Medicine-Food Herbs against Alzheimer’s Disease: A Review of Their Traditional Functional Features, Substance Basis, Clinical Practices and Mechanisms of Action

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that currently has reached epidemic proportions among elderly populations around the world. In China, available traditional Chinese medicines (TCMs) that organically combine functional foods with medicinal values are named “Medicine Food Homology (MFH)”. In this review, we focused on MFH varieties for their traditional functional features, substance bases, clinical uses, and mechanisms of action (MOAs) for AD prevention and treatment. We consider the antiAD active constituents from MFH species, their effects on in vitro/in vivo AD models, and their drug targets and signal pathways by summing up the literature via a systematic electronic search (SciFinder, PubMed, and Web of Science). In this paper, several MFH plant sources are discussed in detail from in vitro/in vivo models and methods, to MOAs. We found that most of the MFH varieties exert neuroprotective effects and ameliorate cognitive impairments by inhibiting neuropathological signs (Aβ-induced toxicity, amyloid precursor protein, and phosphorylated Tau immunoreactivity), including anti-inflammation, antioxidative stress, antiautophagy, and antiapoptosis, etc. Indeed, some MFH substances and their related phytochemicals have a broad spectrum of activities, so they are superior to simple single-target drugs in treating chronic diseases. This review can provide significant guidance for people’s healthy lifestyles and drug development for AD prevention and treatment.


Introduction
Alzheimer's disease (AD) is a specific onset and process of cognitive and functional decline with particular neurological characteristics, especially in people over 65 years of age with high morbidity and mortality [1,2]. Prince M et al. estimated that 65.7 million people in 2030 and 115.4 million people in 2050 will live with dementia worldwide, which implies an extremely serious burden to global public health and social welfare [3]. Deficits in the ability to encode and store new memories characterize the initial stages of the disease. Subsequent progressive changes in cognition and behavior accompany the later stages. Due to the complexity of the etiology of AD, its pathological and physiological mechanisms have been controversial. To date, the core pathological hallmarks recognized by researchers are amyloid plaques, neurofibrillary tangles, synapses, and/or neuronal loss [4,5].
In recent years, with the improvement of public health awareness, people have paid increasing attention to the prevention and treatment of chronic diseases through diet, such as a "low-, fermentable oligo-, and di-, monosaccharides and polyols" diet, Mediterranean diet, a low-lactose diet, and medicinal food herb diet [8][9][10][11]. The concept of medicine food homology (MFH) originally came from the (Huangdi's) Internal Classic in ancient China, which means that Chinese medicine and food are of the same origin, and, thus, they can be used as food and administered to patients as medication to regulate the human body's metabolic disturbances or imbalances [11,12].
In China, many traditional Chinese medicines (TCMs) are functional foods and dietary supplements, such as Panax ginseng C.A. Mey., Crocus sativus L., and Angelica acutiloba (Siebold & Zucc.) Kitag. For cultural reasons, herbal remedies are called alternative therapies in North America and other countries [8]. MFH substances with abundant resources have exhibited pharmacological effects at preventing and treating a variety of diseases, including cancers, diabetes, cardiovascular diseases, Alzheimer's disease, Parkinson's disease, viruses, influenza, and, in particular, chronic diseases [13]. To ensure the safety of functional foods from TCM, the National Health Commission of the People's Republic of China released specific provisions on MFH items, which considered 109 TCMs as functional foods for alleviating or curing various chronic diseases through the diet as of 2019 [8].
For this paper, the literature review covers the period between 2001 and 2021 relating to MFH items with antiAD effects. The literature was collected from the SciFinder, EMBASE, Mendeley, Google Scholar, PubMed, and Web of Science databases. The keywords used for the literature search were as follows: "Medicine-food Herb and Alzheimer's disease", "Medicine-food Herb and chemical components or phytoconstituents or natural products", and "Medicine-food Herb and clinical evidence and Alzheimer's disease". Then, we tried to classify all data pertaining to the pharmacological effects of MFH functional foods on memory in different animal models, methods, mechanisms, etc. The summarized results comprised a total of 28 plant species, 35 phytochemicals, and 9 TCM formulations of MFH resources with antiAD activities exhibited in various preclinical and five clinical studies (Tables 1-5). The main MFH items that will be introduced are those, which are often used, such as "Monarch medicine" and clinical evidence, including Angelica acutiloba (Siebold & Zucc.) Kitag., Panax ginseng C.A. Mey., and Poriacocos (Schw.) Wolf. This review will provide further support for the basic and clinical research on MFH and the use of functional foods in a healthy lifestyle in the future. Cistanches Herba could improve cognitive and independent living ability of moderate AD patients, slow down volume changes of hippocampus, and reduce the levels of T-tau, TNF-α, and IL-1β.

Names Parts to Be Consumed Therapeutic Class Features Chinese Name English Name
Ren shen Panax ginseng C.A. Mey.

Root Qi-reinforcing medicinal
To reinforce the vital energy, to remedy collapse and restore the normal pulse, to benefit the spleen and lung, to promote the production of body fluid, and to calm the nerves.  To supplement body fire, to reinforce yang, and to lead the fire back to the kidney, to dispel cold and relieve pain, and to activate blood circulation and stimulate menstrual discharge.         Panax ginseng, an herb from the Araliaceae family, is a qi-tonifying medicinal substance with the effects of tranquilizing the mind and replenishing wisdom [129]. Its supposed health benefits are such that it is used in many countries. Ginseng is "generally recognized as safe" (GRAS) for consumption by adults by the U.S. Food and Drug Administration [130].

