Table 1.
Summaries of the included studies.
| Study | Severity of AD Sample Size (T/C) Mean Age (T/C) |
Treatment Period (Weeks) |
Intervention of Treatment Group | Intervention of Control Group | Outcomes |
|---|---|---|---|---|---|
| Furuhashi 2011 [20] | Severe 38(18/20) 82.8/83.1 |
4 | Yokukansan 22.5 g/d | Risperidone 1 mg/d | Barthel Index, MMSE, NPI *, CMAI * |
| Furukawa 2017 [21] | Mild to moderate 137(72/65) 78.3/78/5 |
4 | Yokukansan 7.5 g/d | Placebo 7.5 g/d | NPI-Q *, MMSE |
| Heo 2008 [22] | Mild to moderate 46(15/31) 67.73/66.68 |
12 | Korean red ginseng 9 g/d with usual treatment | Control: usual treatment (Treated with donepezil, rivastigmine, memantine for at least 6 months before randomization) | ADAS (total *, cog *, noncog), MMSE, CDR * |
| Lee 2008 [23] | N/A 82(50/32) 66.6/65.6 |
12 | Korean white ginseng powder 4.5 g/d + Usual treatment | Usual treatment | MMSE *, ADAS-cog *, ADAS-noncog |
| Liu 2013 [24] | Mild to moderate 60(30/30) 74/75 |
12 | Bushen-huatan-yizhi Granule 12 g/d | Piracetam 2.4 g/d |
MMSE *, ADL *, serum SOD *, LPO *, TG * |
| Mazza 2006 [25] | Mild to moderate 60 (T:20/G:21/P:19) 66.2/64.5/69.8 |
96 | Ginkgo biloba 160 mg/d | 1. Donepezil 5 mg/d 2. Placebo |
MMSE, SKT *, CGI * |
| Meng 2005 [26] | N/A 58 (30/28) 70.2/68.4 |
12 | Naohuandan 12 capsules/d | Piracetam 4.8 g/d | MMSE *, ADL * |
| Pakdaman 2015 [27] |
Mild to moderate 116(59/57) 71.8/71.8 |
64 | MLC601 (NeuroAiDTM) 3 capsules/d |
Donepezil according to clinical response and recommended maximum or tolerable dose. | MMSE, ADAS-cog |
| Pan 2014 [28] | N/A 91(45/46) 57.2/56.9 |
20 | Shen-Zhi-Ling Oral Liquid 30 cc/d | Placebo 30 cc/d | BEHAVE-AD, NPI, DFA of actigraph activity, MMSE |
| Wang 2020 [29] | Mild to moderate 51(27/24) 65.48/60.88 |
24 | Jiannao Yizhi Formula 10 g/d with Donepezil placebo 5 mg/d | Donepezil 5 mg/d with Jiannao Yizhi Formula placebo 10 g/d | ADAS-cog *, MMSE *, MoCA *, ADL, CMSS *, Serum Ach *, Aβ42 *, Tau * |
| Yancheva 2009 [30] | Mild to moderate 88(30/29/29) 69/66/68 |
22 | 1. Ginkgo biloba 240 mg/d with Donepezil placebo 2. Ginkgo biloba 240 mg/d with (Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period) |
Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period with Ginkgo biloba extract placebo | SKT, CDT, Verbal fluency test, NPI (total, distress), GBS (total, ADL), HAM-D, CSS (Tinnitus, Dizziness) |
| Zhang 2015c [31] | Mild 113(58/55) 72.79/72.97 |
24 | Yishen Huazhuo Decoction 100 mL/d with Donepezil placebo 5 mg/d |
Donepezil 5 mg/d + Yishen Huazhuo Decoction placebo 100 mL/d |
ADAS-cog *, MMSE, ADL, NPI |
| Chen 2011a [32] |
mild to moderate 67(37/30) 73.89/75.27 |
12 | Bu Yuan Cong Nao Tang 100 mL/d | Donepezil 5 mg/d | MMSE *, ADAS-cog *, ADL * |
| Chen 2011b [33] |
N/A 27(14/13) 72.36/74.38 |
12 | Bushen Phlegm Stasis Compound 100 mL/d | Piracetam 2.4 g/d | MMSE *, ADAS-cog *, ADL * |
| Chen 2010 [34] | Mild to moderate 149(120/29) 66.78/68.29 |
12 | Compound Polygonum multiflorum extract 30 mL/d | Piracetam 2.4 g/d | MMSE *, ADL * |
| Cheng 2013 [35] | N/A 36(18/18) 70.33/68.56 |
12 | Yang xue qing nao Granule 12 g/d with (Donepezil 5 mg/d for the first 2 weeks, 10 mg/d for the remaining period) | Donepezil 5 mg/d for the first 2 weeks, 10 mg/d for the remaining period | MMSE, NPI * |
| Chi 2018 [36] |
Mild to severe 94(47/47) 75.36/74.17 |
