Q. Wang1,2, F. Gao1,2, L. Dai1,2, J. Zhang2, D. Bi2, Y. Shen1,2
1. Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; 2. Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Corresponding Author: Yong Shen, Department of Neurology and Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China, E-mail: firstname.lastname@example.org
J Prev Alz Dis 2022;
Published online April 28, 2022, http://dx.doi.org/10.14283/jpad.2022.46
Based on the background of research investigating brain aging and neurodegenerative diseases in China, the present review addresses Alzheimer’s disease (AD), one of the most common types of neurodegenerative diseases, clinical research progress, and prospects for future development in China.
Key words: Alzheimer’s disease, biomarkers, clinical trials, China.
The transition from aging to major chronic disease is an early, critical stage in the development of age-related disease(s). In this regard, the international community has reached consensus to adopt the strategy of “pass forward and mode transformation”, focusing on the monitoring and prevention of age-related diseases. The National Institute on Aging, part of the National Institutes of Health in USA, has invested billions of dollars each year in basic research and translational research in the field of aging (1). The European Union officially launched its “Horizon 2020 2014-2020” program in 2014, with a budget of > 2 billion Euros targeted at population health in the first four years (https://ec.europa.eu/programmes/horizon2020/en/h2020-section/health-demographic-change-and-wellbeing). It mainly supports research and safeguards on population health and aging. With the support of the National Natural Science Foundation of China, China officially launched a major research program, “Mechanism of Organ Aging and Organ Degeneration” in 2016, promoting rapid development in research investigating aging and degenerative diseases in the country. Based on the background of research investigating brain aging and neurodegenerative diseases in China, the present review addresses Alzheimer’s disease (AD), one of the most common types of neurodegenerative diseases, clinical research progress, and prospects for future development in China.
The prevalence, number of deaths, national cost and policies of AD and other dementia (2-4) in China were analyzed and compared with that in Japan, USA, Europe and the global (5-11) as shown in Table 1. In China, the growth in the number of individuals living with dementia is more than 15.1 million and the cost of dementia is estimated to 248 billion USD. Thus, it is crucial to make a strategy for prevention of dementia, especially in AD.
AD primarily affects glutamate and acetylcholinergic neurons in the cortex and hippocampus, with affected patients exhibiting progressively worsening memory and cognitive impairment (12). However, the exact pathogenesis of AD remains unclear, and there is no effective clinical treatment. While aging is widely recognized to be a major risk factor for neurodegenerative disease(s), especially AD, there is still no clear distinction between the two conditions—more specifically, aging and age-related neurodegenerative disorders. In fact, many of the changes that occur in AD, such as accumulation of misfolded proteins, chronic inflammation, mitochondrial dysfunction, and epigenetic modifications, are often evident in the normal aging process (13). Therefore, it is critical to identify key molecular and cellular events, as well as regulatory pathways that can differentiate healthy aging from age-related disease, such as identifying effective biomarkers for the early diagnosis of AD.
Abbreviations: AD, Alzheimer’s disease; USD, United States dollar; NSFC, National Natural Science Foundation of China; CAS, Chinese Academy of Science; MOST, Ministry of Science and Technology; N/A, not applicable.
Genetic risk factors for AD in China
Previous studies have indicated that several risk genes are associated with the pathogenesis of AD, and their effects and potential roles in this regard have also been identified in Chinese AD populations (14-20). Mutations in APP, PSEN1, and PSEN2 have been identified not only in Caucasian familial AD but also in Chinese familial AD (14-16, 18). Jia et al established a longitudinal cohort, named the “Chinese Familial Alzheimer’s Disease Network” (CFAN), to study the genetic features of patients with familial AD in China (16). The major result was that the rate of PSENs/APP mutations in CFAN was 13.12%, which is similar to that in Japanese populations (11.11% (21) and 16.70% in Korean (22)), but is lower than that in Caucasians (17.50% to 67.74%) (23-25). Moreover, 11 novel missense mutations of PSENs/APP were identified in the CFAN (16).The results of this study revealed PSENs/APP mutations and higher apolipoprotein E (ApoE) ε4 frequencies, as well as 11 novel missense mutations of PSENs/APP in those with familial AD (16). Importantly, the potential roles of these gene mutations in the pathogenesis of AD, including the levels of Aβ42 and phosphorylated tau, have been confirmed in vitro (26-30).