MOAs of the Extract
Korean white ginseng, red ginseng extract, and black ginseng are the main processed products of ginseng. Lee et al. reported that their extracts can inhibit AChE and BuChE in a concentration-dependent manner in scopolamine (SCOP)-induced amnesic mice. The IC50 values are 1.72 mg/mL, 5.89 mg/mL, and 6.30 mg/mL [16]. Simultaneously, the processed products of ginseng showed their antiAD mechanisms. Specifically, in vitro and in vivo findings indicated that red ginseng significantly ameliorated AD-related pathologies, such as Aβ deposition, gliosis, and neuronal loss [33]. Fermented ginseng extract enhanced behavioral memory function in an effort to reduce Aβ levels in ICR mice and TG mice and in HeLa cells [34]. Furthermore, white ginseng extract (100 and 500 mg/kg/day) could improve memory impairment by attenuating neuronal damage and neuroinflammation caused by AβO in intrahippocampal AβO (10 µM)-injected mice [35] (Figure 1).
In addition, in vivo and in vitro pharmacological studies have shown that ginseng plays a key role in antiAD as a "Jun medicine" in TCM prescriptions, such as Shenmayizhi decoction (SMYZD), Yizhi Qingxin formula (YZQXF), and Jangwonhwan.
Evidence has revealed that YZQXF alleviates cognitive deficits by increasing the levels of LC3II/LC3I and Beclin1, remarkably activating 4EBP1 and inhibiting the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 in early-onset AD mice [24]. Researchers also showed that YZQXF ameliorated cognitive decline by decreasing BDNF, TrkB, TNFα, IL-2, and IL-6 levels and upregulating acetylcholine and IL-10, thus promoting the activation of Erk and Akt signaling in APP/PS1 mice [23]. In an in vivo model of AD, SMYZD at concentrations of 11.88 g/kg/d can significantly improve memory abilities associated with an increase in the levels of NG2 and Ang1 protein expression levels in Wistar rats [22]. An in vitro study showed that Jangwonhwan at 400 mg/kg/day notably reduced Abeta (1-42) levels and beta-amyloid deposition and partially suppressed oxidative stress accumulation in SH-SY5Y neuroblastoma cells [25].

MOAs of Ingredients
Ginsenoside Rg1, ginsenoside Rh2, and ginsenoside Rd are the main saponins of Panax ginseng. Evidence has indicated that ginsenoside Rg1 can improve cognitive ability, protect NSCs/NPCs, and promote neurogenesis by enhancing antioxidant (GSH-Px, SOD) and antiinflammatory (IL-1β, IL-6, and TNF-α) capacities in the hippocampus [75]. Ginsenoside Rh2, another saponin component of ginseng, was reported to improve learning and memory function by inhibiting cholesterol and lipid raft concentrations, thus reducing amyloid-beta secretion and APP endocytosis in tg2576 mice [76]. Additionally, ginsenoside Rd (10 mg/kg for 7 days) prevented okadaic acid-induced neurotoxicity through the upregulation of PP-2A in cultured cortical neurons (2.5 or 5 µmol/L for 12 h) [77] (Figure 2). Notably, gintonin, a novel lysophosphatidic acid-protein complex in ginseng, can exert nervous system protection through the LPA receptor-Gαq/11 protein-phospholipase C-IP3 receptor-[Ca 2+ ] I transient pathway [78,131]. In addition, ginsenoside Compound K is a metabolite of panaxadiol generated by the metabolic actions of intestinal flora in humans. A study demonstrated that Compound K promoted the clearance of Aβ by enhancing autophagy via the mTOR signaling pathway in primary astrocytes [79]. Notably, gintonin, a novel lysophosphatidic acid-protein complex in ginseng, can exert nervous system protection through the LPA receptor-Gαq/11 protein-phospholipase C-IP3 receptor-[Ca 2+ ] I transient pathway [78,131]. In addition, ginsenoside Compound K is a metabolite of panaxadiol generated by the metabolic actions of intestinal flora in humans. A study demonstrated that Compound K promoted the clearance of Aβ by enhancing autophagy via the mTOR signaling pathway in primary astrocytes [79].

Clinical Evidence
In an open-label study, the Mini-Mental State Examination (MMSE) and AD Assessment Scale (ADAS) began to show improvements and continued up to 12 weeks (p = 0.029 and p = 0.009 vs. baseline, respectively) during 12 weeks of ginseng treatment. The results indicated that Panax ginseng is clinically effective in the treatment of AD. Simultaneously, three randomized open-label studies have shown that Korean Red Ginseng extract is clinically effective and gradually improves cognitive function in AD patients [14][15][16].

Clinical Evidence
In an open-label study, the Mini-Mental State Examination (MMSE) and AD Assessment Scale (ADAS) began to show improvements and continued up to 12 weeks (p = 0.029 and p = 0.009 vs. baseline, respectively) during 12 weeks of ginseng treatment. The results indicated that Panax ginseng is clinically effective in the treatment of AD. Simultaneously, three randomized open-label studies have shown that Korean Red Ginseng extract is clinically effective and gradually improves cognitive function in AD patients [14][15][16].

Traditional Functional Features
Crocus sativus L., a stemless herb that belongs to the Iridaceae family, has bloodactivating and menstruation-regulating properties and has been considered an edible food since ancient times. It is mainly used in activating blood circulation and eliminating blood stasis, removing heat from blood and counteracting toxicity, and calming the nerves [132].

MOAs of the Extract
In recent years, researchers have found that Crocus sativus L. has various useful pharmacological properties, such as anticonvulsant, antidepressant, anti-inflammatory, antitumor, and learning and memory-improving effects [133]. A review by Hatziagapiou K et al. summarized the anti-AD mechanism of Crocus sativus L., including the following: antioxidative stress, inhibitory effects of Aβ fibrillogenesis, inhibitory effects of tau aggregation, reduction of glutamatergic synaptic transmission, restoration of cellular antioxidant defenses, and inhibition of cellular apoptosis or death [134]. For example, Soeda et al. designed an experiment to investigate the neuroprotection mechanisms of Crocus sativus L. by inhibiting cellular apoptosis/death. It was found that Crocus sativus L. prevented ethanol-induced impairment of learning and memory with a marked reduction in the caspase-3 and TNFalpha-induced release of cytochrome c from the mitochondria in PC-12 cells [36] (Figure 1).

