INTRODUCTION

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, representing one of the most pressing neurological and public health challenges of the twenty-first century. Recent global estimates indicate that over 55 million individuals are currently living with dementia, with AD accounting for approximately 60-70% of cases, a burden projected to rise substantially with population aging and increased life expectancy1,2,3. Despite decades of intensive research, therapeutic strategies targeting the classical pathological hallmarks of AD amyloid-β plaques and tau neurofibrillary tangles have demonstrated only modest or inconsistent clinical benefits, particularly when administered after the onset of symptoms4,5,6. These limitations have prompted a paradigm shift toward understanding AD as a multifactorial disorder involving complex interactions between neurodegenerative and systemic processes. In this evolving framework, neuroimmune dysregulation has emerged as a critical contributor to early disease pathogenesis7,8,9. Increasing evidence suggests that neurodegeneration unfolds within a broader context of age-associated immune remodeling, encompassing both central and peripheral immune compartments. Alterations in innate immune cells, particularly microglia, along with dysregulated adaptive immune responses, contribute to the establishment of a chronic neuroinflammatory milieu that may precede overt neuronal damage10,11,12. Peripheral immune components, including T lymphocytes and monocyte-derived macrophages, further participate in this process, reflecting dynamic bidirectional communication along the neuroimmune axis13,14.

Within this context, immune checkpoint signaling pathways have gained increasing attention for their dual roles in maintaining immune homeostasis and modulating neuroinflammatory responses. Molecules such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) are essential for preserving immune tolerance and preventing excessive immune activation; however, their age-associated upregulation may also contribute to impaired immune surveillance and diminished capacity for tissue repair in the central nervous system15,16,17. Experimental and translational studies suggest that modulation of these pathways can influence microglial activation states, peripheral immune cell infiltration, and amyloid clearance mechanisms, although the clinical applicability of such approaches remains under active investigation18,19. Parallel advances in biomarker research are transforming the study of early AD. Technologies such as cerebrospinal fluid immune profiling, peripheral immunophenotyping, and molecular neuroimaging targeting neuroinflammation are beginning to reveal measurable neuroimmune signatures associated with preclinical disease stages10,11. Emerging analytical platforms, including high-resolution spectroscopic techniques, further offer the potential to detect metabolic and molecular signatures linked to immune aging and cellular stress responses, although these approaches remain largely investigational.

Importantly, the intersection of aging biology and immune regulation provides a broader mechanistic context for these observations. Immunosenescence, defined as the progressive decline in immune competence with aging, is characterized by features such as T-cell exhaustion, altered cytokine production, and epigenetic remodeling of immune gene expression12,13. Recent evidence indicates that age-associated epigenetic alterations including DNA methylation changes at immune regulatory loci such as PDCD1 and histone modifications influencing microglial genes like TREM2 may contribute to sustained immune dysfunction and chronic neuroinflammation in the aging brain14,15,16. These findings support the concept that neuroimmune dysregulation represents a fundamental component of AD susceptibility rather than merely a secondary response to neuronal injury. From a public health perspective, recognizing the contribution of immune dysfunction to AD pathogenesis underscores the importance of early detection and risk stratification strategies. However, translating immune-based biomarkers and immunomodulatory interventions into routine clinical practice remains challenging. Limitations in biomarker specificity, lack of standardized assay platforms, and variability across patient populations present significant barriers to clinical implementation17,18,19. These challenges are particularly pronounced in low- and middle-income countries, where limited healthcare infrastructure, economic constraints, and a high burden of infectious diseases may further complicate large-scale deployment of advanced diagnostic technologies.

In this context, the present review synthesizes current evidence on neuroimmune mechanisms in the early stages of AD, focusing on four interconnected themes: (i) the molecular and cellular roles of immune checkpoint signaling in neurodegenerative processes; (ii) the influence of immune aging and immunosenescence on AD susceptibility; (iii) emerging biomarkers reflecting neuroimmune dysfunction; and (iv) the translational opportunities and limitations associated with immune-targeted therapeutic strategies. By integrating insights from immunology, neuroscience, and translational research, this review aims to clarify how immune regulatory pathways contribute to the earliest phases of AD and to identify critical knowledge gaps that must be addressed to advance preventative and therapeutic approaches.