Moreover, coding variants of triggering receptor expressed on myeloid cells 2 (TREM2) and its contribution to the increased risk for late-onset AD have been identified in Chinese cohorts (17, 20). Studies by Chinese researchers have demonstrated the important role of TREM2 as a microglial Aβ receptor in the regulation of microglia responses as well as Aβ degradation (31-33). Additionally, their results demonstrated that AD-related mutations in TREM2 affected the binding of TREM2 and oligomer Aβ, which may modify the progression of AD (32, 33). Except for surface receptor TREM2, soluble TREM2 (sTREM2), which is abundant in the cerebrospinal fluid (CSF) has been reported to be correlated with neuronal injury. Attentionally, sTREM2 plays a protective role in AD by promoting microglial phagocytosis and clearance of Aβ (34).
As another strong genetic risk factor for AD, ApoE ε4 could influence AD pathogenesis (35) through regulation of the Aβ process, as well as lipid transport and delivery (36). Wang et al. reported that the transcription factor CCAAT/enhancer binding protein-β (C/EBPβ)-driving asparagine endopeptidase (AEP) is a potential upstream mechanism of ApoE gene expression under pathological conditions, which induce robust senile plaques and tau pathologies (37). Chinese researchers have characterized several new molecular and cellular mechanisms of ApoE. Shi et al. demonstrated the important role of ApoE ε4 in the hypermetabolism of AD; more specifically, that ApoE ε4-induced mitochondrial dysfunction through the PGC-1α-sirtuin3 (peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC-1α]) pathway (38), which could lead to oxidative stress and further synaptic and cognitive impairments (39). More recently, a study by Liu et al reported that ApoE expressed by astrocytes could vector a series of microRNAs and epigenetically regulate genes involved in the neuronal metabolic system, highlighting a novel mechanism for how astrocytes regulate neuronal function and memory consolidation (40).
Additionally, Lee et al summarized the causative genes and some susceptibility genes of AD with their mutations sites newly discovered in China (41). Overall, these studies addressing genetic risk factors provide extensive evidence and new insights into AD, and may also be considered as potentially important therapeutic targets for blocking AD progression.
AD Pathogenics Identified in China
Neural fibril tangles formed by hyperphosphorylated tau, together with Aβ plaques, is a pathological hallmark of AD (42). A study by Wang et al identified glycogen synthase kinase-3 (GSK-3) as a key kinase that phosphorylates tau and promotes AD-like cognitive impairment(s). They also identified several upstream stimulators of GSK-3, including advanced glycation endproducts and peroxynitrite (43-47).
Adult neurogenesis modulates synaptic plasticity and cognitive functions, and is impaired in the dentate gyrus of the hippocampus in patients with AD (48, 49). Sun et al reported that two AD mouse models (hAPP-J20 and APP/PS1, genetic AD mouse models expressing a mutant human APP gene and developing Aβ plaques) exhibited impaired neurogenesis in the hippocampal dentate gyrus (50). The underlying mechanism is that Aβ-induced increases in GABAergic neurotransmission contributes to morphological and functional impairment of the adult born dentate gyrus granule cells in hAPP mice (51). Furthermore, hyperphosphorylated tau also accumulates in dentate gyrus GABAergic neurons and impairs adult neurogenesis by suppressing GABAergic transmission (52). Consistent with the established connection between GABAergic inhibition and adult neurogenesis in the hippocampal dentate gyrus, these studies suggest new mechanisms underlying the neurogenesis of impairments in the AD brain (44, 53).
Synaptic dysfunction is an early event in AD (54). Glutamatergic and cholinergic synapses are traditionally regarded to be more vulnerable to AD pathology (55-59). In addition, GABAergic dysfunction has been increasingly reported to mediate AD pathogenesis by other mechanisms (60, 61). GABAergic neurons are more susceptible to ApoE ε4-induced neurodegeneration dependent on tau pathology (62, 63). Parvalbumin (PV) neurons are a major subtype of GABAergic neurons targeting the soma and perisomatic compartments of pyramidal cells in the forebrain (64). Erb-B2 receptor tyrosine kinase 4 (ErbB4) impairs synaptic plasticity and cognitive functions via interaction with Aβ in PV neurons (65). Furthermore, attenuated GABAA receptor-mediated inhibitory currents due to reduced expression of the α1 and γ2 subunits emerges earlier than Aβ deposition and contributes to hyperactivity of CA1 pyramidal neurons and cognitive impairments in 5xFAD mice (another classical genetic AD mouse model developing Aβ plaques at 2–3 months of age) (66). Thus, the GABAergic system may represent another therapeutic target for AD.
A series of neural circuits related to cognitive impairments has been identified in the brain with AD. Choline acetyltransferase neurons in the vertical diagonal band of Broca (vChATs) regulate the survival of adult-born dentate gyrus granule cells in the dorsal hippocampus through direct innervation (67). In AD mice, cholinergic transmission between vChATs and adult-born granule cells is impaired, and theta-burst activation of vChATs restores neurogenesis (67). Furthermore, selective degeneration of glutamatergic projections from the entorhinal cortex to PV neurons in CA1 is due to activation of death-associated protein kinase 1 (DAPK1) (68). Dysfunction of the neural circuit from the dentate gyrus mossy cells to local somatostatin neurons, another major type of GABAergic neurons, contributes to memory imprecision in AD mice (69). Based on these neural circuits, deep brain stimulation, which has been shown to have beneficial effects in neurological and psychiatric diseases, has been evaluated in several clinical trials for AD (70).
Neuroinflammation in AD in China
Increasing evidence suggests that different components of the immune system lead to neuroinflammation and play important roles in the pathogenesis of AD (71). Microglia, the critical resident innate immune cells in the central nervous system, play different roles during AD. In AD pathological conditions, beta-amyloid (Aβ) plaques are surrounded by microglia in the brain, which limits the growth of Aβ plaques and the loss of plaque-associated dendritic spine (72). Transcriptomic profiling of microglia has identified up-regulated, aging-driven genes associated with the inflammatory response, which were expressed at higher levels in AD (73). However, how the microglial transcriptome can be regulated to mitigate AD pathology remains unknown. A recent study revealed that the PU.1-transcription factor interaction-dependent pathway that drives interleukin 33-induced microglia functional state transition, results in enhanced Aβ clearance (74).
Interestingly, the function of microglia in AD can also be regulated by various immune modulators. The level of Nogo receptor (NgR), a receptor for three axon growth inhibitors associated with inflammation, is elevated with aging and inhibits the adhesion and migration of microglia to Aβ (75). Consistently, blockage of the Nogo/NgR signal pathway accelerates the clearance of fibril Aβ and alleviates plaque deposition (76, 77). TREM2 is a receptor of ApoE (78), and TREM2 deficiency significantly reduced microglial survival via inhibiting the Wnt/β-catenin signaling pathway (79).
Similarly, sTREM2 has been shown to promote microglial migration, survival, and activation in a PI3K/Akt-dependent manner (34, 80). Moreover, oligomeric Aβ42 (oAβ42)—but not monomeric Aβ—has a high binding affinity for TREM2 and promotes the migration of microglia (33), suggesting that microglial responses are modulated by such an interaction. However, a recent study demonstrated that microglial TREM2 could also induce synaptic loss at the early-middle stage of AD (in 2–6-month-old APP/PS1 mice), whereas it prevents amyloid deposition at the middle-late stage of AD (6–10-month-old APP/PS1 mice). TREM1, another member of the TREM2 family, has the ability to ameliorate Aβ neuropathology and improve the spatial cognitive function of AD mice because it facilitates microglial phagocytosis of Aβ (81). Moreover, Yuan group identified that receptor-interacting protein kinase 1 (RIPK1) mediates activation of microglia through a non-cell death mechanism in AD, thus suggesting the potential of RIPK1 as a therapeutic target for the treatment of AD (82). Furthermore, the same authors also proposed that inhibiting necroptosis targeting RIPK1 helps suppress neuroinflammation and mitigates multiple cell death in central nervous system diseases, including AD (83).
In addition to the innate immune system, adaptive immunity, especially CD4-positive (+) T cells and autoantibodies to Aβ, are strongly implicated in the pathology of AD. However, the mechanism of CD4+ T cell dysfunction in AD remains largely unknown. Recently, a study by Shen group demonstrated that the high expression of beta-secretase 1 (BACE1), which is the critical enzyme involved in the cleavage of amyloid precursor protein (APP) to produce amyloid beta-peptides (Aβ), facilitates CD4+ T cell activation via PGE2 signaling, whereas PGE2 receptor antagonist significantly lowers CD4+ T cell activation and ameliorates Aβ pathology in the 5xFAD mouse brain (84). T-helper 1 cells, a subpopulation of CD4+ T cells with proinflammation, were recently found to be stimulated by the peripheral accumulation of phenylalanine and isoleucine released from the gut microbiota, whereas GV-971, a sodium oligomannate, has been shown to have significant effectiveness in suppressing gut dysbiosis and mitigating neuroinflammation (85).
Recent advances in molecular detection technologies have led to the identification of antibodies to Aβ in both the cerebrospinal fluid (CSF) and plasma. Wang et al reported higher levels of Aβ antibodies targeting the mid-domain of Aβ in both the CSF and plasma of AD patients, and plasma levels of Aβ at baseline were associated with cognitive decline (86).
Furthermore, tumor necrosis factor (TNF) receptor-I (TNFRI), an immune molecular receptor expressed on neurons, has a high binding affinity for TNF-alpha, and can directly induce neuronal death via its “intracellular death domain” (87). In particular, Aβ-induced neuronal apoptosis and neuronal AMPAR-mediated excitotoxicity are prevented by deletion of TNFRI (88, 89). However, TNF receptor II, another member of the TNF receptor superfamily, appears to be neuroprotective by inhibiting Aβ reduction and activation of microglia (90). Thus, different TNF receptors may exert opposite effects through distinct molecular mechanisms of neuropathology.
Collectively, these studies support the concept that immunological processes are actively involved in AD progression and severity, and that modulation of inflammatory effectors could be a promising therapeutic strategy for AD in the future.
AD Biomarker Research in China
Early and accurate diagnosis of AD provides an opportunity to monitor disease progression and interventions for AD (91). Thus, it is essential to search effective biomarkers to achieve this goal. Below, we have reviewed the development of AD biomarkers by Chinese scientists in recent years (Table 2).
Studies involving Caucasian populations have accepted several plasma molecules, including Aβ42, Aβ40, NFL, p-tau 181, and p-tau 217, as core biomarkers for AD (92). These AD core biomarkers have been demonstrated to precisely differentiate AD dementia from non-AD dementia. However, few studies have involved Chinese populations (93, 94). A clinical study by Ding et al, from Huashan Hospital (Shanghai, China), has managed cohort recruitment from 2018 to 2020. The authors described the profile of plasma biomarkers, including Aβ40, Aβ42, t-tau, NFL, and p-tau 181, in the cohort. They demonstrated that plasma p-tau181 is the most likely reliable blood-based biomarker for Chinese patients with AD (95, 96). Additionally, Shen group, from University of Science and Technology of China the first affiliated Hospital in Hefei, measured plasma BACE1 activity among AD, MCI and health control subjects, and found that it is significantly increased in AD patients and MCI converters. The results indicated that plasma BACE1 activity may be a biomarker for AD risk (97). Meanwhile, an exploratory study by Wang group, from Daping Hospital (Chongqing, China) based on the Chongqing cohort study, aimed to detect naturally occurring antibodies to Aβ (NAbs-Aβ) in patients with AD (86). Due to changes in the epitope-specific pattern of NAbs-Aβ in preclinical and clinical AD patients, the results suggested a potential biomarker for AD. Furthermore, a study by Ip group, from Hong Kong based on the cohort from Prince of Wales Hospital of the Chinese University of Hong Kong from 2013 to 2018, has identified a 19-protein biomarker panel for specific stages of AD (98). They demonstrated that a composite plasma biomarker panel can improve highly accurate AD diagnosis.
Synaptic damage has been suggested to occur in the non-symptomatic stage of AD; as such, the potential of synaptic proteins as biomarkers for AD has been gradually confirmed (99). In 2019, Jia et al, from the Xuanwu Hospital (Beijing, China) conducted a two-stage cross-sectional study involving four datasets. The authors found that synaptic proteins in neuronal-derived exosomes from the blood may serve as predictive factors for AD at the asymptomatic stage (100). More specifically, the authors demonstrated that neuronal-derived exosomes in patients with AD or preclinical AD exhibited decreased levels of several synaptic proteins, including growth-associated protein 43 (GAP43), neurogranin, synaptotagmin, and synaptosome associated protein 25 (SNAP25). These plasma exosome molecules are highly correlated with those in the CSF, and have a high ability to detect AD at the asymptomatic stage.
Meta-analysis is a method for systematically combining qualitative and quantitative data from several prospective studies (101). A study by Yu et al, from the Huashan Hospital in Shanghai, took full advantage of the abundant validated and accessible data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, and analyzed the association between CSF levels of progranulin (PGRN) with genetic variation, as revealed by genome-wide association study in ADNI (102). These results suggest a novel down-regulation effect of FAM171A2 gene variation on PGRN expression. Importantly, they confirmed the association of FAM171A2 variants with reduced CSF PGRN levels in a clinical cohort of Chinese patients.
The aging of the Chinese population has become a challenge for the government and society. Moreover, the number of individuals diagnosed with dementia has reached 6.0% of the aged Chinese population, which accounts for approximately one-quarter of patients with dementia worldwide (103). However, all Chinese patients with AD have not been systematically evaluated according to the Amyloid/Tau/Neurodegeneration (i.e., ATN) framework criteria. Therefore, clinical research focusing on early diagnostic markers for AD in the Chinese population requires huge amounts of efforts to complete it.
Abbreviations: AD, Alzheimer’s disease; CN, cognitively normal; aMCI, amnestic mild cognitive impairment; NAbs-Aβ, naturally occurring antibodies to Aβ; BACE1, β-site APP-cleaving enzyme 1.
Clinical management of dementia in China
In China, patients with memory complaining or even with dementia without psychological symptoms usually visit neurologists rather than psychiatrists or geriatricians. The neurology department or memory clinics by neurologists are often the primary settings for patients to receive their early diagnosis. The clinical practice guideline of dementia and memory disorders was proposed in 2018 by the Committee of Cognitive Impairment Disorders of the Neurology Branch of the Chinese Medical Doctor Association. However, the diagnosis criteria of cognitive disorders differ among the types of hospital, which was summarized by the group for the project of dementia situation in China in 2019 (8). In general, at academic hospital, professionals of dementia can make a clinical diagnosis of dementia according to the criteria of NINCDS-ADRDA in 1984 (104), revised NIA-AA in 2011 (105) through clinical symptoms and neuropsychological tests; and make a research criteria according to the revised NIA-AA guidelines in 2018 (106), which combined neuropsychological tests with brain MRI, amyloid-PET or lumber puncture for CSF biomarkers. In community -based hospital, the diagnosis of dementia is usually determined by primary-care physicians without specialized training in dementia. Inspiring, the National health Commission of the People’s Republic of China has released a work plan for prevention and treatment of dementia in 2020, which will improve the screening rate of cognitive disorders of elderly in the community. Furthermore, wang’s group, from Beijing University 6th hospital, demonstrated that enhanced training of primary care providers on dementia screening skills was better on continuous service on dementia detection in community in China (107).
Medications for AD in China includes four FDA approved and one approved by Chinese National Medical Product Administration (CNMPA). These include three cholinesterase inhibitors, such as donepezil, rivastigmine and galantamine, and the NMDA receptor antagonist memantine. Additionally, donepezil is the most used in symptomatic AD in China (108). Between 2019 and 2020, GV-971, a sodium oligomannate extracted from brown algae, developed by Green Valley Pharmaceuticals (Shanghai, China), was approved for the treatment of mild to moderate AD by the CNMPA. However, the exact mechanisms of GV-971 are inconclusive. Meanwhile, Aducanumab, an anti-amyloid β monoclonal antibody, was recently approved by the FDA in 2021 to AD treatment. While it has not been used in Chinese patients in China. Additionally, traditional Chinese medicine (TCM) for dementia has been summarized by Le group (109). For example, the “Qi-Fu-Yin” can ameliorate dementia through inhibit neuronal apoptosis, reduce neuroinflammation, elevate cholinergic neurotransmission and so on (110). However, the efficacy of the TCM on dementia has not been rigorously validated in domestic or international multicentric randomized-blinded-controlled trials, which are also needed more efforts on the theories and mechanisms studies.
Diverse Interventional Clinical Trials Investigating Dementia in China
In recent 10 years, multidomain interventions targeting diverse factors of dementia have been studied in China. Currently, 23 interventions in China’s domestic research (Table 3) and 11 agents in international studies (Table 4) are registered at http://clinicaltrials.gov/ in 49 clinical trials. Among the domestic trials, which can be classified into five categories: Chinese medicines (herbal medicine, ginkgo biloba dispersible tablets, GRAPE granules, VGH-AD1, yangxue qingnao pills, and Flos gossypii flavonoids tablets), innovative Chinese compounds (octohydroaminoacridine succinate, huperzine A, AD-35, sulforaphane, GV-971), supplement or dietary (probiotic supplemented, probiotics supplement, astaxanthin, EPA+DHA) and others (an anti-amyloid antibody SHR-1707, an Aβ vaccine UB-311 and Mesenchymal stem cells derived exosome), and there are five procedural interventions (acupuncture or electroacupuncture, transcranial current stimulation, transcranial magnetic stimulation, transcranial ultrasound stimulation and deep brain stimulation) being studied to treat symptomatic cognitive symptoms. Notably, an increasing number of international agent trials are being initiated in mainland China and Chincese Taipei, which included five anti-amyloid agents (gantenerumab, solanezumab, aducanumab, crenezumab, and lecanemab), one aggregation inhibitor (TRx0237), secretase inhibitors (semagacestat, lanabecestat, umibecestat), other small molecules (intepirdine, semaglutide).
In a phase II clinical trial in China, GV-971 improved cerebral glucose metabolites in several AD-related brain regions, and was safe and well tolerated (111). Moreover, GV-971 significant efficacy in improving cognitive function was observed in a phase III clinical trial in China (112). However, the effects on biomarkers and specific mechanisms of action of GV-971 remain unclear. To this end, a global phase III trial, Green Memory (Identifier: NCT04520412), was initiated in 2020 to assess the efficacy, safety, and validation on new AD biomarkers of GV-971.
In addition to conventional pharmacological intervention methods for mild cognitive impairment (MCI) in AD, studies investigating acupuncture treatment have been widely initiated in China. A meta-analysis revealed that acupuncture was effective in treating amnestic MCI (113). Similarly, Kim et al. compared different acupuncture treatment methods for MCI through a mini single-center randomized controlled trial from Korea (114). Interestingly, the study demonstrated that acupuncture at specific acupoints modulated functional activity and connectivity in the brain, which was confirmed by resting-state functional magnetic resonance imaging in a sample of Chinese patients with AD (115). However, more rigorous international multicenter randomized controlled clinical trials are needed to validate the results. The specific mechanisms involved in acupuncture in AD treatment require further molecular and cellular studies.
Notes: GRAPE granules, a prepared granules of Chinese herbs; VGH-AD1, a traditional Chinese herbal medicine powder; AD-35, a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil; GV-971, a sodium oligomannate extracted from brown algae; EPA+DHA, Docosahexaenoic acid and eicosapentaenoic acid; SHR-1707, a monoclonal antibody targeting Aβ protein; UB-311, a novel UBITh ® amyloid β peptide vaccine; MSCs, Mesenchymal stem cells.
Acknowledgments: This work was supported by the Chinese Academy of Sciences (QYZDY-SSW-SMC012 and XDB39000000); the National Natural Sciences Foundation of China (82030034; 92149304; 32100796); the Fundamental Research Funds for the Central Universities (YD2070002003).
Conflicts of Interest: The authors declare that they have no conflicts of interest.
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