Beyond Amyloid and Tau: Systemic Immune Homeostasis Reconstruction as a Transformative Strategy for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder driven jointly by immune imbalance, protein aggregation, and metabolic dysregulation. Emerging evidence indicates that its pathological progression is not confined to amyloid-β (Aβ) accumulation or tau hyperphosphorylation, but rather reflects a network-level dysregulation between central and peripheral immune systems. Immunotherapeutic strategies have advanced considerably, including passive and active approaches targeting Aβ (e.g., aducanumab and lecanemab) and tau (e.g., gosuranemab), as well as modulators of microglial function and systemic immunity (e.g., AL002, XPro1595, masitinib, sargramostim, and baricitinib). Additionally, interventions targeting the gut–brain axis (e.g., sodium oligomannate, probiotics, and prebiotics) and metabolic regulators (e.g., semaglutide) expand the immunomodulatory landscape. However, translating such changes into sustained and clinically meaningful cognitive benefits remains constrained by disease heterogeneity, intervention timing, intracellular target accessibility, and safety-tolerability considerations. Future work should emphasize precise stratification, early intervention, artificial intelligence (AI)-enabled analytics, and multimodal biomarker guidance, while advancing central nervous system-penetrant and safer therapeutic and delivery strategies. Collectively, AD immunotherapy is undergoing a paradigm shift from “pathology clearance” to “immune network restoration,” aiming to achieve durable disease modification through multidimensional and systemically coordinated interventions.

Keywords

Alzheimer’s disease / immunotherapy / neuroinflammation / gut–brain axis

Introduction

Alzheimer’s disease (AD) represents the most prevalent form of dementia and a leading cause of disability among the elderly, posing an escalating threat to global health systems. Characterized by progressive cognitive deterioration, memory loss, and behavioral decline, AD imposes a profound socioeconomic burden that continues to rise with population aging[1,2]. In 2019, the global cost of AD and related dementias was estimated at $2.8 trillion, a figure projected to surge to $16.9 trillion by 2050, underscoring the urgent need for disease-modifying strategies[3].

Pathologically, AD is defined by extracellular β-amyloid (Aβ) plaque deposition and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein[4]. These hallmark lesions trigger a cascade of secondary neurobiological events, including synaptic dysfunction, mitochondrial impairment, oxidative stress, and widespread neuroinflammation[5–7]. Despite decades of research, currently approved therapies—such as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists—offer only transient symptomatic relief without effectively halting disease progression[8].

Emerging evidence has illuminated the pivotal role of the immune system in both the initiation and propagation of AD pathology. Within the central nervous system (CNS), immune responses mediated by microglia and astrocytes are essential for maintaining homeostasis and clearing misfolded proteins. However, sustained or dysregulated activation of these glial cells provokes the excessive release of cytokines, proteases, and reactive oxygen species, thereby amplifying neuronal injury and synaptic loss. This dualistic nature of neuroinflammation—protective in acute phases yet detrimental when chronic—has reframed AD from a purely neurocentric disorder to a complex neuroimmune disease[9,10].

Importantly, the pathophysiological significance of immune dysfunction in AD extends beyond localized neuroinflammation to encompass a broader breakdown of systemic immune homeostasis. In this context, “systemic immune homeostasis” refers to a dynamic, multilevel equilibrium integrating functionally competent microglial states, balanced peripheral immune cell subsets, coordinated cytokine and chemokine signaling networks, intact barrier integrity, and tightly coupled immune–metabolic regulation across central and peripheral compartments. Disruption of this equilibrium fosters a self-reinforcing cycle of chronic inflammation, impaired clearance capacity, and metabolic stress that accelerates neurodegeneration.

Accordingly, immunotherapy has emerged not only as a means to reduce pathological protein burden but also as a strategy to recalibrate immune network states and restore homeostatic regulation. Contemporary immunotherapeutic approaches encompass both antigen-specific strategies, including passive and active immunization targeting Aβ or tau, and immune-modulatory interventions that reprogram microglial phenotypes, inhibit proinflammatory signaling, or enhance phagocytic competence. Beyond the CNS, the recognition of a bidirectional gut–brain axis has expanded the conceptual landscape of AD immunopathology. Gut microbiota communicate with the brain via immune, metabolic, and neural pathways; dysbiosis in AD has been linked to systemic inflammation, disruption of the blood-brain barrier, and aberrant microglial activation[11]. Consequently, microbiota-based immunotherapies—such as probiotics, prebiotics, fecal microbiota transplantation, and microbial metabolite modulation—are increasingly viewed as components of a systemic immune remodeling strategy, capable of restoring peripheral immune balance and indirectly reshaping central neuroimmune responses rather than acting as isolated adjuncts.

Collectively, AD research is undergoing a paradigm shift from single-target interventions toward integrative immune homeostasis reconstruction, encompassing both central and peripheral immune regulation. Future progress depends on the rational combination of multi-targeted immunotherapies, precise patient stratification, and mitigation of immune-related adverse events such as amyloid-related imaging abnormalities (ARIA). This review aims to provide a comprehensive synthesis of the immunological underpinnings, therapeutic strategies, and representative advances in AD immunotherapy, spanning from Aβ and tau-directed interventions to gut–brain axis modulation, and to outline emerging perspectives for precision immune remodeling as a cornerstone of next-generation AD therapeutics.