MOAs of Ingredients
The in vitro and in vivo research of Ochiai T et al. showed that crocin, a constituent of Crocus sativus L., effectively promoted mRNA expression of gamma-glutamylcysteinyl synthase, contributing to GSH synthesis in mice and, thus, inhibiting neutral sphingomyelinase activity and ceramide formation [135]. Another study indicated that Crocus sativus compounds (trans-Crocin 4 and trans-Crocetin) suppressed the levels of GSK3β and ERK1/2 kinases and significantly reduced total tau and tau phosphorylation, which may be promising candidates in the prevention and treatment of AD [80] (Figure 2).

Clinical Evidence
In a double-blind and randomized study on patients with mild-to-moderate AD, 54 Persian-speaking adults were randomly assigned to receive a capsule of saffron at 30 mg/day (15 mg twice per day) or donepezil at 10 mg/day (5 mg twice per day). This phase II study (Clinical Trials Registry: IRCT138711051556N1) provides preliminary evidence that saffron extract may be used as a potential TCM for mild-to-moderate AD patients [17]. A 16-week, randomized and placebo-controlled study on patients randomly assigned to receive 30 mg/day of saffron capsule or placebo capsule (two capsules/day) demonstrated comparable results with the placebo capsule, and saffron was both safe and effective in mild-to-moderate AD in the short-term [18]. Another single-blind randomized clinical trial by the Tsolaki M et al. group also showed that Crocus is efficacious and safe for the management of amnesic and multidomain MCI [19].

Traditional Functional Features
As a tonic herb, Herba Cistanches has earned the honor of "Ginseng in the deserts" with its function of reinforcing the kidney, replenishing vital essence and blood, and inducing taxation [136].

MOAs of the Extract
Herba Cistanches, a yang-tonifying medicine in China, possesses broad medicinal functions in immunomodulation, endocrine regulation, hepatoprotection, and antiaging, antibacterial, antiviral, and antitumor [137]. In recent years, several excellent reviews have described that Herba Cistanches have great potential in the treatment of age-related diseases. On the one hand, the mechanisms were mainly involved in blocking Aβ 1-42 amyloid deposition, decreasing P-tau phosphorylation, inhibiting the formation of NO, affecting the signaling pathway between ROS, and the opening of Ca 2+ channels. On the other hand, Herba Cistanches could induce neuroprotection by inducing cell cycle arrest and apoptosis, increasing the expression of the antiapoptotic proteins, stimulating intestinal epithelial cell proliferation, upregulating TGF-β and CRMP-2 expression levels, and improving antioxidant enzymes [138][139][140].
In addition, tubuloside B, a phenylethanoid of the stems of Cistanche salsa, has neuroprotective effects, such as antioxidative stress and antiapoptotic actions (Figure 3). Deng et al. then revealed that tubuloside B (1, 10, or 100 mg/L) attenuated TNF-a-induced apoptosis and the accumulation of intracellular ROS and [Ca 2+ ]I in SH-SY5Y neuronal cells [81]. the gut-liver-brain axis, oxidative stress (MDA), and gastrointestinal tract barrier in APP/PS1 mice [29].

MOAs of Ingredients
RAK and Astragalus aaronii (Eig) Zohary are both important MFH substancess, and many of their active ingredients have been tested in vivo and in vitro to prove their therapeutic effect on AD, such as decursinol, vanillic acid, and ligustilide [143,144]. Pretreatment of mice with decursinol significantly attenuated the Abeta (1-42)-induced impairment in passive avoidance performance in ICR mice [84]. Additionally, decursinol exerted a neuroprotective effect against Aβ25-35-induced neurotoxicity in PC12 cells by suppressing the mitochondrial pathway of cellular apoptosis [85]. In addition, a study  . It is a bloodtonifying medicine that can activate blood circulation, regulate menstruation, relieve pain and feminine hernias, and is also called "female ginseng" [142]. DGBXT, a historical Chinese herbal decoction, contains just two MFH materials: Astragali Radix and Radix Astragali. An in vitro assay demonstrated that DGBXT protected β-amyloid-induced cell death by altering the expression ratio of Bcl2 to Bax and markedly suppressed the Aβ-induced expression of apoptotic markers (cleaved-caspase 3/9 and PARP) in cultured cortical neurons [26]. Emerging evidence also showed that DGSYS could increase E2, NO, and glycine in SAMP8 mice, contributing to cognitive improvement [27]. Another study showed that DGSYS ameliorated oxidative stress and inflammation by decreasing the levels of PEG2, TXB2, and LTB4 and inhibiting the expression of cPLA2, COX-1, and COX-2, thus ameliorating cognitive deficits in APP/PS1 mice [28]. The FSS formula was reported to ameliorate the symptoms of AD by regulating the gut-liver-brain axis, oxidative stress (MDA), and gastrointestinal tract barrier in APP/PS1 mice [29].

MOAs of Ingredients
RAK and Astragalus aaronii (Eig) Zohary are both important MFH substancess, and many of their active ingredients have been tested in vivo and in vitro to prove their therapeutic effect on AD, such as decursinol, vanillic acid, and ligustilide [143,144]. Pretreatment of mice with decursinol significantly attenuated the Abeta (1-42)-induced impairment in passive avoidance performance in ICR mice [84]. Additionally, decursinol exerted a neuroprotective effect against Aβ25-35-induced neurotoxicity in PC12 cells by suppressing the mitochondrial pathway of cellular apoptosis [85]. In addition, a study showed that vanillic acid reduced AChE, TNF-α, and corticosterone, thus improving antioxidants to contribute to neuroprotection in Swiss albino mice [83].
Importantly, Z-ligustilide (40 mg/kg) significantly ameliorated both AD-related neuropathological signs (Abeta, amyloid precursor protein, and phosphorylated Tau immunoreactivity) and proinflammatory mediators (TNF-alpha and NF-kappaB) in the hippocampus of Wistar rats [86]. In addition, Z-ligustilide can resist the neurotoxicity induced by β -amyloid by simultaneously regulating p38 and PI3-K/Akt pathways in SH-SY5Y cells and PC12 cells [87]. It is worth noting that ligustilide has been demonstrated to permeate the blood-brain barrier in freely moving rat brains, suggesting that ligustilide may be a promising compound for the treatment of AD [145] (Figure 3).