By decoding the interface of immune aging and neurodegeneration, this work aims to provide a roadmap for immune-informed prevention strategies in AD bridging basic immunology, biomarker science, and translational neurology to redefine therapeutic paradigms. Figure 1 schematically illustrates the progressive neuroimmune remodeling underlying Alzheimer’s Disease, delineating how escalating microglial activation, immune checkpoint–mediated immunosuppression, and peripheral immune biomarker signatures converge with advanced neuroimaging and multi-omic platforms to enable early diagnosis, risk stratification, and scalable public health implementation across diverse aging populations.

Literature Search Strategy and Study Selection

To ensure transparency and minimize selection bias, this review followed a structured literature identification and synthesis strategy aligned with recommendations from the EQUATOR Network and the methodological principles outlined in the SANRA (Scale for the Assessment of Narrative Review Articles). The present study is designed as a narrative integrative review and does not adhere to formal systematic review or scoping review reporting frameworks.

THE GLOBAL BURDEN OF PRECLINICAL ALZHEIMER’S DISEASE

Alzheimer’s Disease (AD) has traditionally been conceptualized as the clinical endpoint of progressive neurodegeneration, characterized by memory impairment, cognitive decline, and functional deterioration. However, converging evidence from longitudinal cohorts and biomarker-driven studies indicates that AD pathogenesis begins decades prior to symptom onset, within a prolonged preclinical phase marked by silent yet progressive neurobiological alterations20. These changes include the gradual accumulation of amyloid-β (Aβ), early tau hyperphosphorylation, mitochondrial dysfunction, synaptic impairment, and critically, neuroimmune remodeling21,22. Accordingly, the true global burden of AD extends far beyond clinically manifest disease and encompasses a substantial, yet largely unrecognized, reservoir of preclinical pathology.

Advanced age is the strongest and most well-established non-modifiable risk factor for Alzheimer’s Disease (AD) and its preclinical forms, as consistently demonstrated across large-scale epidemiological and longitudinal studies Lancet Commission on Dementia Prevention, Intervention, and Care23. Parallel to this, global demographic shifts are accelerating disease burden, with the population aged ≥60 years projected to increase from approximately 1 billion in 2020 to 2.1 billion by 2050, thereby amplifying the prevalence of preclinical AD on an unprecedented scale24. Cognitive aging, once considered a benign and inevitable process, is now increasingly understood as a continuum underpinned by progressive neuropathological changes. Landmark epidemiological studies, including the Mayo Clinic Study of Aging and the Framingham Heart Study, have demonstrated that approximately 30-40% of cognitively normal older adults harbor biomarker evidence of Aβ deposition or tau pathology, fulfilling criteria for preclinical AD25,26.

Importantly, this silent neuropathological burden is not confined to high-income countries (HICs). Low- and middle-income countries (LMICs), which are undergoing rapid demographic and epidemiological transitions, are projected to bear a disproportionate share of the global dementia burden. By 2050, nearly 70-71% of individuals with dementia are expected to reside in LMICs, where limitations in diagnostic infrastructure, specialist access, and disease awareness persist World Health Organization27. The convergence of increased life expectancy, suboptimal cardiovascular risk management, metabolic comorbidities, and chronic systemic inflammation in these regions accelerates the progression from preclinical pathology to overt neurodegeneration28,29. Additional modifiers including environmental exposures, lower educational attainment, and diminished cognitive reserve further exacerbate susceptibility to disease onset and progression30.

Despite these advances, early diagnosis of Alzheimer’s Disease remains a critical unmet need in global public health. Current diagnostic paradigms are largely predicated on the onset of clinical symptoms, relying on neuropsychological assessment and caregiver-reported cognitive decline, thereby failing to identify individuals in the asymptomatic but biologically active stages of disease31. Although biomarker-based approaches, including cerebrospinal fluid (CSF) assays and amyloid/tau positron emission tomography (PET), offer high sensitivity for early detection, their widespread implementation is constrained by cost, infrastructure requirements, and limited technical expertise, particularly in resource-limited settings32. This diagnostic gap perpetuates global inequities and delays the initiation of preventive or disease-modifying strategies during the earliest and most therapeutically tractable phase of AD.