24 | Bushen Tianjing Yisui Prescription 1 dose/d with (Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period) | Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period | ADAS-cog *, SIB *, BEHAVE-AD *, ADL *, HAMA *, CSDD * |
| Gong 2019 [37] | N/A 60(30/30) 73.32/72.46 |
12 | “Reinforcing Kidney and Removing Blood Stasis” Formula 300 mL/d | Piracetam 3.6 g/d | MMSE *, FAQ * |
| Gu 2014 [38] |
Mild to moderate 100(50/50) 67.3/66.9 |
24 | Dihuang Yizhi Formula 1 pouch/d with Donepezil 5–10 mg/d | Donepezil 5–10 mg/d | MMSE *, MoCA *, ADAS-cog *, ADL * |
| Gu 2019 [39] |
Mild to severe 66(44/22) 76.18/78.73 |
12 | Yizhi Chidai Prescription 400 mL/d with Donepezil 5 mg/d | Donepezil 5 mg/d | MMSE *, TCM symptoms * |
| Guan 2017 [40] | Mild to severe 60(30/30) 69.3/70.2 |
8 | Di Yong Yizhi Granule 1 dose/d with Donepezil 5 mg/d | Donepezil 5 mg/d | MMSE *, ADAS-cog *, ADL * |
| Guo 2011 [41] | Moderate to severe 60(30/30) 73.8/73/14 |
4 | Zhibai Dihuang Tang 1 dose/d with Donepezil 5 mg/d | Donepezil 5 mg/d | MMSE *, BEHAVE-AD * |
| Hu 2015 [42] |
Mild to moderate 80(40/40) 68.4/69.2 |
24 | Bushen Tongluo Decoction 1 dose/d with (Donepezil 10 mg/d + Piracetam 2.4 g/d) | Donepezil 10 mg/d with Piracetam 2.4 g/d | MMSE *, ADAS-cog *, ADL *, NPI *, serum SOD *, MDA *, TNF-α *, IL-1 *, IL-6 * |
| Huang 2018 [43] | Mild 62(33/29) 72.3/72.8 |
24 | Bushenyisui Formula 1 dose/d with Donepezil placebo | Donepezil 5 mg/d + Bushenyisui formula placebo | MMSE * |
| Jiang 2018 [44] | Mild to moderate 50(25/25) 67.2/70.4 |
12 | Jiannao Powder 10 g/d with (Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period) | Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period | MMSE *, ADL *, HDS-R *, CSF (Aβ42, tau, p-tau) *, TCM symptom score * |
| Li 2015 [45] |
N/A 66(35/31) 69.1/68.4 |
24 | Bupi Yishen Decoction 1 dose/d | Donepezil 10 mg/d | MMSE *, ADAS-cog *, ADL *, TCM symptoms *, serum SOD *, MDA *, T-AOC *, 8-iso-PGF2α *, ox-LDL * |
| Li 2018a [46] | N/A 98(49/49) 74.45/74.27 |
24 | Compound Congrong Yizhi Capsule 3.6 g/d with (Rivastigmine: First month 3 mg/d, second month 6 mg/d. If well tolerated, increased to 12 mg/d) | Rivastigmine: First month 3 mg/d, second month 6 mg/d. If well tolerated, increased to 12 mg/d | MMSE *, ADAS-cog *, BEHAVE-AD *, ADL *, serum Aβ *, IL-6 *, IL-1β *, BK * |
| Li 2016a [47] | N/A 98(49/49) 67.5/67.6 |
12 | Renshen Bujing Anshen Formula with Donepezil 20 mg/d | Donepezil 20 mg/d | BEHAVE-AD *, ACE-R *, Barthel Index * |
| Li 2016b [48] | N/A 50(25/25) 65.60/66.29 |
8 | Huang Cong Formula with Donepezil 5 mg/d | Donepezil 5 mg/d | ADAS-cog, TCM symptoms, MMSE *, FAQ *, HDS *, ADL * |
| Li 2016c [49] | Mild 113(58/55) 72.79/72.97 |
24 | Tonifying Kidney Prescription 1 pouch/d | Donepezil 5 mg/d | MMSE *, ADAS-cog *, ADL * |
| Li 2014 [50] |
Mild to moderate 65(40/25) 73.55/74.12 |
12 | Bushen Huoxue Decoction 1 pouch/d with (Huperzine-A 200 μg/d + Nicergoline 20 mg/d) | Huperzine-A 200 μg/d with Nicergoline 20 mg/d | MMSE *, ADL * |
| Li 2018b [51] | N/A 100(50/50) 69.87/68.19 |
12 | Bushen Yizhi formula 600 mL/d with (Clozapine started with 25 mg/d and gradually increased to 200 mg/d) | Clozapine started with 25 mg/d and gradually increased to 200 mg/d | BEHAVE-AD *, serum MDA * and SOD * |
| Li 2017 [52] |
Mild to moderate 63(31/32) 74.82/75.06 |
12 | Modified Shuyu Pill 30 mL/d | Donepezil 5 mg/d | MMSE *, ADAS-cog *, ADL *, SDSD * |