Traditional Functional Features
Astragalus aaronii (Eig) Zohary, derived from the roots of Astragalus membranaceus and A. membranaceus var. mongholicus, is a qi-tonifying herb that is widely used in China and shows potent cardiovascular protective effects [146].

MOAs of the Extract
Astragalus aaronii (Eig) Zohary plays a powerful role in the Tiaoxin Recipe and Fuzheng Quxie Decoction (FZQXD). Compared with the normal control group, treatment with the Tiaoxin Recipe decreased the content of serum Aβ1-42 accumulation in APP/PS1 mouse serum. Studies have also shown that microRNA-34a (miR-34a) expression can significantly lead to neuronal apoptosis [147]. The administration of a Tiaoxin Recipe significantly decreased miR-34a expression in APP/PS1 mice [30]. In vivo experiments confirmed that FZQXD could exert a neuroprotective effect on AD via VEGF and VEGF-receptor signaling [31].

MOAs of Ingredients
Astragaloside IV (AS-IV) is a small molecular weight (MW = 784 Da) saponin purified from Astragalus membranaceus that has shown multiple beneficial effects in the prevention and treatment of neurodegenerative disorders [148] (Figure 4). The literature has demonstrated that AS-IV prevents AβO-induced memory impairment by promoting the PPARγ/BDNF signaling pathway [88]. An in vivo study showed that AS-IV treatment increased PPARγ and BACE1 expression and reduced neuritic plaque formation and Aβ levels in the brains of APP/PS1 mice and ultimately attenuated the generation of Aβ [89]. In addition, pretreatment with AS-IV prevented Aβ1-42-induced SK-N-SH cell apoptosis by inhibiting the mPTP opening and ROS generation for the prevention and treatment of neurodegenerative disorders such as AD [90].  In addition, Poriacocos (Schw.) Wolf is the most important herb of Lingui Zhugan decoction (LGZGD) with neuroprotective effects. LGZGD, a notable prescription for the treatment of AD, significantly improved learning and memory ability by regulating Aβ transportation and inhibiting RAGE/MAPK and NF-κB signaling [32].

Traditional Functional Features
Alpinia oxyphylla Miq. (AOM), derived from the mature and dried fruits of the Zingiberaceae plant Alpinia oxyphylla Miq., has good effects as a medicine and food in China. AOM is an astringent herb that arrests discharge due to insecure healthy qi and decreases visceral functions, such as excessive sweating, chronic diarrhea, and enuresis [151].

MOAs of the Extract
Recently, a systematic overview of progress on the anti-AD mechanism of AOM was

Traditional Functional Features
Poriacocos (Schw.) Wolf, an edible mushroom, grows underground on the roots of pine trees. It is a water-draining and swelling-dispersing herb for the treatment of edema, nephrosis, gastric atony, acute gastroenteric catarrh, dizziness, and nausea. Poria cocos is often commercially available and is popularly used in Asia [149].

MOAs of the Extract
Extracts from Poriacocos (Schw.) Wolf have various pharmacological properties, including anti-inflammatory, immunomodulatory, anticancer, and antihyperglycemic effects [150]. Huang et al. found that P. cocos water extract significantly attenuated the UCMS-induced turnover rate of DA and 5-HT and inhibited the UCMS-induced activated inflammatory response (p38, NF-κB, and TNF-α) in the frontal cortex by using an SD rat model [38]. Sun Y et al. applied the APP/PS1 mouse model to study the effects of learning and memory and the mechanisms of the aerial part of Poria cocos. The results showed that this medicinal plant, which is also a functional food, might ameliorate cognitive function by reducing the formation of Aβ, increasing its clearance and reversing gut microbiota dysbiosis [37] ( Figure 1).
In addition, Poriacocos (Schw.) Wolf is the most important herb of Lingui Zhugan decoction (LGZGD) with neuroprotective effects. LGZGD, a notable prescription for the treatment of AD, significantly improved learning and memory ability by regulating Aβ transportation and inhibiting RAGE/MAPK and NF-κB signaling [32].

Traditional Functional Features
Alpinia oxyphylla Miq. (AOM), derived from the mature and dried fruits of the Zingiberaceae plant Alpinia oxyphylla Miq., has good effects as a medicine and food in China. AOM is an astringent herb that arrests discharge due to insecure healthy qi and decreases visceral functions, such as excessive sweating, chronic diarrhea, and enuresis [151].

MOAs of the Extract
Recently, a systematic overview of progress on the anti-AD mechanism of AOM was reported. Research has demonstrated that AOF exerts great therapeutic potential in the treatment of AD by inhibiting the formation of Aβ and phosphorylation of tau, increasing antioxidant capacity, anti-inflammatory and anti-apoptosis effects, and inhibiting the activity of acetylcholinesterase [41,152].
Wang et al. found that AOM extracts attenuated LPS-induced learning and memory impairment due to their inhibitory effect on neuroinflammation, amyloid -β (Aβ) deposition, and p-tau [40]. Chang et al. also confirmed in vivo and in vitro that AOM increased the expression of uPA, tPA, MMP-9, and MAPKs and induced ERK1/2, JNK, and p38 phosphorylation to exert nerve regeneration [39]. In addition, a study also showed that treating neurons with AOM extract (80-200 µg/mL) significantly increased cell viability and reduced the number of apoptotic cells, thus exerting neuroprotection [42]. 81Moreover, the butanol extract of AOM (180 mg/kg, 360 mg/kg) was reported to be efficacious in preventing neuronal damage by inhibiting β-secretase and the level of Aβ  in ICR mice [92] (Figure 1).

MOAs of Ingredients
5-Hydroxymethylfurfural (5-HMF) and tetochrysin (TEC) are the main effective compounds of AOF ethanol extract and exert neuroprotective activities against AD (Figures 2 and 3). For example, both 5-HMF and TEC significantly decreased the content of Aβ 1-42 and increased the activities of antioxidative enzymes, including SOD and GPx [91,153].

Traditional Functional Features
Zingiber officinale Roscoe (ZOR) is the fresh rhizome of Zingiber officinale Roscoe traced from Shen Nong Ben Cao Jing. In the Chinese Pharmacopoeia, ZOR has the function of inducing perspiration and dispelling cold, warming the stomach, stopping vomiting, resolving phlegm, and relieving coughs [154].