In this context, current global health strategies and dementia care frameworks remain predominantly oriented toward symptomatic diagnosis and management, with limited integration of structured screening pathways for individuals at risk of preclinical Alzheimer’s Disease based on age, genetic susceptibility (e.g., APOE ε4), or emerging metabolic and immune biomarkers. This reflects a broader implementation gap between advancing biomarker science and real-world healthcare policy adoption, particularly in low- and middle-income countries33,34. An underappreciated yet transformative factor in this landscape is the emerging recognition of neuroimmune dysregulation as a sentinel biomarker and driver of preclinical AD. Studies from both human postmortem brains and longitudinal cohort data (e.g., the Religious Orders Study and the Alzheimer’s Disease Neuroimaging Initiative) have shown that elevations in peripheral pro-inflammatory cytokines, T cell exhaustion markers, and microglial activation occur prior to measurable cognitive decline35,36,37. These immune features not only correlate with amyloid and tau deposition but may also contribute causally to disease initiation by disrupting homeostatic clearance, impairing synaptic pruning, and accelerating neurovascular dysfunction38.

In LMICs, where access to PET imaging and lumbar punctures is limited, the integration of immune biomarkers and blood-based spectroscopic tools offers a more scalable and equitable approach to early detection. Raman spectroscopy, FTIR, and NMR-based platforms can detect epigenetic and metabolic signatures of immune aging and T cell dysfunction, offering a non-invasive, low-cost alternative to traditional biomarker pipelines39,40. These technologies are particularly relevant in public health surveillance contexts, where high-throughput, rapid screening could facilitate early risk stratification and longitudinal tracking. Socioeconomic inequities also compound the challenge of addressing preclinical AD globally. In many LMICs, individuals at risk of cognitive decline have limited access to preventive healthcare, insurance coverage, or cognitive rehabilitation services. Furthermore, gendered patterns of health-seeking behaviour, education, and caregiving mean that women who constitute two-thirds of AD cases are particularly vulnerable to delayed diagnosis and intervention41. These disparities are compounded by structural underinvestment in mental health infrastructure, fragmented elder care systems, and poor integration of geriatric and neurological services42. Despite the scale of the problem, opportunities for intervention abound. Immune-targeted therapies, including checkpoint inhibitors and immune rejuvenation agents, have shown early promise in preclinical AD models and small human trials, suggesting that targeting neuroimmune failure may delay the onset or progression of disease43,44. Furthermore, population-level interventions such as cardiovascular risk control, diet modification, cognitive stimulation, and anti-inflammatory lifestyle measures may reduce the cumulative burden of neuroimmune stressors, especially if initiated during midlife45. Framing preclinical AD as a modifiable and immunologically active stage encourages a shift from reactive to preventive paradigms in both policy and practice.

Ultimately, addressing the global burden of preclinical AD requires an integrated, multidisciplinary strategy that bridges clinical neuroscience, public health policy, molecular immunology, and health equity frameworks. This includes: (i) redefining diagnostic criteria to incorporate immune and metabolic risk profiles; (ii) promoting biomarker development tailored for low-resource settings; (iii) embedding cognitive and immune health into primary care and aging programs; and (iv) fostering global research collaborations focused on diverse populations. A failure to act now will result not only in escalating dementia prevalence but also in deepening social and health inequities across generations. To contextualize the multidimensional drivers underlying the global burden of preclinical Alzheimer’s Disease, Table 1 synthesizes key epidemiological, demographic, and healthcare-system determinants including population aging, silent disease prevalence, socioeconomic disparities, and health system capacity highlighting how these interconnected factors collectively shape disease vulnerability and diagnostic inequities across diverse global settings.

IMMUNE CHECKPOINT SIGNALING IN THE AGING BRAIN

The central nervous system (CNS) has long been regarded as an immune-privileged site; however, this paradigm has evolved to accommodate the dynamic and tightly regulated role of immune surveillance in maintaining neural homeostasis. Among the most critical regulators of CNS immune balance are immune checkpoint molecules, which fine-tune the activation thresholds of immune cells to prevent excessive inflammation or autoimmunity. In the context of aging and neurodegeneration, these regulatory pathways become increasingly dysregulated, contributing to the pathogenesis of Alzheimer’s Disease (AD) even before clinical symptoms arise. Immune checkpoint receptors such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) play central roles in modulating the activity of T lymphocytes, microglia, macrophages, and astrocytes within the aging brain. These molecules, typically upregulated during chronic immune stimulation, serve as co-inhibitory receptors that limit excessive immune activation. In the context of chronic neurodegenerative stress such as the presence of amyloid-β (Aβ) plaques or hyperphosphorylated tau checkpoint expression is often pathologically elevated, impairing immunosurveillance and fostering a permissive environment for neurodegeneration (Table 2).