Immunopathological mechanisms

Alzheimer’s disease should be conceptualized not solely as a disorder of aberrant protein aggregation but as a chronic, system-level inflammatory condition driven by sustained dysregulation of central and peripheral immune networks. A reciprocal interplay among CNS innate immune elements, peripheral adaptive and innate immune populations, and humoral and metabolic mediators shapes the temporal evolution of pathology, such that early protective responses can transition into self-sustaining, neurotoxic processes[12]. Within this framework, loss of immune homeostasis represents a critical inflection point at which initially adaptive immune activation becomes maladaptive, shifting the system from regulated surveillance toward chronic inflammatory amplification.

Within the CNS, microglia constitute the principal immune sentinels and are among the first cells to detect accumulating Aβ via pattern-recognition receptors (e.g., Toll-like receptors) and triggering receptors expressed on myeloid cells (notably TREM2)[13,14]. In initial stages, microglial activation facilitates phagocytic clearance of oligomeric Aβ and supports synaptic maintenance. However, prolonged exposure to proteinopathy and metabolic stress induces microglial phenotypic reprogramming—characterized in transcriptomic studies as a shift toward disease-associated microglia (DAM) states—accompanied by impaired phagocytic competence and heightened production of proinflammatory effectors[15,16]. Rather than a binary M1/M2 polarization, these states reflect a spectrum of functional imbalances involving metabolic insufficiency, defective debris clearance, and exaggerated inflammatory signaling. Activation of intracellular danger sensors such as the NLRP3 inflammasome promotes maturation and release of IL-1β, while sustained secretion of TNF-α and IL-6 exacerbates oxidative stress and neuronal vulnerability[17]. Concomitantly, complement cascade components (e.g., C1q and C3) become aberrantly engaged, tagging synapses for microglia-mediated pruning and thereby contributing to synaptic loss that correlates with cognitive decline[18–20].

Astrocytes participate in this maladaptive loop through reactive transformation. Reactive astrocytes—often described in dichotomous terms as neuroprotective versus neurotoxic phenotypes—lose homeostatic functions (notably glutamate uptake via EAAT2/GLT-1) under chronic inflammatory stimuli, with resultant excitotoxic stress and disruption of neurotransmitter balance[21,22]. Cross-talk between reactive astrocytes and microglia amplifies cytokine and metabolic signaling, forming a positive-feedback network that perpetuates local inflammation and dismantles neural circuit integrity[23]. Failure to restore astrocytic homeostatic support further destabilizes neuroimmune equilibrium.

Peripheral immune compartments exert both modulatory and effector influences on cerebral pathology. CD4⁺ T-cell subsets demonstrate differential impacts: Th1 and Th17 responses are associated with proinflammatory cytokine profiles, impaired synaptic plasticity, and exacerbation of Aβ deposition, whereas Th2 polarization and regulatory T cells (Tregs) are linked to attenuation of inflammation and preservation of cognitive function in experimental models[24]. B cells, through MHC-II–mediated antigen presentation, can shape CD4⁺ T-cell differentiation and thereby influence the balance between pro- and anti-inflammatory adaptive responses. Under conditions of blood-brain barrier (BBB) compromise, recruited peripheral monocytes/macrophages and T cells may translocate across parenchymal or meningeal routes (including via choroid plexus and meningeal lymphatics), where they modulate antigen clearance, secrete cytokines, and influence microglial polarization—actions that can be either reparative or deleterious depending on context and timing[25].

Emerging evidence positions the gut–brain axis as a critical peripheral regulator of neuroimmune status. Gut microbial communities produce bioactive metabolites—short-chain fatty acids (SCFAs), tryptophan derivatives, secondary bile acids—and molecular patterns such as lipopolysaccharide (LPS) that shape systemic immune tone[26,27]. Dysbiosis observed in AD cohorts is associated with perturbations in these metabolites, promotion of systemic low-grade inflammation, and alterations in T-cell differentiation profiles. Increased circulating inflammatory mediators and microbial products can compromise intestinal and BBB integrity, facilitating peripheral immune cell trafficking and microglial priming[28]. Moreover, mucosa-derived lymphocytes and plasma cells can migrate to meningeal and choroid plexus compartments, where secretion of cytokines such as IFN-γ further modulates meningeal macrophage and microglial activity, sustaining central inflammation[29].

Collectively, these lines of evidence delineate a multi-compartment, dynamic immunopathology in which central glial dysfunction, peripheral immune dysregulation and microbiome-derived signals interact to accelerate synaptic deterioration and neurodegeneration. Therapeutic strategies, therefore, must aim not merely to suppress inflammatory mediators or clear aggregated proteins but to restore coordinated immune functionality across CNS and peripheral systems—thereby re-establishing systemic immune homeostasis as a prerequisite for durable disease modification.

Immunotherapeutic strategies targeting Aβ pathology

Aberrant production and aggregation of Aβ peptides constitute one of the earliest pathological events in AD, disrupting synaptic signaling, promoting oxidative stress, and inducing chronic neuroinflammation. Aβ oligomers interact with postsynaptic NMDA and α7-nACh receptors, impair neurotransmitter release, and activate glial cells, establishing a self-perpetuating cycle of neurotoxicity[30]. Consequently, Aβ-directed immunotherapies aim to neutralize toxic Aβ assemblies, facilitate their clearance, and reprogram neuroimmune responses toward a homeostatic state.

Active vaccination induces endogenous antibodies via adaptive immune activation. First-generation vaccines (AN1792[31]) elicited both humoral and T-cell responses, leading to immunopathology. Second-generation vaccines (e.g., Vanutide Cridificar[32,33], AD02/AD03[34,35], CAD106[36], and UB-311[37]) retain only N-terminal B-cell epitopes, improving safety and maintaining immunogenicity. Active strategies are particularly suited for early-stage intervention, providing durable antibody titers with limited dosing, yet their clinical efficacy remains under investigation.

Passive monoclonal antibodies selectively bind aggregated or soluble Aβ species to facilitate direct clearance. Approved or late-stage candidates (aducanumab[38,39], Bapineuzumab[40–42], Solanezumab[43,44], Crenezumab[45], Gantenerumab[46,47], Donanemab[48,49], and Lecanemab[50–52]) consistently reduce amyloid burden, but translation into robust cognitive benefit is variable. Differences in epitope specificity, oligomer versus fibril targeting, and BBB penetration largely determine efficacy and adverse event profiles. Emerging bispecific or “brain-shuttle” constructs (e.g., trontinemab[53]) significantly improve CNS delivery, highlighting the potential of next-generation antibody platforms.

Overall, Aβ-directed immunotherapies illustrate that pathological amyloid is a modifiable target. Optimal outcomes likely require early intervention, precise epitope targeting, enhanced CNS delivery, and integration with strategies addressing tau pathology or neuroinflammation. Representative active and passive immunotherapies, with mechanistic features, clinical stage, and safety considerations, are summarized in Table 1.

Immunotherapeutic strategies targeting tau pathology

Tau, a microtubule-associated protein essential for axonal stability, becomes abnormally hyperphosphorylated and aggregates into neurofibrillary tangles (NFTs) in AD[54]. Excessive phosphorylation driven by kinases such as GSK3β and CDK5, along with reduced phosphatase activity, promotes misfolding and trans-synaptic propagation of tau aggregates[55,56]. Tau-directed immunotherapy aims to neutralize toxic conformers, block propagation, and preserve neuronal function.

Active immunization induces endogenous antibodies against pathological tau epitopes. The most advanced candidate, AADvac1[57–59], targeting a microtubule-binding region, elicited robust IgG responses and favorable biomarker changes but no significant cognitive benefit. Next-generation vaccines, such as ACI-35.030 and JACI-35.054[60], designed against phosphorylated tau peptides (pS396/pS404), enhance conformational specificity and show promising immunogenicity with good tolerability in early trials.

Passive immunization delivers monoclonal antibodies (mAbs) targeting extracellular or propagation-competent tau. Agents such as semorinemab[61,62], Gosuranemab[63], Tilavonemab[64], Zagotenemab[65], and Bepranemab[66] demonstrated target engagement and reductions in extracellular tau but failed to achieve clinical efficacy in Phase II studies[67]. These results highlight the challenges of epitope accessibility, timing of intervention, and limited intracellular penetration.

Although clinical outcomes remain modest, tau immunotherapy continues to evolve. Refinement of epitope selection, delivery strategies, and early-stage intervention guided by tau biomarkers may enhance future efficacy. A summary of current active and passive immunotherapies is presented in Table 2.

Multi-target immunomodulation

Beyond direct Aβ- or tau-targeted approaches, recent research emphasizes rebalancing the dysregulated neuroimmune network that sustains AD pathology. Chronic activation of microglia, peripheral immune infiltration, and systemic inflammatory signals collectively contribute to progressive neuronal loss, highlighting the need for therapeutic strategies that act across multiple immune compartments.

Microglial modulation has become a central focus. Agents such as AL002[68–70] (a TREM2 agonistic antibody) and VG3927[71,72] (targeting microglia via membrane-bound TREM2) aim to restore microglial homeostasis by promoting phagocytosis while limiting proinflammatory signaling. TB006[73], a humanized antibody targeting galectin-3, further attenuates microglial-driven inflammation and protects against tau-mediated neurotoxicity. Modulators of CSF1R or the complement cascade (e.g., C1q inhibitors) have also shown potential in preserving synaptic integrity by controlling excessive innate immune activation.

Other immunoregulatory strategies act through peripheral or systemic mechanisms. Sargramostim[74] (GM-CSF) enhances innate immune renewal and may promote amyloid clearance, whereas XPro1595[75], a selective soluble TNF inhibitor, reduces neuroinflammation without suppressing protective TNF signaling. Targeting intracellular pathways such as JAK/STAT with baricitinib[76,77] or tyrosine kinase signaling with masitinib[78] represents additional means of dampening glial hyperactivation. Moreover, the combination of dasatinib and quercetin[79] has emerged as a senolytic strategy to eliminate senescent immune and glial cells, thereby alleviating chronic inflammatory stress. Metabolic regulators such as semaglutide[80–83], a GLP-1 receptor agonist, have also demonstrated anti-inflammatory and neuroprotective properties by modulating microglial polarization and insulin signaling pathways.