MOAs of the Extract
ZOR is a traditional pungent-cool exterior-releasing medicine and is widely used as an antioxidant, anti-inflammatory, antidiabetic, antinausea, neuroprotective, and cardiovascular protective agent [155].
Accumulated investigations have demonstrated that ginger positively affects memory function by anti-inflammatory effects in the treatment of AD. The results from the SD rat model revealed that the operation + high dose (4 g/kg) groups of ginger root extract had lower levels of the nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) expression than the operation + moderate dose (2 g/kg) and operation + low dose groups (1 g/kg) [43]. Further experiments in the hippocampus of Wistar rats revealed that ZOR extracts at a dose of 200 mg/kg significantly suppressed the inflammatory response of GFAP and IL-1β expression [44].
Mathew M et al. evaluated the antioxidant activity and cholinesterase inhibition properties of a methanolic extract of dry ginger (GE). The extract of total phenolic content and dry material contained 18 ± 0.6 mg/g gallic acid equivalents and 4.18 ± 0.69 mg quercetin equivalents/g, respectively. They found that GE expressed high antioxidant activity with an IC50 value of 70 ± 0.304 microg/mL in the DPPH assay and 845.4 ± 56.62 microM Fe (II) equivalents/g dry weight in the FRAP assay. They also found that GE had IC50 values of 41 ± 1.2 microg/mL and 52 ± 2 microg/mL for the inhibition of acetylcholinesterase and butyrylcholinesterase, respectively, in Ellman's assay [46]. Another study found that water-extractable red and white ginger inhibited acetylcholinesterase (AChE) activities in a dose-dependent manner, and white ginger had higher acetylcholinesterase inhibitory activity than red ginger. Both extracts significantly decreased the MDA content induced by sodium nitroprusside and quinolinic acid in a dose-dependent manner [45] (Figure 1).

MOAs of Ingredients
6-Gingerol, a phenolic compound, is the major pharmacologically active component in ginger rhizomes with diverse pharmacological activities, such as antitumor, anti-inflammatory, and antioxidant effects, etc. [156]. At present, there have been sufficient in vivo and in vitro experiments to prove that 6-gingerol has potential neuroprotective effects. An in vitro experiment resulted in 6-gingerol exhibiting neuroprotective effects, and pretreatment with 6-gingerol significantly increased cell viability and reduced cell apoptosis in Aβ1-42-treated PC12 cells. Additionally, 6-gingerol pretreatment markedly reduced the levels of intracellular ROS, MDA, NO, and lactate dehydrogenase (LDH) leakage and increased SOD activity compared with the Aβ1-42 treatment group. Moreover, pretreatment with 6-gingerol (80, 120 µM) also markedly enhanced the protein levels of p-Akt and p-GSK-3β caused by Aβ1-42 [93].
In vivo, in a rat C57BL/6N mouse model induced by a high-fat, high-sugar Western diet (HFSD), 6-shogaol dose-dependently ameliorated obesity and emotional memory deficits [94]. In another study with an ICR mouse model, administration of 6-shogaol at a concentration of 10 mg/kg significantly elevated the expression levels of NGF, PSD-95, and synaptophysin in hippocampal tissues, compared with the vehicle-treated group [95].

Traditional Functional Features
Polygonatumodoratum (Mill.) Druce (PMD), a kind of native citrus germplasm with yin-tonifying medicine that tonifies and nourishes yin fluid, is used to strengthen the body's resistance to TCM in Southwest China [157].

MOAs of the Extract
PMD extract is rich in flavonoids and phenolics that might ameliorate cognitive dysfunction in βamyloid-induced rats. Research proved that oral consumption of a flavonoid-rich yuzu extract normalized insulin signaling and improved energy and glucose metabolism in the hippocampus of β-amyloid-infused rats [47].
Rutin, as a multifunctional biological molecule, can treat and prevent Alzheimer's disease by regulating various pharmacological mechanisms, such as antioxidant mechanisms, mechanisms related to metal chelation, anti-inflammatory mechanisms, Aβ mechanisms, formation of Aβ, Aβ aggregation and toxicity, and acetyl cholinesterase (AChE) mechanisms [158].
In vitro bioassays have revealed that narirutin is a high-affinity BACE1 inhibitor and extends its applicability as a functional food in AD management [161]. Studies have shown that treatment with naringin (100 mg/kg) enhanced the autophosphorylation of CaMKII and the phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic (AMPA) receptor in the APPswe/PS1dE9 transgenic mouse model of AD [96].
Furthermore, Zaplatic E et al. suggested that quercetin has a potential protective effect against neurodegenerative diseases, including AD. On the one hand, the molecular mechanisms of quercetin in attenuating AD are antioxidant activities, mainly involving the nuclear factor (erythroid-derived 2)-like 2 pathway, paraoxonase-2 pathway, JNKmediated pathways, PKC pathway, MAPK signaling cascades, and PI3K/Akt pathway. On the other hand, the neuroprotective properties of quercetin were able to inhibit Aβ aggregation, NFT formation, amyloid precursor protein (APP) cleaving enzyme (BACE1), and acetylcholinesterase (AChE) [163].
Moreover, limonene (+) from PMD essential oil has a neuroprotective function against the neurotoxicity of Aβ42 [100].

Traditional Functional Features
Piper nigrum L., is widely distributed in tropical regions, and its fruits are used for spices and seasonings as a functional food. P. nigrum, an interior-warming medicine in TCM, can dispel cold from the stomach and eliminate phlegm [164].

