2 and excitotoxicity induced by glutamate and kainic acid with an optimal dose of 20-40 µ M [67]. In an AD mouse model, Rg1 showed neuroprotective effects through improved cognition and amyloid pathology, modulation of the amyloid precursor protein process and activation of the hippocampal-dependent protein kinase/hippocampal-respond element-binding protein (PKA/CREB) signalling [78]. The

Physostigma venenosum, Streptomyces pseudogriseolus
AChE inhibitor [57] tolserine Biomolecules 2022, 12, x FOR PEER REVIEW 6 of 27 and phenserine were synthesized to improve the short half-life and to prevent side effects.
Only phenserine was tested in clinical studies [66].

Plant Natural Products with Antioxidant and Anti-Inflammatory Efficacy
Ginseng. Extracts of the rhizome of the plant Panax ginseng have been used in Asia for thousands of years to treat different diseases including neurological disorders [67].The extract of the plant has several active compounds, ginsenosides, ginseng polysaccharides, volatile oils, peptides and amino acids [68,69]. There are several ginsenosides identified as useful in the treatment of neurodegenerative disease such as AD, PD and HD. The ginsenoside Rb1, Rg1, Rg2, Rg3, Re and Rh2 and Gintonin showed a beneficial effect on AD symptomatology; Rg1, Re and Rd in PD and Ginseng total saponins and Ginsenosides in HD [70][71][72]. The ginsenosides are classified in two groups: the 20(S)-protopanaxadiol (PPD) group and the 20(S)-protopanaxtriol (PPT) group. Rb1, Rc, Rb2, Rd and Rg3 belong to the 20(S)-protopanaxadiol group, while Rg1, Re, Rg2 and Rh1 belong to the 20(S)-protopanaxtriol group [73]. The chemical structure of the ginsenosides is shown in Table 3. Ginsenosides prevent neuroinflammation and oxidative stress. They also have a positive influence on the brain function by apparently diverse mechanisms [74][75][76][77].
For instance, the ginsenoside Rb1 and Rg1 protects spinal cord neurons from oxidative stress induced by H2O2 and excitotoxicity induced by glutamate and kainic acid with an optimal dose of 20-40 µ M [67]. In an AD mouse model, Rg1 showed neuroprotective effects through improved cognition and amyloid pathology, modulation of the amyloid precursor protein process and activation of the hippocampal-dependent protein kinase/hippocampal-respond element-binding protein (PKA/CREB) signalling [78]. The

Physostigmine derivative
AChE inhibitor [66] eseroline Biomolecules 2022, 12, x FOR PEER REVIEW 6 of 27 and phenserine were synthesized to improve the short half-life and to prevent side effects.
Only phenserine was tested in clinical studies [66].

Plant Natural Products with Antioxidant and Anti-Inflammatory Efficacy
Ginseng. Extracts of the rhizome of the plant Panax ginseng have been used in Asia for thousands of years to treat different diseases including neurological disorders [67].The extract of the plant has several active compounds, ginsenosides, ginseng polysaccharides, volatile oils, peptides and amino acids [68,69]. There are several ginsenosides identified as useful in the treatment of neurodegenerative disease such as AD, PD and HD. The ginsenoside Rb1, Rg1, Rg2, Rg3, Re and Rh2 and Gintonin showed a beneficial effect on AD symptomatology; Rg1, Re and Rd in PD and Ginseng total saponins and Ginsenosides in HD [70][71][72]. The ginsenosides are classified in two groups: the 20(S)-protopanaxadiol (PPD) group and the 20(S)-protopanaxtriol (PPT) group. Rb1, Rc, Rb2, Rd and Rg3 belong to the 20(S)-protopanaxadiol group, while Rg1, Re, Rg2 and Rh1 belong to the 20(S)-protopanaxtriol group [73]. The chemical structure of the ginsenosides is shown in Table 3. Ginsenosides prevent neuroinflammation and oxidative stress. They also have a positive influence on the brain function by apparently diverse mechanisms [74][75][76][77].
For instance, the ginsenoside Rb1 and Rg1 protects spinal cord neurons from oxidative stress induced by H2O2 and excitotoxicity induced by glutamate and kainic acid with an optimal dose of 20-40 µ M [67]. In an AD mouse model, Rg1 showed neuroprotective effects through improved cognition and amyloid pathology, modulation of the amyloid precursor protein process and activation of the hippocampal-dependent protein kinase/hippocampal-respond element-binding protein (PKA/CREB) signalling [78]. The

Physostigmine derivative
AChE inhibitor [66] phenserine Biomolecules 2022, 12, x FOR PEER REVIEW 6 of 27 and phenserine were synthesized to improve the short half-life and to prevent side effects.
Only phenserine was tested in clinical studies [66].

Plant Natural Products with Antioxidant and Anti-Inflammatory Efficacy
Ginseng. Extracts of the rhizome of the plant Panax ginseng have been used in Asia for thousands of years to treat different diseases including neurological disorders [67].The extract of the plant has several active compounds, ginsenosides, ginseng polysaccharides, volatile oils, peptides and amino acids [68,69]. There are several ginsenosides identified as useful in the treatment of neurodegenerative disease such as AD, PD and HD. The ginsenoside Rb1, Rg1, Rg2, Rg3, Re and Rh2 and Gintonin showed a beneficial effect on AD symptomatology; Rg1, Re and Rd in PD and Ginseng total saponins and Ginsenosides in HD [70][71][72]. The ginsenosides are classified in two groups: the 20(S)-protopanaxadiol (PPD) group and the 20(S)-protopanaxtriol (PPT) group. Rb1, Rc, Rb2, Rd and Rg3 belong to the 20(S)-protopanaxadiol group, while Rg1, Re, Rg2 and Rh1 belong to the 20(S)-protopanaxtriol group [73]. The chemical structure of the ginsenosides is shown in Table 3. Ginsenosides prevent neuroinflammation and oxidative stress. They also have a positive influence on the brain function by apparently diverse mechanisms [74][75][76][77].
For instance, the ginsenoside Rb1 and Rg1 protects spinal cord neurons from oxidative stress induced by H2O2 and excitotoxicity induced by glutamate and kainic acid with an optimal dose of 20-40 µ M [67]. In an AD mouse model, Rg1 showed neuroprotective effects through improved cognition and amyloid pathology, modulation of the amyloid precursor protein process and activation of the hippocampal-dependent protein kinase/hippocampal-respond element-binding protein (PKA/CREB) signalling [78]. The

Physostigmine derivative
AChE inhibitor [66] 2.2. Plant Natural Products with Antioxidant and Anti-Inflammatory Efficacy Ginseng. Extracts of the rhizome of the plant Panax ginseng have been used in Asia for thousands of years to treat different diseases including neurological disorders [67].The extract of the plant has several active compounds, ginsenosides, ginseng polysaccharides, volatile oils, peptides and amino acids [68,69]. There are several ginsenosides identified as useful in the treatment of neurodegenerative disease such as AD, PD and HD. The ginsenoside Rb1, Rg1, Rg2, Rg3, Re and Rh2 and Gintonin showed a beneficial effect on AD symptomatology; Rg1, Re and Rd in PD and Ginseng total saponins and Ginsenosides in HD [70][71][72]. The ginsenosides are classified in two groups: the 20(S)-protopanaxadiol (PPD) group and the 20(S)-protopanaxtriol (PPT) group. Rb1, Rc, Rb2, Rd and Rg3 belong to the 20(S)-protopanaxadiol group, while Rg1, Re, Rg2 and Rh1 belong to the 20(S)protopanaxtriol group [73]. The chemical structure of the ginsenosides is shown in Table 3. Ginsenosides prevent neuroinflammation and oxidative stress. They also have a positive influence on the brain function by apparently diverse mechanisms [74][75][76][77].
For instance, the ginsenoside Rb1 and Rg1 protects spinal cord neurons from oxidative stress induced by H 2 O 2 and excitotoxicity induced by glutamate and kainic acid with an optimal dose of 20-40 µM [67]. In an AD mouse model, Rg1 showed neuroprotective effects through improved cognition and amyloid pathology, modulation of the amyloid precursor protein process and activation of the hippocampal-dependent protein kinase/hippocampal- respond element-binding protein (PKA/CREB) signalling [78]. The ginsenoside Rb1 has several neuroprotective effects. It promotes neural growth, the expression of growthpromoting kinases and helps prevent their levels from decreasing and has played the role of an antiapoptotic agent after Aβ-induced apoptosis in an AD cell model [79,80]. Furthermore, Rb1 seemed to protect the brain from Aluminium-induced toxicity. It reversed the glycogen synthase kinase 3β and the protein phosphates level and thereby reduced tau phosphorylation [81]. Table 3. Chemical structures of ginsenosides [82].

Structure
Ginsenoside R1 R2 R3 Biomolecules 2022, 12, x FOR PEER REVIEW 7 of 27 ginsenoside Rb1 has several neuroprotective effects. It promotes neural growth, the expression of growth-promoting kinases and helps prevent their levels from decreasing and has played the role of an antiapoptotic agent after Aβ-induced apoptosis in an AD cell model [79,80]. Furthermore, Rb1 seemed to protect the brain from Aluminium-induced toxicity. It reversed the glycogen synthase kinase 3β and the protein phosphates level and thereby reduced tau phosphorylation [81]. Table 3. Chemical structures of ginsenosides [82].
Ginkgo biloba. Ginkgo biloba is the oldest living tree species in the world. The standardized Ginkgo biloba extract (GBE) from the dried leaves has neuroprotective effects and is used for the treatment of memory impairment and dementia [83,84]. GBE contains 6% terpenoids, 24% flavonoid glycosides and 5-10% organic acids [85]. The terpenoids include the ginkgolides A, B, C and J (Table 4). Flavonoids and terpenoids are considered to be the pharmacologically active compounds of GBE [86,87]. GBE was shown to reduce the expression of transgenic human amyloid precursor protein expression in mouse brain [88] and to compensate for changes in brain glucose metabolism induced by streptozotocin treatment in rat brain [89].
There are several studies showing a positive effect of GBE on the cognitive function in elderly and AD patients [90][91][92][93]. However, other studies did not show a significant effect in the prevention or treatment of mild cognitive impairment [94,95]. The contradicting outcomes of the studies may be caused by differing compositions of the GBE. The chemical composition depends on the growth conditions and the preparation of the GBE, which highlights the importance to define the composition of drugs derived from natural sources. Table 4. Chemical structures of ginkgolides [86,87] from GBE extracts. GBE has been described to reduce APP expression and to improve cognitive function [88,[90][91][92][93].

Name
Structure Name Structure Ginkgo biloba. Ginkgo biloba is the oldest living tree species in the world. The standardized Ginkgo biloba extract (GBE) from the dried leaves has neuroprotective effects and is used for the treatment of memory impairment and dementia [83,84]. GBE contains 6% terpenoids, 24% flavonoid glycosides and 5-10% organic acids [85]. The terpenoids include the ginkgolides A, B, C and J (Table 4). Flavonoids and terpenoids are considered to be the pharmacologically active compounds of GBE [86,87]. GBE was shown to reduce the expression of transgenic human amyloid precursor protein expression in mouse brain [88] and to compensate for changes in brain glucose metabolism induced by streptozotocin treatment in rat brain [89].
There are several studies showing a positive effect of GBE on the cognitive function in elderly and AD patients [90][91][92][93]. However, other studies did not show a significant effect in the prevention or treatment of mild cognitive impairment [94,95]. The contradicting outcomes of the studies may be caused by differing compositions of the GBE. The chemical composition depends on the growth conditions and the preparation of the GBE, which highlights the importance to define the composition of drugs derived from natural sources. Table 4. Chemical structures of ginkgolides [86,87] from GBE extracts. GBE has been described to reduce APP expression and to improve cognitive function [88,[90][91][92][93].

Name
Structure Name Structure ginkgolide A treatment in rat brain [89]. There are several studies showing a positive effect of GBE on the cognitive fun elderly and AD patients [90][91][92][93]. However, other studies did not show a significant the prevention or treatment of mild cognitive impairment [94,95]. The contradict comes of the studies may be caused by differing compositions of the GBE. The c composition depends on the growth conditions and the preparation of the GBE, whi lights the importance to define the composition of drugs derived from natural sour Table 4. Chemical structures of ginkgolides [86,87] from GBE extracts. GBE has been des reduce APP expression and to improve cognitive function [88,[90][91][92][93].

Name
Structure Name Structure treatment in rat brain [89]. There are several studies showing a positive effect of GBE on the cognitive function in elderly and AD patients [90][91][92][93]. However, other studies did not show a significant effect in the prevention or treatment of mild cognitive impairment [94,95]. The contradicting outcomes of the studies may be caused by differing compositions of the GBE. The chemical composition depends on the growth conditions and the preparation of the GBE, which highlights the importance to define the composition of drugs derived from natural sources. Table 4. Chemical structures of ginkgolides [86,87] from GBE extracts. GBE has been described to reduce APP expression and to improve cognitive function [88,[90][91][92][93].

Others
Curcumin is extracted from the rhizome of the Curcuma species. It is the main com of the curcuminoids and has shown antioxidant and anti-inflammatory properties [96] rological disorders, curcumin decreased inflammation and ROS. Combined with yoga, curcumin should improve memory and cognitive function (NCT01811381, Tabl The main active compounds in elderberry juice, grape powder and Meganat grape seed extract are anthocyanins. Anthocyanins have anti-inflammatory and dative properties. In animal models of AD, a neuroprotective activity was observ thocyanins extracted from black soybeans reversed D-galactose-, lipopolysaccha Aβ1-42-induced oxidative stress and reduced the ROS level [97][98][99][100]. Other antho inhibited the Aβ-and oxidative stress-induced GSK-3β hyperactivation and hyp phorylation of tau protein [101]. Omega-3 poly unsaturated fatty acids (PUFAs) are known to reduce inflammat vascular risk factors. They decrease cell adhesion molecules which could be rel cerebral small vessel disease [102]. Cerebral small vessel disease influences the acc tion of white matter hyperintensities that results in cognitive decline [103]. Also, m lites showed neuroprotective properties. The ethyl ester icosapent ethyl from Eico taenoic acid (EPA), an omega-3 PUFA, improves the synaptic function and redu flammation (Table 5).
Rapamycin is a macrolide compound from the bacteria Streptomyces hygrosco inhibits the T and B cell proliferation and was therefore approved by the US Fo Drug Administration (FDA) to suppress the immune system after organ transpla [104][105][106]. Rapamycin has been shown to reduce Aβ deposition and pathogenic ta phorylation to improve synaptic plasticity and to decrease neuroinflammation in models [107][108][109][110][111][112][113].
Cannabinoids from THC-free cannabidiol (CBD) oil target the behavioural an chological symptoms of dementia. The cannabinoid CBD may act via different nisms (Table 5). Several studies suggest that it may protect against Aβ-induced a croglia-activated neurotoxicity in vitro, prevent hippocampal and cortical neurod ation, reduce tau hyperphosphorylation and regulate microglial cell migration [11 Furthermore, CBD showed anti-inflammatory and antioxidant activities [119]. T inflammatory properties may result from the decrease of inducible nitric oxide sy (iNOS) and interleukin-1β protein expression [120]. The anti-inflammatory and ne tective properties were investigated in a rat model [121].
Yangxue qingnao is a traditional Chinese medicine composed of 11 differen [122]. It is used to improve the cerebral blood flow and thereby the brain nourishm a mouse model of AD, Yangxue qingnao pills improved cognitive deficits and r Aβ deposition [122]. They possibly promote the expression of α-secretase and ther non-amyloidogenic processing of APP [122].

Others
Curcumin is extracted from the rhizome of the Curcuma species. It is the main compound of the curcuminoids and has shown antioxidant and anti-inflammatory properties [96]. In neurological disorders, curcumin decreased inflammation and ROS. Combined with aerobic yoga, curcumin should improve memory and cognitive function (NCT01811381, Table 1).
The main active compounds in elderberry juice, grape powder and Meganatural-Az grape seed extract are anthocyanins. Anthocyanins have anti-inflammatory and antioxidative properties. In animal models of AD, a neuroprotective activity was observed: anthocyanins extracted from black soybeans reversed D-galactose-, lipopolysaccharide-or Aβ1-42-induced oxidative stress and reduced the ROS level [97][98][99][100]. Other anthocyanins inhibited the Aβ-and oxidative stress-induced GSK-3β hyperactivation and hyperphosphorylation of tau protein [101].
Omega-3 poly unsaturated fatty acids (PUFAs) are known to reduce inflammation and vascular risk factors. They decrease cell adhesion molecules which could be related to cerebral small vessel disease [102]. Cerebral small vessel disease influences the accumulation of white matter hyperintensities that results in cognitive decline [103]. Also, metabolites showed neuroprotective properties. The ethyl ester icosapent ethyl from Eicosapentaenoic acid (EPA), an omega-3 PUFA, improves the synaptic function and reduces inflammation (Table 5).
Rapamycin is a macrolide compound from the bacteria Streptomyces hygroscopicus. It inhibits the T and B cell proliferation and was therefore approved by the US Food and Drug Administration (FDA) to suppress the immune system after organ transplantation [104][105][106]. Rapamycin has been shown to reduce Aβ deposition and pathogenic tau phosphorylation to improve synaptic plasticity and to decrease neuroinflammation in mouse models [107][108][109][110][111][112][113].
Cannabinoids from THC-free cannabidiol (CBD) oil target the behavioural and psychological symptoms of dementia. The cannabinoid CBD may act via different mechanisms (Table 5). Several studies suggest that it may protect against Aβ-induced and microglia-activated neurotoxicity in vitro, prevent hippocampal and cortical neurodegeneration, reduce tau hyperphosphorylation and regulate microglial cell migration [114][115][116][117][118]. Furthermore, CBD showed anti-inflammatory and antioxidant activities [119]. The antiinflammatory properties may result from the decrease of inducible nitric oxide synthase (iNOS) and interleukin-1β protein expression [120]. The anti-inflammatory and neuroprotective properties were investigated in a rat model [121].
Yangxue qingnao is a traditional Chinese medicine composed of 11 different herbs [122]. It is used to improve the cerebral blood flow and thereby the brain nourishment. In a mouse model of AD, Yangxue qingnao pills improved cognitive deficits and reduced Aβ deposition [122]. They possibly promote the expression of α-secretase and thereby the non-amyloidogenic processing of APP [122].