Collectively, these interventions converge on a shared therapeutic rationale—to recalibrate the immune–metabolic interface rather than merely eliminate pathological proteins. Integrating multi-axis modulation of innate, adaptive, and systemic immunity may represent a more durable approach to disease modification in AD. Table 3 summarizes representative multi-target immunotherapeutic agents under clinical or preclinical evaluation.

Immunotherapeutic strategies targeting the gut–brain axis

Emerging evidence underscores the bidirectional crosstalk between the gut and the brain, mediated through immune, endocrine, and neural pathways[84]. Dysbiosis of the gut microbiota contributes to peripheral immune activation and microglial priming, thereby amplifying Aβ- and tau-related neuroinflammation. Consequently, modulation of the gut microbiome or its metabolites has been proposed as an indirect immunotherapeutic approach, aiming to restore systemic immune homeostasis and dampen chronic neuroinflammatory signaling.

Microbiota-based interventions, including probiotics[85,86], prebiotics[87], synbiotics[88], and fecal microbiota transplantation (FMT), have shown promise in preclinical AD models. Probiotic strains such as Lactobacillus, Bifidobacterium, and Akkermansia muciniphila can suppress inflammatory cytokine release, enhance intestinal barrier integrity, and reduce amyloid deposition[27,89]. Prebiotics such as mannan oligosaccharide (MOS)[90] further promote beneficial bacterial growth and short-chain fatty acid (SCFA) production, collectively improving cognition and reducing neuroinflammation. Synbiotic formulations that combine probiotics and prebiotics may yield synergistic effects by simultaneously enhancing microbial viability and metabolic output. Meanwhile, FMT has been shown to restore microbial diversity, mitigate Aβ and p-tau pathology, and improve behavioral performance, although large-scale clinical validation is still lacking.

Beyond live microbial modulation, small-molecule and natural compounds that act along the gut-immune-brain axis have gained increasing attention. Sodium oligomannate (GV-971)[91,92], a marine-derived oligosaccharide mixture, demonstrated cognitive benefit in a Phase 3 clinical trial and is thought to alleviate neuroinflammation by reprogramming gut microbiota and suppressing peripheral immune activation. Other candidates such as sea cucumber egg oligopeptides (SCEP)[93] and Pseudostellaria heterophylla polysaccharides (PH-PS)[94] modulate microbial composition, increase cerebral SCFAs, and elevate neurotrophic factors such as BDNF and NT-3, thereby attenuating Aβ and tau pathology. In addition, the herbal formulation Lingguizhugan decoction (LGZG)[95] has been shown to enhance tight junction integrity and restore blood–brain barrier permeability by normalizing gut microbial and metabolic profiles.

Collectively, gut-targeted immunomodulation represents a systemic extension of central immune therapies. By reshaping microbial communities and their immunometabolic outputs, these strategies may offer a novel route toward restoring neuroimmune equilibrium and mitigating disease progression in AD. Table 4 summarizes representative gut–brain-axis-targeted immunotherapeutic candidates and their clinical development status.

Challenges and future directions

Over the past decade, immunotherapy for AD has evolved from protein-targeted interventions to a multidimensional strategy encompassing neuroimmune modulation, metabolic reprogramming, and gut–brain axis regulation. However, the translation of these advances into durable clinical benefit remains constrained by several interrelated challenges.

Foremost among these is the pronounced pathological and individual heterogeneity of AD. The disease arises from the convergence of Aβ deposition, tau hyperphosphorylation, chronic neuroinflammation, metabolic dysregulation, and systemic immune imbalance, each varying in dominance across patients. This heterogeneity implies that restoration of immune homeostasis cannot be achieved through uniform suppression of inflammatory pathways but requires personalized recalibration of immune network states. Such complexity undermines the efficacy of single-target therapies and highlights the necessity for individualized, biomarker-guided interventions. Equally critical is the therapeutic window: converging evidence indicates that early immunomodulatory intervention—prior to extensive neuronal loss—offers a greater likelihood of translating biological modification into cognitive improvement.

Safety and accessibility represent additional barriers to clinical translation. While passive immunotherapies effectively reduce pathological burden at the molecular level, their association with ARIA and high monitoring costs restrict broad use. Conversely, systemic immune modulators offer functional immune rebalancing but pose long-term risks of immune overactivation or suppression. Bridging this gap requires innovative delivery systems, improved CNS penetration, and dynamic safety surveillance.

How to achieve systemic immune homeostasis reconstruction: combination strategies and personalized medicine

Achieving durable immune homeostasis in AD will likely require rational combination strategies that concurrently target multiple nodes of the immune network rather than isolated pathways. In this context, synergistic integration of central microglial modulation with peripheral immune regulation—particularly via the gut–brain axis—represents a promising avenue. For example, therapies enhancing microglial phagocytic competence and metabolic fitness may be complemented by interventions that reshape gut microbiota composition, attenuate peripheral immune activation, and normalize systemic inflammatory tone, thereby reinforcing bidirectional neuroimmune communication.

Crucially, the effectiveness of such combination strategies is expected to depend on personalized medicine frameworks guided by multimodal biomarkers. Integrating neuroimaging, fluid biomarkers (e.g., cytokine profiles and microglial activation markers), microbiome signatures, and multi-omics data may enable stratification of patients according to dominant immune–pathological states. This approach would allow tailoring of therapeutic combinations—both in target selection and temporal sequencing—to individual immune landscapes, thereby moving closer to genuine reconstruction of systemic immune homeostasis rather than transient pathway modulation.

Future progress will likely depend on an integrative framework that explicitly targets systemic immune homeostasis reconstruction, moving beyond isolated pathological targets toward restoration of immune homeostasis across molecular, inflammatory, and metabolic dimensions. Mechanistically informed combination or sequential therapies may provide synergistic efficacy, particularly when guided by multimodal biomarkers and longitudinal multi-omics profiling. Advances in artificial intelligence (AI) and computational modeling are expected to facilitate this transition by integrating immunogenomic, imaging, and clinical data to optimize patient stratification, predict response trajectories, and refine trial design.

Ultimately, the paradigm of AD immunotherapy is shifting from pathological clearance toward adaptive immune restoration. Sustainable clinical benefit will rely on establishing long-term equilibrium within the neuroimmune network—transforming immunotherapy from transient symptomatic relief to a truly disease-modifying approach grounded in precision, safety, and mechanistic rationality.

References

[1] Kamatham PT, Shukla R, Khatri DK, Vora LK. Pathogenesis, diagnostics, and therapeutics for alzheimer’s disease: breaking the memory barrier. Ageing Res Rev. 2024;101:102481.

[2] Revi M. Alzheimer’s disease therapeutic approaches. Adv Exp Med Biol. 2020;1195:105-116.

[3] Nandi A, Counts N, Chen S, et al. Global and regional projections of the economic burden of alzheimer’s disease and related dementias from 2019 to 2050: a value of statistical life approach. EClinicalMedicine. 2022;51:101580.

[4] Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357-367.

[5] Jurcău MC, Andronie-Cioara FL, Jurcău A, et al. The link between oxidative stress, mitochondrial dysfunction and neuroinflammation in the pathophysiology of alzheimer’s disease: therapeutic implications and future perspectives. Antioxidants (Basel). 2022;11(11):2167.

[6] Selkoe DJ, Hardy J. The amyloid hypothesis of alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595-608.

[7] Onyango IG, Jauregui GV, Čarná M, Bennett JP, Stokin GB. Neuroinflammation in alzheimer’s disease. Biomedicines. 2021;9(5):524.

[8] Zhang F, Zhong RJ, Cheng C, Li S, Le WD. New therapeutics beyond amyloid-β and tau for the treatment of alzheimer’s disease. Acta Pharmacol Sin. 2021;42(9):1382-1389.

[9] Shi FD, Yong VW. Neuroinflammation across neurological diseases. Science. 2025;388(6753):eadx0043.

[10] Song C, Shi J, Zhang P, et al. Immunotherapy for alzheimer’s disease: targeting β-amyloid and beyond. Transl Neurodegener. 2022;11(1):18.

[11] Zhuang M, Zhang X, Cai J. Microbiota-gut-brain axis: interplay between microbiota, barrier function and lymphatic system. Gut Microbes. 2024;16(1):2387800.

[12] Zhang S, Gao Y, Zhao Y, Huang TY, Zheng Q, Wang X. Peripheral and central neuroimmune mechanisms in alzheimer’s disease pathogenesis. Mol Neurodegener. 2025;20(1):22.

[13] Ulrich JD, Finn MB, Wang Y, et al. Altered microglial response to aβ plaques in aPPPS1-21 mice heterozygous for TREM2. Mol Neurodegener. 2014;9:20.

[14] Fakhoury M. Microglia and astrocytes in alzheimer’s disease: implications for therapy. Curr Neuropharmacol. 2018;16(5):508-518.

[15] Miao J, Ma H, Yang Y, et al. Microglia in alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials. Front Aging Neurosci. 2023;15:1201982.

[16] Ellwanger DC, Wang S, Brioschi S, et al. Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2021;118(3):e2017742118.

[17] Stancu IC, Cremers N, Vanrusselt H, et al. Aggregated tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded tau pathology in vivo. Acta Neuropathol. 2019;137(4):599-617.

[18] Dejanovic B, Wu T, Tsai MC, et al. Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in alzheimer’s disease mouse models. Nat Aging. 2022;2(9):837-850.

[19] Scott-Hewitt N, Mahoney M, Huang Y, et al. Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain. Cell. 2024;187(16):4193-4212.e24.

[20] Kumari S, Dhapola R, Sharma P, et al. Unravelling neuronal death mechanisms: the role of cytokines and chemokines in immune imbalance in alzheimer’s disease progression. Ageing Res Rev. 2025;112:102883.

[21] Shi JH, Tang QL, Wang JH, et al. Pigment epithelium-Derived factor deficiency impairs hippocampal glutamate homeostasis and cognitive function by downregulating astrocytic GLT-1. Adv Sci (Weinh). 2025;12(45):e00402.

[22] Endo F, Kasai A, Soto JS, et al. Molecular basis of astrocyte diversity and morphology across the CNS in health and disease. Science. 2022;378(6619):eadc9020.

[23] Singh D. Astrocytic and microglial cells as the modulators of neuroinflammation in alzheimer’s disease. J Neuroinflammation. 2022;19(1):206.

[24] Van Eldik LJ, Carrillo MC, Cole PE, et al. The roles of inflammation and immune mechanisms in Alzheimer’s disease. Alzheimers Dement (N Y). 2016;2(2):99-109.

[25] Yan P, Kim KW, Xiao Q, et al. Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease. J Clin Invest. 2022;132(11):e152565.

[26] Mafe AN, Büsselberg D. Modulation of the neuro-cancer connection by metabolites of gut microbiota. Biomolecules. 2025;15(2):270.

[27] Kapoor B, Biswas P, Gulati M, Rani P, Gupta R. Gut microbiome and alzheimer’s disease: what we know and what remains to be explored. Ageing Res Rev. 2024;102:102570.

[28] White Z, Cabrera I, Mei L, et al. Gut inflammation promotes microbiota-specific CD4 T cell-mediated neuroinflammation. Nature. 2025;643(8071):509-518.

[29] Chen X, Firulyova M, Manis M, et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023;615(7953):668-677.

[30] Cannata B, Sposito L, Albini M, et al. Functional deletion of α7 nicotinic acetylcholine receptor impairs Ca²⁺-dependent glutamatergic synaptic transmission by affecting both presynaptic and postsynaptic protein expression and function. Front Physiol. 2025;16:1662171.

[31] Gilman S, Koller M, Black RS, et al. Clinical effects of abeta immunization (AN1792) in patients with aD in an interrupted trial. Neurology. 2005;64(9):1553-1562.

[32] Pasquier F, Sadowsky C, Holstein A, et al. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate alzheimer’s disease. J Alzheimers Dis. 2016;51(4):1131-1143.

[33] Ketter N, Liu E, Di J, et al. A randomized, double-Blind, phase 2 study of the effects of the vaccine vanutide cridificar with QS-21 adjuvant on immunogenicity, safety and amyloid imaging in patients with mild to moderate alzheimer’s disease. J Prev Alzheimers Dis. 2016;3(4):192-201.

[34] Schneeberger A, Hendrix S, Mandler M, et al. Results from a phase II study to assess the clinical and immunological activity of aFFITOPE® aD02 in patients with early alzheimer’s disease. J Prev Alzheimers Dis. 2015;2(2):103-114.

[35] Schneeberger A, Hendrix S, Mandler M, et al. Results from a phase II study to assess the clinical and immunological activity of aFFITOPE® aD02 in patients with early alzheimer’s disease. J Prev Alzheimers Dis. 2015;2(2):103-114.

[36] Riviere ME, Langbaum JB, Turner RS, et al. Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired aPOE ε4 homozygotes. Alzheimers Dement. 2024;20(3):1839-1850.

[37] Wang CY, Wang PN, Chiu MJ, et al. UB-311, a novel UBITh^® amyloid β peptide vaccine for mild Alzheimer’s disease. Alzheimers Dement (N Y). 2017;3(2):262-272.

[38] Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of aducanumab in early alzheimer’s disease. J Prev Alzheimers Dis. 2022;9(2):197-210.

[39] Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces aβ plaques in alzheimer’s disease. Nature. 2016;537(7618):50-56.

[40] Vandenberghe R, Rinne JO, Boada M, et al. Bapineuzumab for mild to moderate alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016;8(1):18.

[41] Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate alzheimer’s disease. N Engl J Med. 2014;370(4):322-333.

[42] Ivanoiu A, Pariente J, Booth K, et al. Long-term safety and tolerability of bapineuzumab in patients with alzheimer’s disease in two phase 3 extension studies. Alzheimers Res Ther. 2016;8(1):24.

[43] Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild alzheimer’s disease patients. Alzheimers Dement. 2016;12(2):110-120.

[44] Renteros MS, Barreto-Abanto R, Huapaya DC, et al. The efficacy of solanezumab in patients with alzheimer’s disease: a systematic review and meta-Analysis of clinical trials. Pharmaceutics. 2025;17(8):999.

[45] Ostrowitzki S, Bittner T, Sink KM, et al. Evaluating the safety and efficacy of crenezumab vs placebo in adults with early alzheimer disease: two phase 3 randomized placebo-Controlled trials. JAMA Neurol. 2022;79(11):1113-1121.

[46] Bateman RJ, Smith J, Donohue MC, et al. Two phase 3 trials of gantenerumab in early alzheimer’s disease. N Engl J Med. 2023;389(20):1862-1876.

[47] Bittner T, Tonietto M, Klein G, et al. Biomarker treatment effects in two phase 3 trials of gantenerumab. Alzheimers Dement. 2025;21(2):e14414.

[48] Mintun M, Ritchie CW, Solomon P, et al. Donanemab in early symptomatic alzheimer’s disease: efficacy and safety in TRAILBLAZER-ALZ 2, a phase 3 randomized clinical trial. Alzheimer’s & Dementia. 2023.

[49] Salloway S, Pain A, Lee E, et al. TRAILBLAZER-ALZ 4: a phase 3 trial comparing donanemab with aducanumab on amyloid plaque clearance in early, symptomatic alzheimer’s disease. Alzheimers Dement. 2025;21(5):e70293.

[50] Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021;13(1):80.

[51] Willis BA, Penner N, Rawal S, et al. Subcutaneous (SC) lecanemab is predicted to achieve comparable efficacy and improved safety compared to lecanemab IV in early alzheimer’s disease (AD). Alzheimer’s & Dementia. 2023.

[52] Tarawneh R, Pankratz VS. The search for clarity regarding “clinically meaningful outcomes” in alzheimer disease clinical trials: CLARITY-AD and beyond. Alzheimers Res Ther. 2024;16(1):37.

[53] Grimm HP, Schumacher V, Schäfer M, et al. Delivery of the brainshuttle^™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans. MAbs. 2023;15(1):2261509.

[54] Gyparaki MT, Arab A, Sorokina EM, et al. Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates [cell biology]. Proc Natl Acad Sci U S A. 2021;118(19):e2021461118.

[55] Chakraborty P, Ibáñez de Opakua A, Purslow JA, et al. GSK3β phosphorylation catalyzes the aggregation of tau into alzheimer’s disease-like filaments. Proc Natl Acad Sci U S A. 2024;121(52):e2414176121.

[56] Jiang M, Zhang X, Yan X, et al. GSK3β is involved in promoting alzheimer’s disease pathologies following chronic systemic exposure to porphyromonas gingivalis lipopolysaccharide in amyloid precursor protein^NL-F/NL-F knock-in mice. Brain Behav Immun. 2021;98:1-12.

[57] Novak P, Kovacech B, Katina S, et al. ADAMANT: a placebo-controlled randomized phase 2 study of aADvac1, an active immunotherapy against pathological tau in alzheimer’s disease. Nat Aging. 2021;1(6):521-534.

[58] Cullen NC, Novak P, Tosun D, et al. Efficacy assessment of an active tau immunotherapy in alzheimer’s disease patients with amyloid and tau pathology: a post hoc analysis of the “ADAMANT” randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial. EBioMedicine. 2024;99:104923.

[59] Kovacech B, Cullen NC, Novak P, et al. Post hoc analysis of aDAMANT, a phase 2 clinical trial of active tau immunotherapy with aADvac1 in patients with alzheimer’s disease, positive for plasma p-tau217. Alzheimers Res Ther. 2024;16(1):254.

[60] Sol O, Mermoud J, Hallikainen M, et al. Safety and immunogenicity of two tau-targeting active immunotherapies, aCI-35.030 and JACI-35.054, in participants with early alzheimer’s disease: a phase 1b/2a, multicentre, double-blind, randomised, placebo-controlled study. EBioMedicine. 2025;120:105940.

[61] Monteiro C, Toth B, Brunstein F, et al. Randomized phase II study of the safety and efficacy of semorinemab in participants with mild-to-Moderate alzheimer disease: lauriet. Neurology. 2023;101(14):e1391-e1401.

[62] Teng E, Manser PT, Pickthorn K, et al. Safety and efficacy of semorinemab in individuals with prodromal to mild alzheimer disease: a randomized clinical trial. JAMA Neurol. 2022;79(8):758-767.

[63] Shulman M, Kong J, O’Gorman J, et al. TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early alzheimer’s disease. Nat Aging. 2023;3(12):1591-1601.

[64] Florian H, Wang D, Arnold SE, et al. Tilavonemab in early alzheimer’s disease: results from a phase 2, randomized, double-blind study. Brain. 2023;146(6):2275-2284.

[65] Fleisher AS, Munsie LM, Perahia DGS, et al. Assessment of efficacy and safety of zagotenemab: results from PERISCOPE-ALZ, a phase 2 study in early symptomatic alzheimer disease. Neurology. 2024;102(5):e208061.

[66] Barton ME, Steen BVD, Van Tricht HLG, et al. Update on the TOGETHER study: a patient‐ and investigator‐blind, randomized, placebo‐controlled study evaluating the efficacy, safety and tolerability of bepranemab, UCB0107, in prodromal‐to‐mild alzheimer’s disease. Alzheimer’s & Dementia. 2022.

[67] Cai W, Zhang H, Wu Y, Yao Y, Zhang J. Comparative the efficacy and safety of gosuranemab, semorinemab, tilavonemab, and zagotenemab in patients with alzheimer’s disease: a systematic review and network meta-analysis of randomized controlled trials. Front Aging Neurosci. 2024;16:1465871.

[68] Long H, Simmons A, Mayorga A, et al. Preclinical and first-in-human evaluation of aL002, a novel TREM2 agonistic antibody for alzheimer’s disease. Alzheimers Res Ther. 2024;16(1):235.

[69] Ma YN, Hu X, Karako K, Song P, Tang W, Xia Y. The potential and challenges of TREM2-targeted therapy in alzheimer’s disease: insights from the INVOKE-2 study. Front Aging Neurosci. 2025;17:1576020.

[70] Colonna M, Holtzman DM. Rethinking TREM2 as a target for alzheimer’s disease after the INVOKE-2 trial failure. Nat Med. 2025;31(10):3217-3218.

[71] Yuan S, El Gaamouch F, Cho S, Kuncewicz K, Nada H, Gabr MT. Discovery of a small molecule TREM2 agonist with improved in vitro pharmacokinetic profile and validated target engagement. ACS Med Chem Lett. 2025;16(8):1634-1640.