MOAs of the Extract
Modern pharmacological research has been founded on broad biological activities, including antioxidant, antimicrobial, and insecticidal activities [165,166]. Mahdy K et al. revealed that the total plant extracts of P. nigrum reduced oxidative stress and ameliorated neurodegeneration characteristics by significantly increasing Ach and serum total antioxidant capacity (TAC) and SOD and significantly decreasing AchE, MDA, and NO in AD-induced rats [48]. The methanolic extract of P. nigrum (50 and 100 mg/kg) restored the activities of SOD and Catalase (CAT) and increased GPX activity in the hippocampus of Aβ (1-42)-treated rats. Simultaneously, as an antioxidant agent, both doses of the methanolic extract (50 and 100 mg/kg) decreased the protein carbonyl and MDA levels and increased GSH in hippocampal homogenates [49].
Liu et al. demonstrated that β-caryophyllene can alleviate the Alzheimer-like phenotype by inhibiting inflammation and reducing the β-amyloid burden. Their research showed that β-caryophyllene prevented cognitive impairment in APP/PS1 mice by reducing the β-amyloid burden in both the hippocampus and the cerebral cortex. In addition, β-caryophyllene reduced the protein levels of COX-2 and the mRNA levels of the proinflammatory cytokines TNF-α and IL-1β in the cerebral cortex. This study also explored the possibility that in an in vivo experiment, β-caryophyllene ameliorates memory impairment through CB2 receptor activation and the PPARγ pathway in APP/PS1 mice for the treatment of AD [106]. It is well known that α -synuclein forms amyloid aggregates in vitro in the presence of some metal ions or alcohol. A large number of experiments show that the mixture of curcumin and β-caryophyllene can not only inhibit the aggregation of αsynuclein, but also almost completely decompose the preformed aggregates at a relatively low concentration [168].
Nazifi M et al. showed that piperine significantly ameliorated cognitive deficits by attenuating oxidative status compared to AD-or AD-Tween-treated groups [108]. Piperine at various doses of 5, 10, and 20 mg/kg significantly improved memory impairment and neurodegeneration in the hippocampus, partly associated with the decrease in lipid peroxidation and the acetylcholinesterase enzyme [109]. In vitro AChE inhibition demonstrated that piperine showed greater AChE inhibition with an IC50 of 76.6 ± 0.08 µg/mL in the SH-SY5Y cell model. Research also found that combined curcumin and piperine inhibited and disaggregated fibril formation and Aβ-induced oxidative damage compared to the Aβ group [107] (Figure 2).

Traditional Functional Features
Ganoderma lucidum (Leyss.ex Fr.) Karst. is also known as "the mushroom of immortality", a basidiomycete white rot microfungus used extensively in China for 2000 years. In fact, during ancient times, G. lucidum was a qi-tonifying medicine that tonifies health for treating qi deficiency [170].
Alleviate nerve injury and neurotoxicity: Ganoderma lucidum can improve behavior disorders associated with a decrease in the levels of the Aβ-40 protein and an increase in the levels of ApoA1, ApoE, and Syt1 [173]. Further studies elucidated that the aqueous extract of G. lucidum attenuated the phosphorylation of c-Jun, N-terminal kinase, c-Jun, and p38 MAP kinase, thus blocking Abeta-induced synaptoxicity [174].
Anti-inflammatory effects: Ganoderma lucidum ethanol extract (EGL) in the treatment of neurodegenerative diseases inhibited the NF-κB and TLR signaling pathways, thereby reducing the inflammatory response in activated microglia. And an in vitro study showed that EGL exhibited a potential neuroprotective effect by blocking IκB degradation and inhibiting TLR4 and MyD88 expression, which exerted its anti-inflammatory effects in LPS-stimulated BV2 cells [175].
Antioxidative effects: A study by Lee et al. revealed that EGL augmented the cellular antioxidant defense capacity by increasing the expression and phosphorylation of Nrf2 and HO-1 in a C2C12 myoblast cell line [118] (Figure 1).

Traditional Functional Features
Puerarialobata (Willd.) Ohwi is a pungent-cool exterior-releasing medicine in Shennong Bencao Jing common during the Western Han Dynasty . In the traditional sense, the main effect of Pueraria is to release flesh, clear heat, engender fluid, and outthrust rashes [178].

MOAs of the Extract
Existing pharmacological experiments show that Puerariae Radix offers neuroprotective effects, cardiovascular protection, and osteonecrosis prevention, etc. [116]. To clarify the mechanism of Puerariae Radix for neuroprotective effects, Huang HJ et al. designed C57BL/6J mice that received a direct infusion of soluble oligomeric A to evaluate the extract of Puerariae Radix alleviation of Aβ deposition in the rat hippocampus. Experimentally, it was observed that Puerariae Radix aqueous extract decreased Aβ deposition, tau protein phosphorylation, inflammation, and loss of noradrenergic and serotonergic neurons, while increasing synaptophysin-and insulin-degrading enzymes against the toxicity of oligomeric Aβ [54].

MOAs of Ingredients
Puerarin, isolated from Puerariae Radix, has the potential to cure angiocardiopathy and cerebrovascular diseases [179]. The effect of puerarin in the prevention of Aβ-induced neurotoxicity through the inhibition of neuronal apoptosis was also examined. Experiments revealed that treatment of PC12 cells with puerarin dose-dependently ameliorated Bax expression and cytochrome c release and increased P-Akt, Bcl-2, and p-Bad expression [117].
Additionally, in an in vivo experiment, puerarin may improve cognitive performance by activating the Akt/GSK-3β signaling pathway associated with a decrease in the levels of GSK-3β and an increase in the levels of Akt in the hippocampus of APP/PS1 mice [179]. Moreover, in vivo evidence indicates that puerarin can serve as a treatment for age-related neurodegenerative disorders by attenuating tau hyperphosphorylation in D-galactose rats [115].

Traditional Functional Features
Ziziphus jujuba Mill. (SJM) mainly grows in the inland areas of northern China, which has a saying that "thorns are everywhere" in ancient China. SJM, a famous heart-nourishing medicine in China, nourishes the yin blood of the heart to calm the mind in TCM [180].

MOAs of the Extract
SJM is a promising MFH item with various pharmacological actions, including antiinflammatory, anticomplementary activity, hematopoiesis, antioxidant stress, and anticancer properties [181]. In modern pharmacology research experiments, SJM is widely used to alleviate AD-like symptoms. There is evidence that administering SJM orally to 5XFAD mice ameliorated memory impairments by elevating plasmin levels and activity in hippocampal slices from 5XFAD mice [55]. Other studies have demonstrated that SZS ameliorates Aβ-induced LTP deficits through BDNF/TrkB signaling and stimulates plasmin activity in the hippocampus of CD-1 mice [56]. Recent studies suggest that the flavonoid extract of SJM can reduce Aβ-induced toxicity in Caenorhabditis elegans [57].

