The Role of Medical Acupuncture Therapy in Alzheimer's Disease

Abstract

Objective:

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory deficits and other cognitive disorders, which can be accompanied by personality changes. Long-term use of medications available to treat AD today have a variety of side-effects. Acupuncture, as a nonpharmacologic therapeutic modality providing stimulation at acupuncture points, using filiform needles, has been widely tested and used to manage of AD and can be a therapeutic option, considering its effectiveness and lack of side-effects.

Methods:

This literature review examines the role of acupuncture in AD treatment.

Results:

Acupuncture can ameliorate AD symptoms through decreasing amyloid-β protein, reducing neuroinflammation, enhancing the antioxidant system, improving neurogenesis, enhancing prosurvival protein, reducing proapoptotic protein, and regulating brain energy metabolism.

Conclusions:

According to various research findings, acupuncture may be a therapeutic choice for addressing AD that avoids the long-term side-effects caused by medical therapy.

INTRODUCTION

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory and other cognitive impairments, which can be accompanied by personality changes.¹ AD is the most common cause of dementia, accounting for 60%–70% of all cases of dementia.² AD is associated with changes in protein, which are mainly caused by aberration and polymerization of soluble protein accompanied by genetic mutations, external factors, aging processes, and aggregations that cause abnormalities to loss of neuron function.¹

Age is the most-important risk factor for AD. In 2015, there were ∼47 million people with dementia worldwide, and this has been estimated to increase to 135 million by 2050.³ AD is the cause of 60%–70% of all cases of dementia.² In the United States, in 2018, it had been estimated that more than 5 million individuals were suffering from AD.⁴ The prevalence of AD increases exponentially in the elderly starting with 1% at age 65 up to ∼40%–50% by age 95.⁵ In 2014, the cost of AD medication reached $172 billion per year in the United States.⁶ It had been estimated in 2007 that 60% of patients with AD lived in developing countries, with the potential estimated proportion increasing to more than 70% by 2040,⁷ so it can be predicted that AD is a major public-health challenge as a consequence of the rapidly increasing elderly population worldwide, especially in developing countries. The decline in memory and other cognitive functions in AD has a broad impact, such as loss of independence and burdens on the families and health systems.⁸

The pathophysiology of AD is the formation of amyloid plaques, neurofibrillary tangles (NFTs), which are accompanied by loss of neurons in the neocortex, hippocampus, and other subcortical areas of the brain.⁹ The α- and γ-secretase cut the amyloid precursor protein (APP), resulting in soluble and nonpathogenic precursors that have a role in normal synaptic signaling. Cutting APP by β-secretase (BACE1) and γ-secretase produces amyloid-β (Aβ) fiber, which is insoluble and oligomerized. Aβ fiber diffuses through the synaptic cleft and becomes plaque that interferes with synaptic signaling. This polymerization causes activation of the kinase, which causes hyperphosphorylation of the τ-protein in the microtubules, and forms an NFT. NFT causes loss of communication between neurons and causes neuron apoptosis. Plaque and tangle aggregation involves microglia around the plaque causing microglial activation and a local inflammatory response, which contributes to neuroinflammation and causes neurotoxicity.¹⁰

The presence of insulin resistance associated with AD is thought to be linked to defects in glucose absorption by neurons that lead to neuronal dysfunction.¹¹ The PI3K/Akt/GSK-3β [phosphoinositide 3-kinases/Akt/glycogen synthase-3β pathway signaling plays a role in insulin regulation. Dysfunction of this pathway leads to an increase in GSK-3β activity leading to β-amyloid deposition and hyperphosphorylation of the τ-protein, leading to cognitive impairment.¹² The loss of cholinergic neurons also results in a decrease in the neurotransmitter acetylcholine, which contributes to decreased memory and learning. This is associated with dysregulation of the neurotransmitter glutamate, which results in cell hyperactivity and can lead to cell death.¹³