Others
Curcumin is extracted from the rhizome of the Curcuma species. It is the main compound of the curcuminoids and has shown antioxidant and anti-inflammatory properties [96]. In neurological disorders, curcumin decreased inflammation and ROS. Combined with aerobic yoga, curcumin should improve memory and cognitive function (NCT01811381, Table 1).
The main active compounds in elderberry juice, grape powder and Meganatural-Az grape seed extract are anthocyanins. Anthocyanins have anti-inflammatory and antioxidative properties. In animal models of AD, a neuroprotective activity was observed: anthocyanins extracted from black soybeans reversed D-galactose-, lipopolysaccharide-or Aβ 1-42 -induced oxidative stress and reduced the ROS level [97][98][99][100]. Other anthocyanins inhibited the Aβ-and oxidative stress-induced GSK-3β hyperactivation and hyperphosphorylation of tau protein [101].
Omega-3 poly unsaturated fatty acids (PUFAs) are known to reduce inflammation and vascular risk factors. They decrease cell adhesion molecules which could be related to cerebral small vessel disease [102]. Cerebral small vessel disease influences the accumulation of white matter hyperintensities that results in cognitive decline [103]. Also, metabolites showed neuroprotective properties. The ethyl ester icosapent ethyl from Eicosapentaenoic acid (EPA), an omega-3 PUFA, improves the synaptic function and reduces inflammation ( Table 5).
Rapamycin is a macrolide compound from the bacteria Streptomyces hygroscopicus. It inhibits the T and B cell proliferation and was therefore approved by the US Food and Drug Administration (FDA) to suppress the immune system after organ transplantation [104][105][106]. Rapamycin has been shown to reduce Aβ deposition and pathogenic tau phosphorylation to improve synaptic plasticity and to decrease neuroinflammation in mouse models [107][108][109][110][111][112][113].

Carbohydrates
Sodium oligomannate is a mixture of oligosaccharides obtained by the depolymerization of alginate from marine brown algae, followed by its oxidation to oligosaccharides [123,124] (Table 6). In November 2019, it was conditionally approved for the treatment of mild to moderate AD in China [125]. The patients treated with sodium oligomannate showed significant improvement in ADAS-cog12 score compared to the placebo group in a phase II study, whereby the treated group did not show significantly more adverse reactions than the placebo group [126]. The mechanism of action is not completely understood. Studies in mice suggest that oligomannate might act via decreasing neuroinflammation by remodeling gut microbiota and balancing the amino acid metabolism, especially phenylalanine and isoleucine [124].
For other carbohydrates from algae, little or no data are available from in vivo studies. In general, the available data support the mainly anti-oxidative and anti-inflammatory properties of these compounds. Many of these carbohydrates are sulphated and thus strongly negatively charged compounds. Carbohydrates stabilize the cell structure and are involved in ion exchange mechanisms [127,128]. Sulphated polysaccharides from Porphyra haitanesis exhibited antioxidant activity and inhibited lipid peroxidation in rat liver microsomes [129]. The sulphated carbohydrate porphyran from Porphyra yezoensis showed superoxide anion and hydroxyl radical scavenging activity [130]. Sulphated oligosaccharides from the two green algae Ulva lactuca and Enteromorpha prolifera increased concentrations of glutathione, superoxide dismutase (SOD) and catalase (CAT) [131].

Carbohydrates
Sodium oligomannate is a mixture of oligosaccharides obtained by the depolymerization of alginate from marine brown algae, followed by its oxidation to oligosaccharides [123,124] (Table 6). In November 2019, it was conditionally approved for the treatment of mild to moderate AD in China [125]. The patients treated with sodium oligomannate showed significant improvement in ADAS-cog12 score compared to the placebo group in a phase II study, whereby the treated group did not show significantly more adverse reactions than the placebo group [126]. The mechanism of action is not completely understood. Studies in mice suggest that oligomannate might act via decreasing neuroinflammation by remodeling gut microbiota and balancing the amino acid metabolism, especially phenylalanine and isoleucine [124].
For other carbohydrates from algae, little or no data are available from in vivo studies. In general, the available data support the mainly anti-oxidative and anti-inflammatory properties of these compounds. Many of these carbohydrates are sulphated and thus strongly negatively charged compounds. Carbohydrates stabilize the cell structure and are involved in ion exchange mechanisms [127,128]. Sulphated polysaccharides from Porphyra haitanesis exhibited antioxidant activity and inhibited lipid peroxidation in rat liver microsomes [129]. The sulphated carbohydrate porphyran from Porphyra yezoensis showed superoxide anion and hydroxyl radical scavenging activity [130]. Sulphated oligosaccharides from the two green algae Ulva lactuca and Enteromorpha prolifera increased concentrations of glutathione, superoxide dismutase (SOD) and catalase (CAT) [131].

Carbohydrates
Sodium oligomannate is a mixture of oligosaccharides obtained by the depolymerization of alginate from marine brown algae, followed by its oxidation to oligosaccharides [123,124] (Table 6). In November 2019, it was conditionally approved for the treatment of mild to moderate AD in China [125]. The patients treated with sodium oligomannate showed significant improvement in ADAS-cog12 score compared to the placebo group in a phase II study, whereby the treated group did not show significantly more adverse reactions than the placebo group [126]. The mechanism of action is not completely understood. Studies in mice suggest that oligomannate might act via decreasing neuroinflammation by remodeling gut microbiota and balancing the amino acid metabolism, especially phenylalanine and isoleucine [124].
For other carbohydrates from algae, little or no data are available from in vivo studies. In general, the available data support the mainly anti-oxidative and anti-inflammatory properties of these compounds. Many of these carbohydrates are sulphated and thus strongly negatively charged compounds. Carbohydrates stabilize the cell structure and are involved in ion exchange mechanisms [127,128]. Sulphated polysaccharides from Porphyra haitanesis exhibited antioxidant activity and inhibited lipid peroxidation in rat liver microsomes [129]. The sulphated carbohydrate porphyran from Porphyra yezoensis showed superoxide anion and hydroxyl radical scavenging activity [130]. Sulphated oligosaccharides from the two green algae Ulva lactuca and Enteromorpha prolifera increased concentrations of glutathione, superoxide dismutase (SOD) and catalase (CAT) [131].

Carbohydrates
Sodium oligomannate is a mixture of oligosaccharides obtained by the depolymerization of alginate from marine brown algae, followed by its oxidation to oligosaccharides [123,124] (Table 6). In November 2019, it was conditionally approved for the treatment of mild to moderate AD in China [125]. The patients treated with sodium oligomannate showed significant improvement in ADAS-cog12 score compared to the placebo group in a phase II study, whereby the treated group did not show significantly more adverse reactions than the placebo group [126]. The mechanism of action is not completely understood. Studies in mice suggest that oligomannate might act via decreasing neuroinflammation by remodeling gut microbiota and balancing the amino acid metabolism, especially phenylalanine and isoleucine [124].
For other carbohydrates from algae, little or no data are available from in vivo studies. In general, the available data support the mainly anti-oxidative and anti-inflammatory properties of these compounds. Many of these carbohydrates are sulphated and thus strongly negatively charged compounds. Carbohydrates stabilize the cell structure and are involved in ion exchange mechanisms [127,128]. Sulphated polysaccharides from Porphyra haitanesis exhibited antioxidant activity and inhibited lipid peroxidation in rat liver microsomes [129]. The sulphated carbohydrate porphyran from Porphyra yezoensis showed superoxide anion and hydroxyl radical scavenging activity [130]. Sulphated oligosaccharides from the two green algae Ulva lactuca and Enteromorpha prolifera increased concentrations of glutathione, superoxide dismutase (SOD) and catalase (CAT) [131]. may protects against Aβ-induced and microglia-activated neurotoxicity in vitro, prevents hippocampal and cortical neurodegeneration, reduces tau hyperphosphorylation, regulates microglial cell migration, anti-inflammatory, antioxidant [114][115][116][117][118][119][120][121] Yangxue qingnao is a traditional Chinese medicine composed of 11 different herbs [122]. It is used to improve the cerebral blood flow and thereby the brain nourishment. In a mouse model of AD, Yangxue qingnao pills improved cognitive deficits and reduced Aβ deposition [122]. They possibly promote the expression of α-secretase and thereby the non-amyloidogenic processing of APP [122].

Carbohydrates
Sodium oligomannate is a mixture of oligosaccharides obtained by the depolymerization of alginate from marine brown algae, followed by its oxidation to oligosaccharides [123,124] (Table 6). In November 2019, it was conditionally approved for the treatment of mild to moderate AD in China [125]. The patients treated with sodium oligomannate showed significant improvement in ADAS-cog12 score compared to the placebo group in a phase II study, whereby the treated group did not show significantly more adverse reactions than the placebo group [126]. The mechanism of action is not completely understood. Studies in mice suggest that oligomannate might act via decreasing neuroinflammation by remodeling gut microbiota and balancing the amino acid metabolism, especially phenylalanine and isoleucine [124].
For other carbohydrates from algae, little or no data are available from in vivo studies. In general, the available data support the mainly anti-oxidative and anti-inflammatory properties of these compounds. Many of these carbohydrates are sulphated and thus strongly negatively charged compounds. Carbohydrates stabilize the cell structure and are involved in ion exchange mechanisms [127,128]. Sulphated polysaccharides from Porphyra haitanesis exhibited antioxidant activity and inhibited lipid peroxidation in rat liver microsomes [129]. The sulphated carbohydrate porphyran from Porphyra yezoensis showed superoxide anion and hydroxyl radical scavenging activity [130]. Sulphated oligosaccharides from the two green algae Ulva lactuca and Enteromorpha prolifera increased concentrations of glutathione, superoxide dismutase (SOD) and catalase (CAT) [131].
Seleno-polymannuronate is a seleno-derivate from polymannuronate which was synthesized from polymannuronate and Na 2 SO 3 [136]. Polymannuronate is extracted from edible brown algae. Seleno-polymannuronate decreased the production of NO and PGE2 and the expression of COX-2 and iNOS in LPS-treated primary microglia and astrocytes. Sulphated oligosaccharides from the two green algae Ulva lactuca and Enteromorpha prolifera reduced the levels of IL-6, TNF-α and IFN-γ [131]. κ-Carrageenan oligosaccharides and desulphated derivatives inhibited TNF-α secretion in LPS-activated microglia [137].

Lipids and Proteins
Besides oligosaccharides, lipids have also been described as potential natural products originating from algae that have neuroprotective properties. Hielscher-Michael at al. showed that sulfolipids, membrane components of the thylakoid membrane of microalgae, inhibit the enzyme glutaminyl cyclase (QC). QCs are involved in the formation of pyroglutamate (pGlu)-modified Aβ peptides, whose formation is related to AD pathology [138][139][140]. QC activity is also related to other disorders such as arthritis [141]. QCs catalyse the intramolecular cyclization of N-terminal L-glutamine and glutamate residues into pyroglutamic acid. The modified Aβ peptides are no longer degradable by aminopeptidase and accumulate in the brain. Hence, the inhibition of QC is a potential strategy for the treatment of AD [142]. Hielscher-Michael et al. discovered that 22 methanolic extracts with a concentration of 0.2 mg/mL from the algae Scenedesmus rubescens, Scenedesmus producto-capitatus, Scenedesmus accuminatus, Scenedesmus pectinatus, Tetradesmus wisconsinensis and Eustigmatos magnus showed QC inhibitory activity between 15% to 72% [143].  (Table 7) [143]. Table 6. Chemical structures and neuroprotective characteristics of carbohydrates from algae.

Name
Structure Source Characteristics Ref.

Phenols
The bioactive and neuroprotective polyphenols have been typically isolated from brown algae. Typically, they interfere with several signal transduction pathways or function as enzyme inhibitors (Table 8). For instance, eckol, dieckol and 8,8′-bieckol from Ecklonia cava showed anti-inflammatory properties in Aβ25-35-stimulated PC12 cells by inhibition of TNF-α, IL-1β and PGE2 synthesis [147]. These phlorotannins further downregulated the proinflammatory enzymes iNOS and COX-2 by interference with the NF-κB pathway [147]. Dieckol suppressed p38, ERK and JNK, while eckol suppressed the activation of p38 and 8,8′-bieckol decreased the phosphorylation of p38 and JNK [147]. In another experiment, dieckol from Ecklonia cava suppressed the production of NO and PGE2 and the expression of iNOS and COX-2 in LPS-stimulated murine BV2 microglia. The re-Lyngbya sp.

Phenols
The bioactive and neuroprotective polyphenols have been typically isolated from brown algae. Typically, they interfere with several signal transduction pathways or function as enzyme inhibitors (Table 8). For instance, eckol, dieckol and 8,8 -bieckol from Ecklonia cava showed anti-inflammatory properties in Aβ25-35-stimulated PC12 cells by inhibition of TNF-α, IL-1β and PGE2 synthesis [147]. These phlorotannins further downregulated the proinflammatory enzymes iNOS and COX-2 by interference with the NF-κB pathway [147]. Dieckol suppressed p38, ERK and JNK, while eckol suppressed the activation of p38 and 8,8 -bieckol decreased the phosphorylation of p38 and JNK [147]. In another experiment, dieckol from Ecklonia cava suppressed the production of NO and PGE2 and the expression of iNOS and COX-2 in LPS-stimulated murine BV2 microglia. The reduction of IL-1β, TNF-α, NFκB, p38 and ROS was also shown before by others [148]. Antioxidant properties were also observed with diphlorethohydroxycarmalol and 6,6 -bieckol isolated from Ishige okamurae [149,150].

Name
Structure Source Characteristics Ref.

Name
Structure Source Characteristics Ref.

Name
Structure Source Characteristics Ref.

Isoprenoids
Similar to polyphenols, the neuroprotective effect of isoprenoids such as sterols and xanthin derivatives is primarily based on their anti-oxidative radical scavenging and antiinflammatory properties (Table 9). Numerous studies have been published addressing the antioxidative activity in different, mostly cellular model systems. For instance, the steroid fucosterol extracted from Pelvetia siliquosa increased the level of antioxidant enzymes SOD, GPx and CAT and inhibited ROS production [152,168]. It also provided protection from oxidative damage by raising the GSH level and attenuated of the production of iNOS, TNF-α and IL-6, and the phosphorylation of NF-κB, MKK3/6 and MK2 was shown [169][170][171]. Fucosterol from Panida australis and Hizikia fusiformis reduced IL-1β, IL-6, TNFα, NO and PGE2 in LPS-or Aβ-induced BV2 microglia cells or keratinocytes [172,173]. Fucosterol extracted from the algae Ecklonia stolonifera, Panida australis and Sargassum horridum inhibited AChE and BChE in vitro [172,174,175]. Different types of inhibition were detected depending on the origin. Fucosterol from Ecklonia stolonifera showed a selective inhibition of BChE, a non-selective cholinesterase inhibition of AChE and BChE was observed with fucosterol from Panida australis and a non-competitive inhibition was detected with the compound from Sargassum horridum [172,174,175]. A non-competitive inhibition of the β-secretase BACE1 was observed with fucosterol from Ecklonia stolonifera and Undaria pinnatifida [176].

Isoprenoids
Similar to polyphenols, the neuroprotective effect of isoprenoids such as sterols and xanthin derivatives is primarily based on their anti-oxidative radical scavenging and antiinflammatory properties (Table 9). Numerous studies have been published addressing the antioxidative activity in different, mostly cellular model systems. For instance, the steroid fucosterol extracted from Pelvetia siliquosa increased the level of antioxidant enzymes SOD, GPx and CAT and inhibited ROS production [152,168]. It also provided protection from oxidative damage by raising the GSH level and attenuated of the production of iNOS, TNF-α and IL-6, and the phosphorylation of NF-κB, MKK3/6 and MK2 was shown [169][170][171]. Fucosterol from Panida australis and Hizikia fusiformis reduced IL-1β, IL-6, TNFα, NO and PGE2 in LPS-or Aβ-induced BV2 microglia cells or keratinocytes [172,173]. Fucosterol extracted from the algae Ecklonia stolonifera, Panida australis and Sargassum horridum inhibited AChE and BChE in vitro [172,174,175]. Different types of inhibition were detected depending on the origin. Fucosterol from Ecklonia stolonifera showed a selective inhibition of BChE, a non-selective cholinesterase inhibition of AChE and BChE was observed with fucosterol from Panida australis and a non-competitive inhibition was detected with the compound from Sargassum horridum [172,174,175]. A non-competitive inhibition of the β-secretase BACE1 was observed with fucosterol from Ecklonia stolonifera and Undaria pinnatifida [176].

Isoprenoids
Similar to polyphenols, the neuroprotective effect of isoprenoids such as sterols and xanthin derivatives is primarily based on their anti-oxidative radical scavenging and antiinflammatory properties (Table 9). Numerous studies have been published addressing the antioxidative activity in different, mostly cellular model systems. For instance, the steroid fucosterol extracted from Pelvetia siliquosa increased the level of antioxidant enzymes SOD, GPx and CAT and inhibited ROS production [152,168]. It also provided protection from oxidative damage by raising the GSH level and attenuated of the production of iNOS, TNFα and IL-6, and the phosphorylation of NF-κB, MKK3/6 and MK2 was shown [169][170][171]. Fucosterol from Panida australis and Hizikia fusiformis reduced IL-1β, IL-6, TNF-α, NO and PGE 2 in LPS-or Aβ-induced BV2 microglia cells or keratinocytes [172,173]. Fucosterol extracted from the algae Ecklonia stolonifera, Panida australis and Sargassum horridum inhibited AChE and BChE in vitro [172,174,175]. Different types of inhibition were detected depending on the origin. Fucosterol from Ecklonia stolonifera showed a selective inhibition of BChE, a non-selective cholinesterase inhibition of AChE and BChE was observed with fucosterol from Panida australis and a non-competitive inhibition was detected with the compound from Sargassum horridum [172,174,175]. A non-competitive inhibition of the β-secretase BACE1 was observed with fucosterol from Ecklonia stolonifera and Undaria pinnatifida [176].

Conclusions
The recent conditional approval of the monoclonal antibody aducanumab (aduhelm) by the FDA provides a very stimulating signal for all drug development approaches in AD. However, among others, these antibody approaches are still met with doubts about disease modification and safety, as suggested by the decision of the EMA to not provide approval to Aduhelm (Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 13-16 December 2021. Available online: https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-

Conclusions
The recent conditional approval of the monoclonal antibody aducanumab (aduhelm) by the FDA provides a very stimulating signal for all drug development approaches in AD. However, among others, these antibody approaches are still met with doubts about disease modification and safety, as suggested by the decision of the EMA to not provide approval to Aduhelm (Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 13-16 December 2021. Available online: https://www.ema.europa.eu/en/news/ meeting-highlights-committee-medicinal-products-human-use-chmp-13-16-december-20 21, accessed on 2 February 2022). Hence, nutritional approaches and natural products are vital tools for prevention and amelioration of the progression of neurodegeneration. A considerable strength of the natural products is provided by the multifaceted mechanisms of their activity. Prominent examples for that include, for instance, the ginsenosides or the extracts from Ginkgo biloba (GBE), which are currently the subject of late-stage clinical trials ( Table 1). The ingredients exert anti-inflammatory and antioxidative properties and have been described to influence the processing of AD-related proteins, providing a multi-pronged molecular approach of intervention. Also, natural compounds are among the first described to address potential novel pathways in neurodegenerative diseases. The most prominent example for that is GV-971 (sodium oligomannate). The currently available data support an influence on the gut microbiome which leads to the amelioration of AD-related symptomatology. The compound is among the first that addresses the "gut-brain-axis", which has recently become focus of research in neurodegenerative diseases. Besidessodiumoligomannate, the general role of nutrition and nutrient uptake by the digestive tract is further underscored by the recent reports on the LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease [188]. Collectively, the unique properties of these molecules should further encourage the evaluation of combination therapies of, for example, anti-Aβ immunotherapy and treatment with natural products. Because the compounds reviewed here are mostly available without a prescription, a quick introduction into theclinical routine thus appears straightforward.
Funding: This research received no external funding.