MOAs of Ingredients
Spinosin is a C-glycoside flavonoid derived from the seeds of SJM that has pharmacological activities, such as anxiolytic and hypnotic effects, and ameliorates memory impairment [182] (Figure 5). Subchronic disease treatment with spinosin (5 mg/kg) activated the ERK-CREB-BDNF signaling pathway to treat cognitive dysfunction in the hippocampus [174]. Another in vitro study using Neuro-2a cells (N2a/WT) and N2a/APP695 cells showed that spinosyn markedly reduced Aβ1-42 production by activating the Nrf2/HO-1 pathway [119]. In addition, spinosin might be beneficial to treat learning and memory deficits through the regulation of oxidative stress, inflammatory processes, apoptotic programs, and plasmin activity [120][121][122].

MOAs of Ingredients
Gastrodin (GAS) is an active constituent extracted from Gastrodia elata ( Figure 4). Liu Y and other review articles found that GAS has potential therapeutic effects on a variety of central nervous system diseases, including AD, PD, affective disorders, cerebral ischemia/reperfusion, and epilepsy. Its extensive pharmacological activities and principal mechanisms include regulating mitochondrial cascades, antioxidant and antiinflammatory functions, modulating neurotransmitters, suppressing microglial activation, and upregulating neurotrophins [184].

Traditional Functional Features
Lycium barbarum L. (a "berry-type" fruit of the plant Lycium barbarum), a yin-tonifying medicine belonging to the Solanaceae family, is recorded in Shennong Ben Cao Jing (ca 100 AD) [186].

MOAs of the Extract
In recent years, Fructus lycii and its phytochemical components have been increasingly reported as promising anti-AD drugs with key pathological events, such as oxidative stress, anti-immune, antiapoptosis, and antinecrosis effects [187]. 2.14. Gastrodia elata Blume 2.14.

Traditional Functional Features
Gastrodia elata Blume, commonly called Chijian or Ming tian ma in Chinese, is considered a liver-pacifying and wind-extinguishing medicine from the tuber of Gastrodia elata Blume (Orchidaceae) [183].

MOAs of the Extract
Studies in vivo demonstrated that Gastrodia elata significantly reduced the number of amyloid deposits, increased choline acetyltransferase expression, and decreased the activity of acetylcholinesterase [62]. There is further evidence that Gastrodia elata extract (50, 250, and 500 mg/kg) may potentially ameliorate cognitive impairments caused by neuronal cell death in amyloid-β peptide (Aβ)-treated PC12 cells [61].

MOAs of Ingredients
Gastrodin (GAS) is an active constituent extracted from Gastrodia elata (Figure 4). Liu Y and other review articles found that GAS has potential therapeutic effects on a variety of central nervous system diseases, including AD, PD, affective disorders, cerebral ischemia/reperfusion, and epilepsy. Its extensive pharmacological activities and principal mechanisms include regulating mitochondrial cascades, antioxidant and anti-inflammatory functions, modulating neurotransmitters, suppressing microglial activation, and upregulating neurotrophins [184].

MOAs of the Extract
In recent years, Fructus lycii and its phytochemical components have been increasingly reported as promising anti-AD drugs with key pathological events, such as oxidative stress, anti-immune, antiapoptosis, and antinecrosis effects [187].

MOAs of Ingredients
Gao Y et al. showed that there are many antiaging active ingredients in Fructus lycii, such as Fructus lycii polysaccharides, β-sitosterol, caffeic acid, and zeaxanthin [188]. Studies have shown that the ability of organisms to respond to oxidative stress is intricately related to their aging and longevity [189]. Fructus lycii polysaccharides are a good antioxidant [190]. A systematic review and meta-analysis indicated that dietary zeaxanthin may be protective against age-related macular degeneration [191]. Habtemariam S. et al.'s mini review revealed that the antiAD therapeutic potential of caffeic acid is associated with antioxidant effects, specific anti-inflammatory mechanisms in the brain, and the various processes of β-amyloid formation [192].

Traditional Functional Features
Alpinia officinarum Hance (AOH), an interior-warming medicine native to China that can warm the stomach and relieve vomiting, dispel cold, and relieve pain is also known as lesser galangal. AOH, which belongs to the Zingiberaceae family, is indigenous to Southeast China (Guangdong, Guangxi, Hainan) [193].
Mosla chinensis Maxim. (MCM), a pungent-warm exterior-releasing medicine, can promote diaphoresis and release to the exterior and resolve dampness, thus harmonizing the spleen and stomach and promoting water metabolism [21].

MOAs of Ingredients
AOH is a dietary product with medicinal applications and also possesses a wide range of pharmacological effects, including angiogenesis, antimicrobial, anticancer, antiinflammatory, vasorelaxation, and antioxidant activities [194]. Diarylheptanoids are considered as principal phytochemical constituents from the rhizome of A. officinarum, including apigenin and galangin [192]. Apigenin, a pharmacologically active agent, is also widely distributed in herbs (Elsholtzia rugulosa) [195].
Previous studies have proven that apigenin resists Aβ-induced toxicity, has antiinflammatory and antioxidant effects, alleviates learning and memory deficits, and depresses neuronal apoptosis [196,197].
Inhibiting the apoptosis of neurons: Studies have shown that apigenin protects neuronal cells from injury by suppressing the phosphorylation of inducible nitric oxide synthase, cyclooxygenase-2 protein, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) in primary microglial cells [103]. Another study showed that apigenin could exert neuroprotection against Aβ-induced toxicity in the presence of copper mainly through inhibiting the p38 MAPK signaling pathway and SAPK/JNK pathway and depressing neuronal apoptosis in vitro [101].
Neuro-immunomodulatory: Dourado NS et al. evaluated the neuroimmunomodulatory and neuroprotective effects of apigenin on glial cells and neurons of Wistar rats. Treatment with apigenin preserves neuron and astrocyte morphology by reducing the expression of OX42, IL-6, and gp130. In addition, apigenin alone and after an inflammatory stimulus with IL-1β also increased the expression of BDNF to exert anti-inflammatory and neuroprotective effects [104]. In addition, apigenin also downregulated BACE1 and β-CTF levels, affecting APP processing and preventing the Aβ burden. Moreover, apigenin restored the neurotrophic ERK/CREB/BDNF pathway in the cerebral cortex for the prevention and/or therapy of AD [102].
Improving cholinergic neuronal transmission: Acetylcholinesterase (AChE) inhibitors are an important class of drugs for the treatment of AD, such as rivastigmine, galantamine, and huperzine. Galangin is a major flavonoid found in Rhizoma Alpiniae Officinarum with the strongest inhibitory effect on AChE activity (56.53 ± 0.03) [105] (Figure 5).