[72] Ashvin n, Dhapola R, Kumari S, et al. Unraveling the immune puzzle: role of immunomodulation in alzheimer’s disease. J Neuroimmune Pharmacol. 2025;20(1):47.

[73] Cummings JL, Osse AML, Kinney JW. Alzheimer’s disease: novel targets and investigational drugs for disease modification. Drugs. 2023;83(15):1387-1408.

[74] Potter H, Woodcock JH, Boyd TD, et al. Safety and efficacy of sargramostim (GM-CSF) in the treatment of alzheimer’s disease. Alzheimers Dement (N Y). 2021;7(1):e12158.

[75] Jaeger J, Staats KA, Barnum S, et al. XPro1595, a selective soluble TNF neutralizer, in early alzheimer’s disease with inflammation (ADi): results from the phase 2 MINDFuL trial. medRxiv-Neurology. 2025.

[76] Faquetti ML, Slappendel L, Bigonne H, et al. Baricitinib and tofacitinib off-target profile, with a focus on alzheimer’s disease. Alzheimers Dement (N Y). 2024;10(1):e12445.

[77] König LE, Rodriguez S, Hug C, et al. TYK2 as a novel therapeutic target in alzheimer disease. bioRxiv-Neuroscience. 2024.

[78] Dubois B, López-Arrieta J, Lipschitz S, et al. Masitinib for mild-to-moderate alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial. Alzheimers Res Ther. 2023;15(1):39.

[79] Millar CL, Iloputaife I, Baldyga K, et al. A pilot study of senolytics to improve cognition and mobility in older adults at risk for alzheimer’s disease. EBioMedicine. 2025;113:105612.

[80] Cummings JL, Atri A, Feldman HH, et al. evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic alzheimer’s disease. Alzheimers Res Ther. 2025;17(1):14.

[81] Wang W, Wang Q, Qi X, et al. Associations of semaglutide with first-time diagnosis of alzheimer’s disease in patients with type 2 diabetes: target trial emulation using nationwide real-world data in the US. Alzheimers Dement. 2024;20(12):8661-8672.

[82] Widera E. Falsification periods seen with an immediate reduction in alzheimer’s disease with semaglutide. Alzheimers Dement. 2025;21(5):e70150.

[83] Wang ZJ, Li XR, Chai SF, et al. Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of alzheimer’s disease via the GLP-1R/SIRT1/GLUT4 pathway. Neuropharmacology. 2023;240:109716.

[84] Zhang T, Gao G, Kwok LY, Sun Z. Gut microbiome-targeted therapies for alzheimer’s disease. Gut Microbes. 2023;15(2):2271613.

[85] Zheng M, Ye H, Yang X, et al. Probiotic clostridium butyricum ameliorates cognitive impairment in obesity via the microbiota-gut-brain axis. Brain Behav Immun. 2024;115:565-587.

[86] Xiao-Hang Q, Si-Yue C, Hui-Dong T. Multi-strain probiotics ameliorate alzheimer’s-like cognitive impairment and pathological changes through the aKT/GSK-3β pathway in senescence-accelerated mouse prone 8 mice. Brain Behav Immun. 2024;119:14-27.

[87] Ye T, Yuan S, Kong Y, et al. Effect of probiotic fungi against cognitive impairment in mice via regulation of the fungal microbiota-Gut-Brain axis. J Agric Food Chem. 2022;70(29):9026-9038.

[88] Yang C, Sun J, Li L, et al. Synbiotics of lactobacillus suilingensis and inulin alleviates cognitive impairment via regulating gut microbiota indole-3-lactic acid metabolism in female aD mice. Alzheimers Dement. 2025;21(7):e70406.

[89] Megur A, Baltriukienė D, Bukelskienė V, Burokas A. The microbiota-Gut-Brain axis and alzheimer’s disease: neuroinflammation is to blame?. Nutrients. 2020;13(1):37.

[90] Liu Q, Xi Y, Wang Q, et al. Mannan oligosaccharide attenuates cognitive and behavioral disorders in the 5xFAD alzheimer’s disease mouse model via regulating the gut microbiota-brain axis. Brain Behav Immun. 2021;95:330-343.

[91] Bosch ME, Dodiya HB, Michalkiewicz J, et al. Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner. Mol Neurodegener. 2024;19(1):18.

[92] Xiao S, Chan P, Wang T, 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.

[93] Zhang G, Dou Y, Xie H, et al. Sea cucumber egg oligopeptides ameliorate cognitive impairments and pathology of alzheimer’s disease through regulating HDAC3 and BDNF/NT3 via the microbiota-Gut-Brain axis. Nutrients. 2025;17(14):2312.

[94] He C, Jiang J, Liu J, Zhou L, Ge Y, Yang Z. Pseudostellaria heterophylla polysaccharide mitigates alzheimer’s-like pathology via regulating the microbiota-gut-brain axis in 5 × FAD mice. Int J Biol Macromol. 2024;270(Pt 2):132372.

[95] Du L, Chen J, Yan J, et al. Lingguizhugan decoction ameliorates cognitive impairment in aD-like mice by influencing the microbiome-gut-brain axis mediated by SCFAs. Phytomedicine. 2024;133:155942.

RIGHTS & PERMISSIONS

The Author(s) 2026. This article is published by Higher Education Press at journal.hep.com.cn.