| Li 2002 [53] |
Mild to moderate 32(18/14) 66/65 |
8 | Danggui Shaoyao San 1 dose/d | Nimodipine 60–120 mg/d | HDS *, MMSE, ADL, CGI |
| Liang 2010 [54] | Mild to severe 100(50/50) 72.6/71.7 |
24 | Bushenyizhi Granule 1 dose/d with (Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period) | Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period | ADAS-cog *, MMSE *, ADL *, TCM symptoms |
| Lin 2006 [55] | Mild to moderate 60(20/20/20) 76.37/74.43/72.63 |
12 | 1. Taioxin 20 mL/d 2. Bushen 20 mL/d |
Donepezil 5 mg/d | 1.Taioxin: MMSE *, ADL, FOM *, BD, DS *, RVR * 2.Bushen: MMSE *, ADL, FOM, BD *, DS, RVR * |
| Lin 2017 [56] | Mild to moderate 60(30/30) 62.33/64.57 |
24 | Phlegm-resolving Orifice-opening Decoction 1 dose/d with Donepezil 5 mg/d | Donepezil 5 mg/d | MMSE *, ADAS-cog *, ADL *, TCM symptoms * |
| Lin 2018 [57] | Mild 66(33/33) 72.29/72.82 |
24 | Bu Shen Yi Sui Decoction + Donepezil placebo | Donepezil 5 mg/d with Bu Shen Yi Sui Decoction placebo | MMSE, ADL, TCM symptoms *, endocrine (testosterone, cortisol *, estradiol, thyroxine, growth hormone *, ACTH *) |
| Liu 2010 [58] | N/A 20(10/10) 61.5/62.3 |
12 | Yizhi Jiannao Granule 16.5 g/d | Donepezil 5 mg/d | MMSE *, ADAS-cog *, serum IL-1β *, TNF-α * |
| Peng 2009 [59] | Mild to moderate 56(28/28) 67.2/67.5 |
12 | Yizhi Jiannao Granule 16.5 g/d | Donepezil 5 mg/d | MMSE *, ADL * |
| Shan 2017 [60] | N/A 82(41/41) 67.32/68.02 |
24 | Bushen Yizhi Granules 1 pouch/d with (Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period) | Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period | MMSE *, ADAS-cog *, ADL *, TCM symptom * |
| Wu 2018 [61] | Mild to moderate 140(70/70) 70.0/71.0 |
24 | Compound Huonaoshu Capsule 6 granules/d with Donepezil 10 mg/d | Donepezil 10 mg/d | MMSE *, ADL *, EEG signals * |
| Yang 2013 [62] | Mild to moderate 60(30/30) 84.22/82.72 |
12 | Yizhi Jiannao Granule 11 g/d | Donepezil 5 mg/d | MMSE *, ADL *, homocysteine * |
| Yang 2018a [63] | N/A 55(30/25) 64.93/63.44 |
24 | Ma Huang Fu Zi Xi Xin Tang 1 dose/d with Donepezil 10 mg/d | Donepezil 10 mg/d | MMSE *, MoCA *, ADL * |
| Yu 2012 [64] |
Mild to moderate 107(55/52) 74.7/76.4 |
48 | Herbal medicine based on syndrome differentiation | Donepezil 5 mg/d | MMSE *, FOM *, BD *, DS *, fMRI |
| Yang 2018b [65] | Mild 59(31/28) 72.66/73.12 |
12 | Tiaoxin 1 pouch/d | Donepezil 5 mg/d | MMSE *, FOM *, RVR *, BD *, DS * |
| Yu 2006 [66] |
Mild to moderate 82(42/40) Mean 69 |
10 | “Reinforcing kidney, activating blood and resolving phlegm” Formula 1 pouch/d | Hydergine 3 mg/d for the first week, 6 mg/d for the remaining period | MMSE *, ADL * |
| Yuan 2017 [67] | N/A 100(50/50) 70.2/70.4 |
24 | Bushen Yizhi Granule 1 dose/day with (Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period) | Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period | MMSE * |
| Zhang 2015b [68] | Moderate to severe 100(50/50) 70/69 |
12 | Shen Gui Yizhi Formula 1 dose/d with Butylphthalide 0.6 g/d | Butylphthalide 0.6 g/d | MMSE *, ADL *, serum Aβ *, TCM symptoms * |
| Zhang 2015a [69] | Mild to moderate 51(26/25) 67.50/68.72 |
12 | Yizhi Xingnao Fang 1 dose/d with (Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period) | Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period | ADAS-cog *, MMSE *, ADL *, SDSD * |
| Zhang 2018b [70] | N/A 88(44/44) 72.91/72.87 |
4 | Qingxin Yizhi Decoction 1 dose/d with Donepezil 10 mg/d | Donepezil 10 mg/d | MMSE *, ADAS-cog *, ADL *, serum SOD *, MDA *, T-AOC *, ox-LDL * |
| Zhang 2018c [71] | Mild to moderate 60(30/30) 65.2/66.4 |
12 | Dihuang Yinzi Decoction 1 dose/d | Donepezil 5 mg/d | MMSE *, ADAS-cog *, ADL *, Levels of Notch1 *, ADAM10 *, BASE1 * |
| Zhang 2008 [72] | Moderate to severe 45(30/15) Mean 73.5 |
12 | Shenghuang-yizhi Granule 4 pouches/d | Piracetam 3.6 g/d | MMSE *, BBS * |
| Zhang 2018a [73] | N/A 100(50/50) 70.8/69.2 |
12 | Compound Danshen Tablet 2.88 g/d with (Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period) | Donepezil 5 mg/d for the first month, 10 mg/d for the remaining period | MMSE *, ADAS-cog *, ADL *, serum Glu * and Asp * |
| Zhou 2007 [74] | N/A 68(23/21/24) 76.1/74.8/75.4 |
24 | 1. Reinhartdt and Sea Cucumber Capsule 2.7 g/d 2. Reinhartdt and Sea Cucumber Capsule 2.7 g/d + Donepezil 5–10 mg/d |
Donepezil 5–10 mg/d | MMSE *, ADAS-cog, ADL *, thyroid hormones |
| Zhu 2010 [75] | Mild to moderate 40(20/20) Mean 72.3 |
8 | Yizhi Jiannao Granule 16.5 g/d | Donepezil 5 mg/d | MMSE *, 8-IPF2α (blood, urine) * |
| Wang 2018 [76] | Mild to severe 127(63/64) 67.3/68.6 |
12 | Bushen Huatan Yizhi Decoction 1 dose/d + Butylphthalide 800 mg/d | Butylphthalide 800 mg/d | MMSE *, hematocrit *, whole blood high shear rate *, whole blood low shear rate *, erythrocyte aggregation index *, MDA *, SOD *, GSH-Px *, CAT * |
-Note: This table only shows the interventions included in this review. The names of the herbal medicines were written according to the original paper. If the medicine was written only in Chinese, it was translated to English based on pronunciation. -*: Outcomes that significantly improved in the treatment group compared with baseline. -Abbreviations: AD: Alzheimer’s disease; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatry Inventory; CMAI: Cohen-Mansfield Agitation Inventory; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; CDR: Clinical Dementia Rating; ADL: Activities of Daily Living; SOD: superoxide dismutase; LPO: lipid peroxide; TG: triglyceride; SKT: Syndrom Kurz test (Short Cognitive Performance Test); CGI: Clinical Global Impression; BEHAVE-AD: Behavioral Pathology in Alzheimer’s Disease Rating Scale; DFA: Detrended Fluctuation Analysis; MoCA: Montreal Cognitive Assessment; CMSS: Chinese Medicine Symptom Scale; CDT: Clock-Drawing Test; GBS: Gottfries–Bråne–Steen Scale; HAM-D: Hamilton Rating Scale for Depression; CSS: Concomitant Symptoms Scale; SIB: Severe Impairment Battery; HAMA: Hamilton Anxiety Scale; CSDD: Cornell Scale for Depression in Dementia; FAQ: Functional Activities Questionnaire; MDA: malondialdehyde; TNF-α: Tumor necrosis factor-α; IL: interleukin; HDS: Hasegawa Dementia Scale; CSF: cerebrospinal fluid; TCM: Traditional Chinese Medicine; AOC: antioxidant capacity; 8-iso-PGF2α: 8-iso-prostaglandin F2α; ox-LDL: oxidized low-density lipoprotein; BK: bradykinin; ACE-R: Addenbrooke’s Cognitive Examination-Revised; SDSD: Syndrome Differentiation Scale for Dementia; FOM: Fuld Object-Memory Evaluation; BD: Block Design; DS: Digit Span; RVR: Rapid Verbal Retrieval; ACTH: adrenocorticotropic hormone; EEG: electroencephalogram; fMRI: functional magnetic resonance imaging; BBS: Blessed Behavior Scale; CAT: catalase; GSH-Px: Glutathione peroxidase.