Traditional Functional Features
Curcuma longa L., a blood-activating analgesic medicine extensively cultivated in India and China, has been widely used as a spice in foods. It can eliminate blood stasis, promote the flow of qi, stimulate menstrual discharge, and relieve pain [198].
Curcumin (Cur), a potent antiamyloid natural polyphenol, is derived from the root of RCL (Figure 3). Studies have shown that Cur can effectively modify AD pathology by preventing the formation and accumulation of Aβ, tau inhibition, copper-binding and cholesterol-lowering abilities, anti-inflammatory activity and modulation of microglia, acetylcholinesterase inhibition, regulation of the insulin signaling pathway, and antioxidant activity [201,202]. For example, Cur directly bound to PPARγ increased the transcriptional activity and protein levels of PPARγ and inhibited the nuclear factor kappa B (NF-κB) signaling pathway, indicating that the beneficial effects of Cur on AD are attributable to the suppression of neuroinflammation in APP/PS1 mice [110].
Da Costa et al., in a systematic review, indicated that Cur supplementation, a promising approach in AD, reversed neurotoxic and behavioral damage in both in vivo (Sprague-Dawley rats, APPswe/PS1dE9 and 5xFAD transgenic mice) and in vitro (PC12 cells, SK-N-SH cells, and neonate rat cells) models of AD [203]. For instance, Cur (50 mg/kg) also provided antiamyloid and neuroprotective outcomes in 5xFAD mice [111].
Aromatic-turmerone is an analog of curcumin and is rich in Curcuma longa. Accumulating evidence has demonstrated that aromatic-turmerone impairs the Aβ-induced inflammatory response of microglial cells by inhibiting the NF-κB, JNK, and p38 MAPK signaling pathways in hippocampal HT-22 cells [112]. Moreover, aromatic-turmerone significantly limited brain damage by inhibiting TLR4 and lowered the release of inflammatory mediators [113]. Further evidence was provided that aromatic-turmerone prevented cleaved caspase-3, while neither the level of ROS nor the mitochondrial membrane potential was affected in cerebellar granule neurons [114].

Discussion and Conclusions
Historically, Chinese ancestors developed many kinds of TCM through long-term practice and summarized their application in treating disease [204]. They also realized that many of these TCMs could be eaten as functional foods (TCM nutrition) in their daily lives, which reflects the theory of MFH [8,13,205].
Since the 20th century, chronic diseases have become the main cause of global morbidity and mortality. A very important reason for this is the imbalance of nutrition and suboptimal lifestyle behaviors, leading to such diseases as AD [206,207]. In recent years, limited by the complexity of AD pathology, new drugs targeting amyloid-β peptide (Aβ) or tau proteins have failed to show significant clinical benefits, such as Clinical-Trials.gov identifier: CAD106 (NCT01097096), ACC-001 (NCT01284387), and AFFITOPE AD02 (NCT01117818 CAD106) [208,209]. Consequently, the development of new drugs and new treatment methods have encountered considerable obstacles and bottlenecks. Interestingly, some TCMs are used as functional foods with brain targets, nutritional benefits, and long-term applications, adjusting diet nutrition to prevent the occurrence of AD, such as Salvia miltiorrhiza Bunge, Cinnamomum cassia (L.) J.Presl, Zingiber officinale Roscoe, and Panax ginseng C.A. Mey. [210,211] (Figures 1 and 2). Taking MFH substances as the primary functional foods can ensure the safety and therapeutic effect of functional food. At the same time, good social and economic benefits can also be obtained by using the cost and technical advantages of TCM, coupled with the progress of the modern food industry [212]. Therefore, MFH foods are used as a dietary intervention to provide higher specialist guidance for AD.
However, although pharmacological research and clinical research have been devoted to proving the safety and effectiveness of MFH items in treating AD, the MOAs of MFH and their active components against AD are still unclear [211,213]. Fortunately, TCM transcriptomics, metabonomics, and protein omics, as well as TCM systematic pharmacology, are in full swing. Future research can combine multiomics and systems pharmacology to explore the pharmacokinetics of the multiple ingredients in these MFH substances [214,215]. In addition, most studies on the mechanism and efficacy of MFH are still at the animal and cellular levels; therefore, clinical research is scarce. Future clinical research should be performed to discover novel antiAD agents of MFH foods. Moreover, given the diversity of AD pathology, MFH antiAD research should also focus on its multicomponent and multitarget mechanisms in a holistic way.
MFH originated in China, but is now favored by people worldwide in the daily diet to prevent the occurrence and development of AD. The rapid development of modern science and technology should provide an advanced theory and a wider field of vision for explaining the advantages of traditional MFH theory in AD. Particularly in recent years, overcoming chronic diseases requires more basic and clinical research to develop new drugs. As a renewable and promising resource, MFH should be a resource to take ongoing effective measures to develop and produce new antiAD drugs or health care products.
Author Contributions: P.G. designed and implemented the research, carried out the analysis, and wrote the original draft; B.Z., J.Z., C.W. and Z.W. conducted check and calibration; A.L. and G.D. conceived the research idea, supervised the project, and revised the final manuscript. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest.