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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:

J Prev Alz Dis 2022;
Published online April 28, 2022,



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 ( 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.

Table 1. Information of AD or other dementias in China compared to Japan, European, USA and the global

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.

Table 2. Summary researches of AD biomarkers in China

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 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.

Table 3. List of the registered domestic clinical trials in the pipeline of AD treatment in China

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.

Table 4. List of the registered international clinical trials in the pipeline of AD treatment in China


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.



1. Kennedy, B.K., S.L. Berger, A. Brunet, et al. Geroscience: linking aging to chronic disease. Cell, 2014; 159(4): 709-13.doi: 10.1016/j.cell.2014.10.039
2. Jia, L., Y. Du, L. Chu, et al. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health, 2020; 5(12): e661-e671.doi: 10.1016/s2468-2667(20)30185-7
3. Hampel, H., A. Vergallo, T. Iwatsubo, et al. Evaluation of major national dementia policies and health-care system preparedness for early medical action and implementation. Alzheimers Dement, 2022.doi: 10.1002/alz.12655
4. Ren, R.J., P. Yin, Z.H. Wang, et al. Alzheimer’s disease in China, 2021. J Diagn Concepts Pract, 2021; 20(4): 317-337.doi: (in Chinese)
5. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement, 2021; 17(3): 327-406.doi: 10.1002/alz.12328
6. Nakahori, N., M. Sekine, M. Yamada, et al. Future projections of the prevalence of dementia in Japan: results from the Toyama Dementia Survey. BMC Geriatr, 2021; 21(1): 602.doi: 10.1186/s12877-021-02540-z
7. Koyama, T., M. Sasaki, H. Hagiya, et al. Place of death trends among patients with dementia in Japan: a population-based observational study. Sci Rep, 2019; 9(1): 20235.doi: 10.1038/s41598-019-56388-w
8. Jia, L., M. Quan, Y. Fu, et al. Dementia in China: epidemiology, clinical management, and research advances. Lancet Neurol, 2020; 19(1): 81-92.doi: 10.1016/s1474-4422(19)30290-x
9. Collaborators, G.B.D. Global mortality from dementia: Application of a new method and results from the Global Burden of Disease Study 2019. Alzheimers Dement (N Y), 2021; 7(1): e12200.doi: 10.1002/trc2.12200
10. Ikeda, S., M. Mimura, M. Ikeda, et al. Economic Burden of Alzheimer’s Disease Dementia in Japan. J Alzheimers Dis, 2021; 81(1): 309-319.doi: 10.3233/JAD-210075
11. Europe, A. Dementia in Europe Yearbook 2019-Estimating the prevalence of dementia in Europe. 2019.doi:
12. Dugger, B.N. and D.W. Dickson. Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol, 2017; 9(7).doi: 10.1101/cshperspect.a028035
13. Vanni, S., A. Colini Baldeschi, M. Zattoni, and G. Legname. Brain aging: A Ianus-faced player between health and neurodegeneration. J Neurosci Res, 2020; 98(2): 299-311.doi: 10.1002/jnr.24379
14. Gao, Y., R.J. Ren, Z.L. Zhong, et al. Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer’s disease. Neurobiol Aging, 2019; 77: 154-157.doi: 10.1016/j.neurobiolaging.2019.01.018
15. Jia, J., E. Xu, Y. Shao, et al. One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer’s disease. J Alzheimers Dis, 2005; 7(2): 119-24; discussion 173-80.doi: 10.3233/jad-2005-7204
16. Jia, L., Y. Fu, L. Shen, et al. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer’s disease. Alzheimers Dement, 2020; 16(1): 178-191.doi: 10.1002/alz.12005
17. Jiang, T., L. Tan, Q. Chen, et al. A rare coding variant in TREM2 increases risk for Alzheimer’s disease in Han Chinese. Neurobiol Aging, 2016; 42: 217 e1-3.doi: 10.1016/j.neurobiolaging.2016.02.023
18. Jiao, B., B. Tang, X. Liu, et al. Mutational analysis in early-onset familial Alzheimer’s disease in Mainland China. Neurobiol Aging, 2014; 35(8): 1957 e1-6.doi: 10.1016/j.neurobiolaging.2014.02.014
19. Tang, L., W. Zeng, X. Lu, et al. Identification of APOH polymorphisms as common genetic risk factors for venous thrombosis in the Chinese population. J Thromb Haemost, 2014; 12(10): 1616-25.doi: 10.1111/jth.12679
20. Zhou, X., Y. Chen, F.C.F. Ip, et al. Genetic and polygenic risk score analysis for Alzheimer’s disease in the Chinese population. Alzheimers Dement (Amst), 2020; 12(1): e12074.doi: 10.1002/dad2.12074
21. Yagi, R., R. Miyamoto, H. Morino, et al. Detecting gene mutations in Japanese Alzheimer’s patients by semiconductor sequencing. Neurobiol Aging, 2014; 35(7): 1780 e1-5.doi: 10.1016/j.neurobiolaging.2014.01.023
22. An, S.S., S.A. Park, E. Bagyinszky, et al. A genetic screen of the mutations in the Korean patients with early-onset Alzheimer’s disease. Clin Interv Aging, 2016; 11: 1817-1822.doi: 10.2147/CIA.S116724
23. Janssen, J.C., J.A. Beck, T.A. Campbell, et al. Early onset familial Alzheimer’s disease: Mutation frequency in 31 families. Neurology, 2003; 60(2): 235-9.doi: 10.1212/01.wnl.0000042088.22694.e3
24. Lleo, A., R. Blesa, R. Queralt, et al. Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol, 2002; 59(11): 1759-63.doi: 10.1001/archneur.59.11.1759
25. Zekanowski, C., M. Styczynska, B. Peplonska, et al. Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer’s disease in Poland. Exp Neurol, 2003; 184(2): 991-6.doi: 10.1016/S0014-4886(03)00384-4
26. Dong, J., W. Qin, C. Wei, et al. A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer’s Disease Affects Amyloid-beta Production and Tau Phosphorylation. J Alzheimers Dis, 2017; 57(2): 613-623.doi: 10.3233/JAD-161188
27. Fang, B., L. Jia, and J. Jia. Chinese Presenilin-1 V97L mutation enhanced Abeta42 levels in SH-SY5Y neuroblastoma cells. Neurosci Lett, 2006; 406(1-2): 33-7.doi: 10.1016/j.neulet.2006.06.072
28. Qiu, Q., L. Jia, Q. Wang, et al. Identification of a novel PSEN1 Gly111Val missense mutation in a Chinese pedigree with early-onset Alzheimer’s disease. Neurobiol Aging, 2020; 85: 155 e1-155 e4.doi: 10.1016/j.neurobiolaging.2019.05.018
29. Qiu, Q., L. Shen, L. Jia, et al. A Novel PSEN1 M139L Mutation Found in a Chinese Pedigree with Early-Onset Alzheimer’s Disease Increases Abeta42/Abeta40 ratio. J Alzheimers Dis, 2019; 69(1): 199-212.doi: 10.3233/JAD-181291
30. Wang, Q., J. Jia, W. Qin, et al. A Novel AbetaPP M722K Mutation Affects Amyloid-beta Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer’s Disease in Chinese Individuals. J Alzheimers Dis, 2015; 47(1): 157-65.doi: 10.3233/JAD-143231
31. Rong, Z., B. Cheng, L. Zhong, et al. Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Abeta42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models. FASEB J, 2020; 34(8): 10984-10997.doi: 10.1096/fj.202000550RR
32. Zhao, Y., X. Wu, X. Li, et al. TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function. Neuron, 2018; 97(5): 1023-1031 e7.doi: 10.1016/j.neuron.2018.01.031
33. Zhong, L., Z. Wang, D. Wang, et al. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). Mol Neurodegener, 2018; 13(1): 15.doi: 10.1186/s13024-018-0247-7
34. Zhong, L., Y. Xu, R. Zhuo, et al. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model. Nat Commun, 2019; 10(1): 1365.doi: 10.1038/s41467-019-09118-9
35. Zhou, X., Y. Chen, K.Y. Mok, et al. Non-coding variability at the APOE locus contributes to the Alzheimer’s risk. Nat Commun, 2019; 10(1): 3310.doi: 10.1038/s41467-019-10945-z
36. Liu, C.C., C.C. Liu, T. Kanekiyo, H. Xu, and G. Bu. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol, 2013; 9(2): 106-18.doi: 10.1038/nrneurol.2012.263
37. Xia, Y., Z.H. Wang, J. Zhang, et al. C/EBPbeta is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer’s disease. Mol Psychiatry, 2020.doi: 10.1038/s41380-020-00956-4
38. Yin, J., M. Nielsen, T. Carcione, S. Li, and J. Shi. Apolipoprotein E regulates mitochondrial function through the PGC-1alpha-sirtuin 3 pathway. Aging (Albany NY), 2019; 11(23): 11148-11156.doi: 10.18632/aging.102516
39. Yin, J., E.M. Reiman, T.G. Beach, et al. Effect of ApoE isoforms on mitochondria in Alzheimer disease. Neurology, 2020; 94(23): e2404-e2411.doi: 10.1212/WNL.0000000000009582
40. Li, X., J. Zhang, D. Li, et al. Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory. Neuron, 2021; 109(6): 957-970 e8.doi: 10.1016/j.neuron.2021.01.005
41. Gan, C.L., T. Zhang, and T.H. Lee. The Genetics of Alzheimer’s Disease in the Chinese Population. Int J Mol Sci, 2020; 21(7).doi: 10.3390/ijms21072381
42. Wang, J.Z., Z.H. Wang, and Q. Tian. Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer’s disease. Neurosci Bull, 2014; 30(2): 359-66.doi: 10.1007/s12264-013-1415-y
43. Liu, S.J., A.H. Zhang, H.L. Li, et al. Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. J Neurochem, 2003; 87(6): 1333-44.doi: 10.1046/j.1471-4159.2003.02070.x
44. Ge, S., E.L. Goh, K.A. Sailor, et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature, 2006; 439(7076): 589-93.doi: 10.1038/nature04404
45. Zhang, Y.J., Y.F. Xu, Y.H. Liu, et al. Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms. FASEB J, 2006; 20(9): 1431-42.doi: 10.1096/fj.05-5223com
46. Li, H.L., H.H. Wang, S.J. Liu, et al. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer’s neurodegeneration. Proc Natl Acad Sci U S A, 2007; 104(9): 3591-6.doi: 10.1073/pnas.0609303104
47. Li, X.H., B.L. Lv, J.Z. Xie, et al. AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation. Neurobiol Aging, 2012; 33(7): 1400-10.doi: 10.1016/j.neurobiolaging.2011.02.003
48. Zhao, C., W. Deng, and F.H. Gage. Mechanisms and functional implications of adult neurogenesis. Cell, 2008; 132(4): 645-60.doi: 10.1016/j.cell.2008.01.033
49. Moreno-Jimenez, E.P., M. Flor-Garcia, J. Terreros-Roncal, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med, 2019; 25(4): 554-560.doi: 10.1038/s41591-019-0375-9
50. Zhang, X., Y. Mei, Y. He, et al. Ablating Adult Neural Stem Cells Improves Synaptic and Cognitive Functions in Alzheimer Models. Stem Cell Reports, 2021; 16(1): 89-105.doi: 10.1016/j.stemcr.2020.12.003
51. Sun, B., B. Halabisky, Y. Zhou, et al. Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer’s Disease. Cell Stem Cell, 2009; 5(6): 624-33.doi: 10.1016/j.stem.2009.10.003
52. Zheng, J., H.L. Li, N. Tian, et al. Interneuron Accumulation of Phosphorylated tau Impairs Adult Hippocampal Neurogenesis by Suppressing GABAergic Transmission. Cell Stem Cell, 2020; 26(3): 331-345 e6.doi: 10.1016/j.stem.2019.12.015
53. Song, J., J. Sun, J. Moss, et al. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus. Nat Neurosci, 2013; 16(12): 1728-30.doi: 10.1038/nn.3572
54. Selkoe, D.J. Alzheimer’s disease is a synaptic failure. Science, 2002; 298(5594): 789-91.doi: 10.1126/science.1074069
55. Palop, J.J. and L. Mucke. Synaptic depression and aberrant excitatory network activity in Alzheimer’s disease: two faces of the same coin? Neuromolecular Med, 2010; 12(1): 48-55.doi: 10.1007/s12017-009-8097-7
56. Jiang, S., Y. Li, C. Zhang, et al. M1 muscarinic acetylcholine receptor in Alzheimer’s disease. Neurosci Bull, 2014; 30(2): 295-307.doi: 10.1007/s12264-013-1406-z
57. Li, Y., Z. Chen, Y. Gao, et al. Synaptic Adhesion Molecule Pcdh-gammaC5 Mediates Synaptic Dysfunction in Alzheimer’s Disease. J Neurosci, 2017; 37(38): 9259-9268.doi: 10.1523/JNEUROSCI.1051-17.2017
58. Meng, J., L. Han, N. Zheng, et al. TMEM59 Haploinsufficiency Ameliorates the Pathology and Cognitive Impairment in the 5xFAD Mouse Model of Alzheimer’s Disease. Front Cell Dev Biol, 2020; 8: 596030.doi: 10.3389/fcell.2020.596030
59. Zhao, D., J. Meng, Y. Zhao, et al. RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer’s Disease-Associated Cognitive Deficits. Biol Psychiatry, 2019; 86(3): 171-184.doi: 10.1016/j.biopsych.2018.08.009
60. Li, Y., H. Sun, Z. Chen, et al. Implications of GABAergic Neurotransmission in Alzheimer’s Disease. Front Aging Neurosci, 2016; 8: 31.doi: 10.3389/fnagi.2016.00031
61. Bi, D., L. Wen, Z. Wu, and Y. Shen. GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer’s disease. Alzheimers Dement, 2020; 16(9): 1312-1329.doi: 10.1002/alz.12088
62. Tong, L.M., B. Djukic, C. Arnold, et al. Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Abeta accumulation. J Neurosci, 2014; 34(29): 9506-15.doi: 10.1523/JNEUROSCI.0693-14.2014
63. Wang, C., R. Najm, Q. Xu, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med, 2018; 24(5): 647-657.doi: 10.1038/s41591-018-0004-z
64. Huang, Z.J. and A. Paul. The diversity of GABAergic neurons and neural communication elements. Nat Rev Neurosci, 2019; 20(9): 563-572.doi: 10.1038/s41583-019-0195-4
65. Zhang, H., L. Zhang, D. Zhou, et al. Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer’s disease. Neurobiol Dis, 2017; 106: 171-180.doi: 10.1016/j.nbd.2017.07.001
66. Li, Y., K. Zhu, N. Li, et al. Reversible GABAergic dysfunction involved in hippocampal hyperactivity predicts early-stage Alzheimer disease in a mouse model. Alzheimers Res Ther, 2021; 13(1): 114.doi: 10.1186/s13195-021-00859-8
67. Zhu, H., H. Yan, N. Tang, et al. Impairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses. Nat Commun, 2017; 8(1): 1676.doi: 10.1038/s41467-017-01943-0
68. Shu, S., H. Zhu, N. Tang, et al. Selective Degeneration of Entorhinal-CA1 Synapses in Alzheimer’s Disease via Activation of DAPK1. J Neurosci, 2016; 36(42): 10843-10852.doi: 10.1523/JNEUROSCI.2258-16.2016
69. Deng, M., Q. Zhang, Z. Wu, et al. Mossy cell synaptic dysfunction causes memory imprecision via miR-128 inhibition of STIM2 in Alzheimer’s disease mouse model. Aging Cell, 2020; 19(5): e13144.doi: 10.1111/acel.13144
70. Yu, D., H. Yan, J. Zhou, et al. A circuit view of deep brain stimulation in Alzheimer’s disease and the possible mechanisms. Mol Neurodegener, 2019; 14(1): 33.doi: 10.1186/s13024-019-0334-4
71. Wu, K.M., Y.R. Zhang, Y.Y. Huang, et al. The role of the immune system in Alzheimer’s disease. Ageing Res Rev, 2021; 70: 101409.doi: 10.1016/j.arr.2021.101409
72. Zhao, R., W. Hu, J. Tsai, W. Li, and W.B. Gan. Microglia limit the expansion of beta-amyloid plaques in a mouse model of Alzheimer’s disease. Mol Neurodegener, 2017; 12(1): 47.doi: 10.1186/s13024-017-0188-6
73. Pan, J., N. Ma, B. Yu, W. Zhang, and J. Wan. Transcriptomic profiling of microglia and astrocytes throughout aging. J Neuroinflammation, 2020; 17(1): 97.doi: 10.1186/s12974-020-01774-9
74. Lau, S.F., C. Chen, W.Y. Fu, et al. IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer’s Disease. Cell Rep, 2020; 31(3): 107530.doi: 10.1016/j.celrep.2020.107530
75. Fang, Y., J. Wang, L. Yao, et al. The adhesion and migration of microglia to beta-amyloid (Abeta) is decreased with aging and inhibited by Nogo/NgR pathway. J Neuroinflammation, 2018; 15(1): 210.doi: 10.1186/s12974-018-1250-1
76. Wang, J., X. Qin, H. Sun, et al. Nogo receptor impairs the clearance of fibril amyloid-beta by microglia and accelerates Alzheimer’s-like disease progression. Aging Cell, 2021; 20(12): e13515.doi: 10.1111/acel.13515
77. Fang, Y., L. Yao, C. Li, et al. The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Abeta plaques and tau phosphorylation in APP/PS1 transgenic mice. J Neuroinflammation, 2016; 13(1): 56.doi: 10.1186/s12974-016-0522-x
78. Atagi, Y., C.C. Liu, M.M. Painter, et al. Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). J Biol Chem, 2015; 290(43): 26043-50.doi: 10.1074/jbc.M115.679043
79. Zheng, H., L. Jia, C.C. Liu, et al. TREM2 Promotes Microglial Survival by Activating Wnt/beta-Catenin Pathway. J Neurosci, 2017; 37(7): 1772-1784.doi: 10.1523/JNEUROSCI.2459-16.2017
80. Zhong, L., X.F. Chen, T. Wang, et al. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med, 2017; 214(3): 597-607.doi: 10.1084/jem.20160844
81. Jiang, T., Y.D. Zhang, Q. Gao, et al. TREM1 facilitates microglial phagocytosis of amyloid beta. Acta Neuropathol, 2016; 132(5): 667-683.doi: 10.1007/s00401-016-1622-5
82. Ofengeim, D., S. Mazzitelli, Y. Ito, et al. RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc Natl Acad Sci U S A, 2017; 114(41): E8788-E8797.doi: 10.1073/pnas.1714175114
83. Yuan, J., P. Amin, and D. Ofengeim. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci, 2019; 20(1): 19-33.doi: 10.1038/s41583-018-0093-1
84. Dai, L., Q. Wang, X. Lv, et al. Elevated beta-secretase 1 expression mediates CD4(+) T cell dysfunction via PGE2 signalling in Alzheimer’s disease. Brain Behav Immun, 2021; 98: 337-348.doi: 10.1016/j.bbi.2021.08.234
85. Wang, X., G. Sun, T. Feng, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res, 2019; 29(10): 787-803.doi: 10.1038/s41422-019-0216-x
86. Liu, Y.H., J. Wang, Q.X. Li, et al. Association of naturally occurring antibodies to beta-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer’s disease. Sci Adv, 2021; 7(1).doi: 10.1126/sciadv.abb0457
87. Yang, L., K. Lindholm, Y. Konishi, R. Li, and Y. Shen. Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways. J Neurosci, 2002; 22(8): 3025-32.doi: 20026317
88. Li, R., L. Yang, K. Lindholm, et al. Tumor necrosis factor death receptor signaling cascade is required for amyloid-beta protein-induced neuron death. J Neurosci, 2004; 24(7): 1760-71.doi: 10.1523/JNEUROSCI.4580-03.2004
89. He, P., Q. Liu, J. Wu, and Y. Shen. Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons. FASEB J, 2012; 26(1): 334-45.doi: 10.1096/fj.11-192716
90. Jiang, H., P. He, J. Xie, et al. Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IkappaBalpha. Hum Mol Genet, 2014; 23(18): 4906-18.doi: 10.1093/hmg/ddu206
91. Robinson, L., E. Tang, and J.P. Taylor. Dementia: timely diagnosis and early intervention. BMJ, 2015; 350: h3029.doi: 10.1136/bmj.h3029
92. Teunissen, C.E., I.M.W. Verberk, E.H. Thijssen, et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol, 2022; 21(1): 66-77.doi: 10.1016/S1474-4422(21)00361-6
93. Yang, X.Y., X.H. Hou, Y.L. Bi, et al. Anaemia and cerebrospinal fluid biomarkers of Alzheimer’s pathology in cognitively normal elders: the CABLE study. BMC Neurol, 2021; 21(1): 454.doi: 10.1186/s12883-021-02487-z
94. Jiao, B., H. Liu, L. Guo, et al. Performance of Plasma Amyloid beta, Total Tau, and Neurofilament Light Chain in the Identification of Probable Alzheimer’s Disease in South China. Front Aging Neurosci, 2021; 13: 749649.doi: 10.3389/fnagi.2021.749649
95. Wu, X., Z. Xiao, J. Yi, et al. Development of a Plasma Biomarker Diagnostic Model Incorporating Ultrasensitive Digital Immunoassay as a Screening Strategy for Alzheimer Disease in a Chinese Population. Clin Chem, 2021; 67(12): 1628-1639.doi: 10.1093/clinchem/hvab192
96. Xiao, Z., X. Wu, W. Wu, et al. Plasma biomarker profiles and the correlation with cognitive function across the clinical spectrum of Alzheimer’s disease. Alzheimers Res Ther, 2021; 13(1): 123.doi: 10.1186/s13195-021-00864-x
97. Shen, Y., H. Wang, Q. Sun, et al. Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer’s Disease Dementia in Individuals With Mild Cognitive Impairment. Biol Psychiatry, 2018; 83(5): 447-455.doi: 10.1016/j.biopsych.2017.02.007
98. Jiang, Y., X. Zhou, F.C. Ip, et al. Large-scale plasma proteomic profiling identifies a high-performance biomarker panel for Alzheimer’s disease screening and staging. Alzheimers Dement, 2022; 18(1): 88-102.doi: 10.1002/alz.12369
99. Serrano-Pozo, A., M.P. Frosch, E. Masliah, and B.T. Hyman. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med, 2011; 1(1): a006189.doi: 10.1101/cshperspect.a006189
100. Jia, L., Q. Qiu, H. Zhang, et al. Concordance between the assessment of Abeta42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement, 2019; 15(8): 1071-1080.doi: 10.1016/j.jalz.2019.05.002
101. Olsson, B., R. Lautner, U. Andreasson, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol, 2016; 15(7): 673-684.doi: 10.1016/S1474-4422(16)00070-3
102. Xu, W., S.D. Han, C. Zhang, et al. The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases. Sci Adv, 2020; 6(43).doi: 10.1126/sciadv.abb3063
103. Jia, L., Y. Du, L. Chu, et al. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health, 2020; 5(12): e661-e671.doi: 10.1016/S2468-2667(20)30185-7
104. McKhann, G., D. Drachman, M. Folstein, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology, 1984; 34(7): 939-44.doi: 10.1212/wnl.34.7.939
105. Jack, C.R., Jr., M.S. Albert, D.S. Knopman, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement, 2011; 7(3): 257-62.doi: 10.1016/j.jalz.2011.03.004
106. Jack, C.R., Jr., D.A. Bennett, K. Blennow, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement, 2018; 14(4): 535-562.doi: 10.1016/j.jalz.2018.02.018
107. Lv, X., M. Zhao, T. Li, et al. Effects of an Enhanced Training on Primary Care Providers Knowledge, Attitudes, Service and Skills of Dementia Detection: A Cluster Randomized Trial. Front Neurol, 2021; 12: 651826.doi: 10.3389/fneur.2021.651826
108. Jia, J., X. Zuo, X.F. Jia, et al. Diagnosis and treatment of dementia in neurology outpatient departments of general hospitals in China. Alzheimers Dement, 2016; 12(4): 446-53.doi: 10.1016/j.jalz.2015.06.1892
109. Li, S., Z. Wu, and W. Le. Traditional Chinese medicine for dementia. Alzheimers Dement, 2021; 17(6): 1066-1071.doi: 10.1002/alz.12258
110. Ong, W.Y., Y.J. Wu, T. Farooqui, and A.A. Farooqui. Qi Fu Yin-a Ming Dynasty Prescription for the Treatment of Dementia. Mol Neurobiol, 2018; 55(9): 7389-7400.doi: 10.1007/s12035-018-0908-0
111. Wang, T., W. Kuang, W. Chen, et al. A phase II randomized trial of sodium oligomannate in Alzheimer’s dementia. Alzheimers Res Ther, 2020; 12(1): 110.doi: 10.1186/s13195-020-00678-3
112. Xiao, S., P. Chan, T. Wang, et al. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia. Alzheimers Res Ther, 2021; 13(1): 62.doi: 10.1186/s13195-021-00795-7
113. Deng, M. and X.F. Wang. Acupuncture for amnestic mild cognitive impairment: a meta-analysis of randomised controlled trials. Acupunct Med, 2016; 34(5): 342-348.doi: 10.1136/acupmed-2015-010989
114. Kim, J.H., M.R. Cho, J.C. Shin, G.C. Park, and J.S. Lee. Factors contributing to cognitive improvement effects of acupuncture in patients with mild cognitive impairment: a pilot randomized controlled trial. Trials, 2021; 22(1): 341.doi: 10.1186/s13063-021-05296-4
115. Zheng, W., Z. Su, X. Liu, et al. Modulation of functional activity and connectivity by acupuncture in patients with Alzheimer disease as measured by resting-state fMRI. PLoS One, 2018; 13(5): e0196933.doi: 10.1371/journal.pone.0196933