AD in patients younger than age 65 (early onset AD) is mostly associated with mutations in the presenilin 1 (PSEN1) gene on chromosome 14, presenilin 2 (PSEN2) on chromosome 1, and amyloid precursor protein on chromosome 21. Meanwhile, an allele of the apolipoprotein E ɛ4 (APOE4) on chromosome 19 is a polymorphism that was found consistently in late-onset AD. Women have a higher risk factor for AD.⁹ The release of cytokines as a product of intestinal microbiota bacteria can pass through afferent-nerve pathways, including the vagal nerves, triggering an inflammatory reaction in the brain that can cause AD.¹⁴ Other risk factors associated with AD development are high oxidative stress; a history of head trauma⁹; and the presence of metabolic disorders, hypertension, and other conditions that can cause vascular disorders.¹⁵

Diagnosis of AD is based on the 2011criteria of the National Institute on Aging–Alzheimer's Association (NIA-AA; see Table 1),^16,17 and on the Diagnostic and Statistical Manual of Mental Disorders, where dementia is included in the “major neurocognitive disorder” category.^18,19 The latest diagnostic criteria include noninvasive diagnostic imaging techniques, such as positron emission tomography scanning with a tracer injection, as well as biomarkers such as τ-hyperphosphorylation peptide (p-τ), Aβ42, and total τ-protein count in the cerebrospinal fluid.²⁰ Table 2 shows the NIA-AA classifications for AD.^16,17

Table. 1.

Clinical Diagnostic Criteria of the National Institute on Aging–Alzheimer's Association for Alzheimer's Disease for Mild Cognitive Impairment, Dementia, and Probable Dementia caused by Alzheimer's Disease^16,17

Diagnosis	Criteria
MCI	(1) Change in cognition recognized by the affected individual or observers (2) Objective impairment in 1 or more cognitive domains (3) Independence in functional activities (4) absence of dementia
Dementia	(1) Interferes with the ability to function at work or in usual activities; & (2) Represents a decline from previous levels of functioning and performing; & (3) Is not explained by delirium or major psychiatric disorder (4) Cognitive impairment is detected and diagnosed through a combination of: (A) History-taking from the patient & a knowledgeable informant; & (B) An objective cognitive assessment. (5) Cognitive or behavioral impairment involves a minimum of 2 of the following domains: (A) Impaired ability to acquire and remember new information (B) Impaired reasoning & handling of complex tasks, poor judgment (C) Impaired visuospatial abilities (D) Impaired language functions (E) Changes in personality, behavior, or comportment (6) Meets criteria for dementia, & also has the following characteristics: (A) Insidious onset; symptoms have a gradual onset over months to years; not sudden over hours or days (B) Clear-cut history of worsening of cognition according to reports or observations (C) The initial & most-prominent cognitive deficits are evident on history and examination in 1 of the categories of Probable AD dementia
Probable AD dementia	(1) Amnestic presentation: deficits should include impairment in learning & recall of recently learned information; there should also be evidence of cognitive dysfunction in at least 1 other cognitive domain (2) Nonamnestic presentations include: (A) Language presentation: the most prominent deficits are in word-finding, but deficits in other cognitive domains should be present (B) Visuospatial presentation: the most prominent deficits are in spatial cognition, including object agnosia, impaired face recognition, simultanagnosia, & alexia; deficits in other cognitive domains should be present (C) Executive dysfunction: the most prominent deficits are impaired reasoning, judgment, & problem solving; deficits in other cognitive domains should be present (3) Diagnosis of probable AD dementia should not be applied when there is evidence of: (A) Substantial concomitant cerebrovascular disease, defined by history of a stroke temporally related to the onset or worsening of cognitive impairment; or presence of multiple or extensive infarcts or severe white-matter hyperintensity burden; or (B) Core features of dementia with Lewy bodies other than dementia itself; or (C) Prominent features of behavioral variant frontotemporal dementia; or (D) Prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or (E) Evidence of another concurrent, active neurologic disease, or a nonneurologic medical comorbidity, or use of medication that could have a substantial effect on cognition

MCI, mild cognitive impairment; AD, Alzheimer's disease.

Table. 2.

Classifications of the National Institute on Aging–Alzheimer's Association for Alzheimer's Disease²¹

Diagnosis	Classifications	Comments
Preclinical AD	This is the pathophysiologic stage when in-vivo molecular biomarkers of AD are present but symptoms are absent	Established that AD has a long asymptomatic stage. AD can only be identified with in-vivo AD biomarkers
MCI	Diagnosis of MCI due to AD requires evidence of intraindividual decline, manifested by self or informant-reported complaint showing objective cognitive impairment.	Preserved independence in functional abilities; increased diagnostic confidence may be suggested by positive Aβ biomarker and a positive degeneration biomarker
AD dementia	Criteria for “probable AD” now allows nonamnestic presentations of AD dementia.	Identified intraindividual decline in cognition & function as the salient clinical features; AD biomarkers enhance confidence in clinical diagnosis

AD, Alzheimer's disease; MCI, mild cognitive impairment.

Several assessment instruments are often used to evaluate the condition of patients with AD.²¹ The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) contains 11 tasks to assess memory domains, language, praxis, and orientation. The Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus) is used to assess the effect of treatment on overall clinical status in patients with AD, including general condition, mental status, behavior, functional ability, and the patient's condition during and or at the end of therapy. The 23-Item Alzheimer's Disease Cooperative Study Activities of Daily Living Scales (ADAS-ADL23) is used to assess basic and instrumental activities of daily life, The Neuropsychiatric Index (NPI) is used to measure behavioral symptoms of patients who have dementia.²²

Pharmacologic therapies are widely used to manage AD are cholinesterase-inhibitors—such as donepezil, rivastigmine, galantamine, and noncompetitive receptor antagonist N-methyl-d-aspartate (NMDA) antagonists, for example, memantine.²³ Chlolinesterase inhibitors work to activate the cholinesterase enzyme to prevent the decrease in the amount of the neurotransmitter acetylcholine, while NMDA antagonists prevent glutamate overactivity; this treatment is expected to provide symptomatic improvement in patients with AD.¹³ However, this medical therapy has side-effects: nausea; anorexia; diarrhea; insomnia; loss of appetite; bradycardia; extrapyramidal symptoms²³; and cardiovascular disorders, which can occur in as much as 6% of patients.²⁴ Pharmacologic therapy does not change the underlying pathology or prevent the progression of AD, so this therapy can be called noncurative palliative therapy.¹³

The high cost of pharmacologic therapy, which provides no optimal results,²⁵ and the presence of quite-disturbing side-effects, encourages the need for other therapeutic modalities for managing AD.²⁶ Acupuncture, as a nonpharmacologic therapeutic modality providing stimulation at acupuncture points, using filiform needles, has been widely tested and used to manage of AD and can be a therapeutic option, considering its effectiveness and lack of side-effects.²⁷ The mechanism of action of acupuncture against AD is thought to be related to decreasing Aβ protein, enhancing the antioxidant system, improving neurogenesis, and regulating blood-sugar metabolism.

METHODS

A search of studies published from 2013 to 2019 was conducted on the effect of acupuncture on AD on Google Scholar and PubMed using the key words acupuncture, electroacupuncture, laser acupuncture, Alzheimer's disease, amyloid beta plaque, neurofibrillary tangles, and τ protein. Studies in humans or animals were included. The studies were then reviewed and selected to obtain information about the association and mechanism of acupuncture for addressing AD.

RESULTS

Based on the search strategy mentioned above, 11 studies (summarized in Table 3) in humans and animals were included to explain the role of acupuncture in AD.

Table. 3.

Summary of research on Acupuncture Therapy for Alzheimer's Disease

1st author, yr & ref,	Study design	Acupuncture points	Modality
Jia, 2017²²	RCT	TE 5, CV 6, CV 12. CV 17, ST 36, SP 10	Manual acupuncture
Wang, 2014²⁸	RCT	LI 4, LR 3	Manual acupuncture
Zheng, 2018²⁹	RCT	LI 4, LR 3	Manual acupuncture
Yu, 2019¹²	Summary review	GV 20, HT 7, PC6, KI 3, ST 36	Manual acupuncture
Dong, 2015¹⁵	Experimental	GV 14, BL 23	EA
Guo,2015³⁰	Experimental	BL 23, GV 20	EA
Guo, 2016³¹	Experimental	BL 23, GV 20	EA
Li, 2014³²	Experimental	GV 20	EA
Sutalangka, 2013³⁴	Experimental	HT 7	Laser acupuncture
Kan, 2018³⁵	Experimental	CV 6, CV 12, CV17, ST 36, SP 10	Manual acupuncture
Cai, 2019³⁶	Experimental	KI 3	EA

yr, year; EA, electroacupuncture.

Jia et al. conducted a randomized controlled trial in 2017 to compare the efficacy of manual acupuncture versus medication (donepezil hydrochloride).²² The intervention involved 12-week treatment timeperiod with a 12-week follow-up and an assessment at week 28. There were significant between-group differences in ADAS-cog scores at week 28, compared to baseline (P < 0.05). The CIBIC-Plus scores showed obvious decreases for the acupuncture-treated group, compared to the with donepezil group at 16 weeks, and at 28 weeks; significant statistical differences were observed between the 2 groups (P < 0.05).²²

A study conducted by Wang et al., in 2014, involving humans and using functional magnetic resonance imaging (fMRI), proved that, in patients with AD, the right-middle frontal lobe (MFG) showed significantly higher connectivity with the left hippocampus following acupuncture (P < 0,01).²⁸ A study by Zheng in 2018 showed that the functional connectivity between the hippocampus and the precentral gyrus showed enhancement after acupuncture in patients with AD (P < 0,001).²⁹ Acupuncture modulated, functional activity and connectivity of specific cognition-related regions in patients with AD.²⁹ Another imaging study conducted in 2019 by Yu et al. showed that stimulation of single or combined acupuncture points in humans modulated various parts of the brain related to memory function, cognitive, emotional regulation, attention, etc.¹²

Adenosine monophosphate-activated kinase (AMPK) activation can increase impaired brain energy metabolism in AD; suppress phosphorylated-τ and Aβ production; and improve mitochondrial respiration, glucose uptake, fatty-acid oxidation, and lipid metabolism. An electroacupuncture (EA) study on an AD mouse model by Dong et al., in 2015, showed that the intervention group had higher spatial abilities and memory (P < 0.01), and improved p-AMPK (a marker of AMPK activation) values (P < 0.01), compared to controls.¹⁵

In 2015, Guo et al. conducted an electroacupuncture study in animals that showed that mice in the intervention group had a smaller number of apoptotic cells in their brains, accompanied by an increase in the prosurvival protein Bcl-2 and a decrease in the proapoptotic protein Bax (P < 0.01 and P < 0.05, respectively), and synapsin and synaptophysin expression in the hippocampus that was more increased (P < 0.05).³⁰ In 2016, another animal study by Guo et al. proved that EA reduced β-amyloid aggregates levels in neurons through an augmented autophagy pathway (P < 0.001).³¹ Yet another animal study by Li et al., in 2014, suggested that EA improved cognitive function, reduced Aβ deposits in the brain (P < 0.05), regulated BDNF (P < 0.05), and increased neurogenesis (P < 0.05).³²

Antioxidant systems—such as enzyme catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD)—protect cells from damage that can trigger AD.³³ A laser acupuncture study in animals was carried out by Sutalangka et al., in 2013, showing the presence of acetylcholinesterase suppression in the hippocampus (P < 0.001), and increased SOD and CAT (P < 0.05 and P < 0.01) in AD-model mice who underwent laser acupuncture.³⁴ Kan et al., in 2018, showed an increase in memory and spatial learning evidenced by increased retention time in the original platform quadrant (P < 0.001) and shortened escape latency (P < 0.05), as well as improvement in the dendritic structure of the brains (P < 0.05) of AD-model mice receiving manual acupuncture therapy.³⁵ Another animal study, conducted by Cai et al., in 2019, showed that acupuncture statistically significantly lowered the expression of microglia, which play a role in causing neuroinflammation (P < 0.01) and increase brain metabolic activity, such as in the frontal cortex (P < 0.05) and hypothalamus (P < 0.01).³⁶

DISCUSSION

Mechanism of Acupuncture in Alzheimer's Disease

Acupuncture has been shown to ameliorate AD through a variety of mechanisms. Objective evidence suggests that acupuncture can increase p-AMPK (a marker of AMPK activation). which improves brain energy metabolism, mitochondrial respiration, glucose uptake, fatty-acid oxidation, and lipid metabolism; reduces phosphorylated τ and Aβ deposits¹⁵; and reduces APP and BACE protein deposits. Acupuncture also increases the prosurvival protein Bcl-2; decreases the proapoptotic protein Bax³⁰; and regulates BDNF, which is an important factor in neurogenesis. Improving neuroplasticity and regulating memory are also factors that play roles in how acupuncture affects AD.³² Acupuncture can also improve dendritic structures brain, which affects cell survival.³⁵ Biomolecular acupuncture can suppress acetylcholinesterase in the hippocampus, and increase SOD and CAT, which function as antioxidants,³⁴ and reduce expression of microglia, which play a role in causing neuroinflammation.³⁶

Stimulation of acupuncture points activates associated brain parts that, in turn, stimulate the target organs through neuro–endocrine–humoral regulation. Both single and combined acupuncture-point(s) stimulation–imaging studies in humans show that acupuncture modulates various parts of the brain related to memory function, cognition, emotional regulation, attention, etc. Acupuncture-point stimulation also plays a role in regulating blood-glucose metabolism in patients with AD, which is thought to be correlated with the PI3K/Akt/GSK-3β signaling pathway.¹²

Acupuncture as a Treatment Choice for AD

Acupuncture can ameliorate symptoms in AD, which can be assessed based on questionnaires such as ADAS-cog and CIBIC-Plus (P < 0.05).²² Imaging studies have shown that acupuncture modulates various parts of the brain associated with AD, such as the frontal cortex, hypothalamus and hippocampus.¹² In addition, animal studies have shown that acupuncture can induce higher p-AMPK values (P < 0.01),¹⁵ increase the prosurvival protein Bcl-2 (P < 0.01), decrease proapoptotic protein Bax (p < 0.05),³⁰ reduce Aβ deposits in the brain (P < 0.05), regulate BDNF(P < 0.05), increase neurogenesis (P < 0.05),³² suppress acetylcholinesterase (P < 0.001), increase the antioxidant system's SOD and CAT (P < 0.05 and P < 0.01, respectively),³⁴ improve brain dendrite structure (P < 0.05),³⁵ and reduce neuroinflammation (P < 0.01).³⁶

Acupuncture has the potential to reduce symptoms of AD through the mechanisms described. The various mechanisms of acupuncture in AD suggest that acupuncture has the potential for treatment beyond currently available pharmacologic treatment options.

In the various human and animal studies of acupuncture therapy for AD, the most-frequently used point was GV 20, while both manual acupuncture and EA were commonly used for management of AD (Table 3). Stimulation at the GV 20 point can improve neuronal-synaptic transmission, prevent neuronal apoptosis, prevent neuroinflammation,¹² and increase cerebral blood flow.³⁷ In addition, fMRI imaging shows that stimulation of GV 20 enhances various parts of the brain related to emotional control and cognitive processes, such as the orbital frontal cortex and the precuneus.¹²

CONCLUSIONS

Various results of acupuncture research on AD show that acupuncture has a positive effect on AD through various mechanisms, including increasing brain energy metabolism, reducing protein Aβ deposits, increasing prosurvival protein, reducing proapoptosis protein, activating antioxidant function, suppressing neuroinflammation, and increasing neurogenesis. Acupuncture has been shown to improve especially the cognitive domain, an effect that can last for at least 12 weeks. The most frequently used point is GV 20, while both manual acupuncture and EA are commonly used. Acupuncture can be an adjuvant therapy option in AD, avoiding the side-effects that can arise with pharmacologic use.

AUTHORs' CONTRIBUTIONS

Drs. Helianthi, MD and Nareswari, were responsible for the study conception and design. As well as supervising the research. Dr. Teja, MD was involved in data collection, analysis, and interpretation of results as well as preparing a draft of the article. All of the authors reviewed the results and approved the final version of the article.

Footnotes

AUTHOR DISCLOSURE STATEMENT

No financial conflicts of interest exist.

FUNDING INFORMATION

Funding of the present work was wholly provided by the first author.

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