Microglia, the resident innate immune cells of the CNS, express several immune checkpoint ligands including PD-L1 and galectin-9 (the ligand for TIM-3), especially under conditions of chronic inflammation and aging. In early AD, microglia undergo a functional transformation toward a disease-associated microglial (DAM) phenotype, characterized by impaired phagocytosis, altered metabolic states, and increased expression of immune checkpoint molecules46. This altered state diminishes their capacity to clear Aβ and debris, while simultaneously promoting chronic neuroinflammation via cytokine release. Similarly, astrocytes, once considered passive support cells, express checkpoint ligands such as B7 family members and also contribute to immune synapse formation and neuronal injury modulation47. In neuroinflammatory settings, astrocytes engage in cross-talk with infiltrating lymphocytes, further amplifying checkpoint-driven immunosuppression and reactive gliosis. Infiltrating peripheral T lymphocytes, especially CD8 and CD4 T cells, have been increasingly recognized as key players in CNS immune surveillance and AD pathology. With aging and chronic exposure to Aβ, these cells undergo functional exhaustion characterized by sustained expression of PD-1, LAG-3, and TIM-3, and reduced production of effector cytokines such as IL-2 and IFN-γ48. This immunosenescent phenotype limits the ability of T cells to mount effective anti-amyloid or neuroprotective responses, and may also impair clearance of viral reactivations such as latent herpesviruses factors implicated in AD progression. Moreover, CTLA-4 signaling in T regulatory cells (Tregs) becomes upregulated in aged individuals, potentially skewing the balance toward excessive immune tolerance in the brain parenchyma49.

Emerging evidence from human autopsy studies, cerebrospinal fluid (CSF) analyses, and single-cell transcriptomic profiling supports the dysregulation of immune checkpoints in early and preclinical AD. For instance, single-cell RNA sequencing of brain-infiltrating lymphocytes in individuals with mild cognitive impairment (MCI) has revealed elevated expression of PD-1, LAG-3, and TIM-3 transcripts in both CD8 and CD4 populations50. In parallel, microglial populations in preclinical AD brains exhibit upregulated PD-L1 and altered NF-κB signaling, suggesting a compensatory or maladaptive checkpoint engagement in response to early neuropathological triggers51. CSF samples from biomarker-positive but cognitively normal individuals show elevated levels of soluble PD-L1 and TIM-3 ligands, indicating systemic checkpoint activation even before clinical symptoms emerge52.

Checkpoint dysregulation does not occur in isolation; rather, it intersects intricately with the pathological hallmarks of AD amyloid-β, tau, and neuronal loss. PD-1-expressing T cells accumulate near amyloid plaques in both mouse models and human postmortem brains, yet appear functionally inert, unable to mount cytotoxic responses or promote clearance53. In murine models, blockade of PD-1 or CTLA-4 restores T cell effector function, enhances microglial phagocytosis of Aβ, and reduces plaque burden, suggesting a therapeutic window for immune reinvigoration54. Tau pathology, likewise, is exacerbated by chronic checkpoint-mediated immune paralysis. Recent data suggest that immune checkpoint activation in T cells and glial cells may impair tau clearance and potentiate the spread of tau aggregates via extracellular vesicles or compromised glymphatic flow52. In addition to promoting protein aggregation, checkpoint signaling may directly impact neuronal viability through glial-mediated mechanisms. Astrocytes and microglia, under the influence of checkpoint ligands, can adopt neurotoxic phenotypes that release glutamate, ROS, and pro-apoptotic mediators. PD-L1 expression in astrocytes has been shown to suppress synaptic remodeling and contribute to synapse loss in aging models, while CTLA-4 Tregs may limit the recruitment of protective immune cells to sites of neural injury55. These interactions reflect a broader landscape in which chronic immune checkpoint engagement fosters a milieu of immune exhaustion, failed clearance, and synaptic vulnerability. Collectively, these findings highlight that immune checkpoints in the aging brain are not simply inert markers of immune modulation but active participants in the pathophysiology of AD. The aberrant upregulation of PD-1, CTLA-4, TIM-3, and LAG-3 across immune and glial populations reflects a systemic breakdown in immune surveillance that precedes and potentially drives neurodegeneration. Targeting these pathways, either through localized immune checkpoint blockade, metabolic reprogramming, or combined epigenetic modulation, represents a promising frontier in the prevention of symptomatic AD. Understanding the temporal and spatial dynamics of checkpoint signaling particularly in the preclinical phase may offer critical insight into who is most at risk, when to intervene, and how best to restore neuroimmune equilibrium.

Mechanisms Linking Neuroimmune Dysfunction and Cognitive Decline

The intricate interplay between neuroimmune dysregulation and cognitive decline has emerged as a central axis in the pathogenesis of Alzheimer’s Disease (AD) and age-associated neurodegeneration. While classically considered a neurocentric disorder, compelling evidence now implicates peripheral and central immune pathways including chronic inflammation, immune exhaustion, and checkpoint signaling in accelerating neuronal dysfunction and cognitive impairment. These immunological alterations are neither incidental nor reactive but may constitute upstream pathogenic events shaping the disease trajectory from asymptomatic stages to overt dementia61,62.

To mechanistically contextualize the multi-dimensional interplay between central and peripheral immune systems in driving neurodegeneration, Figure 2 illustrates an integrated framework linking immune checkpoint dysregulation, glial activation, blood–brain barrier disruption, and gut–brain axis perturbations to progressive neuronal dysfunction and cognitive decline in Alzheimer’s Disease.

Biomarkers of Neuroimmune Dysregulation in Preclinical Alzheimer’s Disease

The identification of early, reliable biomarkers of neuroimmune dysregulation is critical for intercepting Alzheimer’s Disease (AD) at its preclinical stage prior to irreversible neurodegeneration. Mounting evidence suggests that immunological alterations precede cognitive symptoms by years, if not decades. A growing arsenal of soluble, imaging, and multi-omic biomarkers now enables characterization of neuroimmune states across the disease continuum, with translational potential for both population-level screening and precision-targeted interventions Table 4.

Translational Therapeutics and Immunoprevention in Alzheimer’s Disease

As the immunological underpinnings of Alzheimer’s Disease (AD) become increasingly defined, immunotherapeutic and immune-preventive strategies are rapidly emerging as next-generation tools to combat neurodegeneration. While most historical approaches have targeted amyloid-β and tau directly, newer interventions aim to restore immune homeostasis, enhance glial resilience, and reverse maladaptive Immunosenescence. This paradigm shift opens novel translational avenues that bridge oncology, immunology, and neuroscience, offering hope for disease interception during the preclinical or prodromal stages of AD.

Public Health and Implementation Pathways for Neuroimmune Biomarkers in Alzheimer’s Disease

The recognition of immune dysregulation as an upstream driver of neurodegeneration has catalyzed a paradigm shift in Alzheimer’s Disease (AD) management from late-stage therapeutic intervention to early, preventive action. Integrating neuroimmune biomarkers into public health frameworks, particularly within aging populations, presents both unprecedented opportunity and complex implementation challenges. Realizing the translational potential of these tools demands a coordinated strategy across primary care systems, risk stratification infrastructure, global dementia policy, and equitable access in low- and middle-income countries (LMICs).

DISCUSSION

The expanding intersection between neuroimmunology and Alzheimer’s Disease (AD) pathogenesis has substantially reshaped prevailing models of neurodegeneration, positioning immune dysregulation as a contributory factor in early disease evolution rather than a purely downstream consequence of protein aggregation150,151. This evolving framework highlights the neuroimmune axis as a critical interface linking aging biology, central nervous system (CNS) homeostasis, and systemic inflammatory processes. However, the extent to which immune alterations act as primary drivers versus secondary amplifiers of pathology remains incompletely resolved, necessitating cautious interpretation of emerging findings151.

A central feature of this paradigm is the progressive emergence of age-associated immune remodeling, often described as “inflammaging,” characterized by chronic low-grade inflammation, immunosenescence, and functional exhaustion of adaptive immune compartments152. Within the CNS, alterations in microglial activation states, impaired phagocytic capacity, and sustained pro-inflammatory signaling contribute to a permissive environment for neurodegenerative processes. Concurrently, dysregulated peripheral immune responses including altered trafficking of T lymphocytes and monocyte-derived cells reinforce bidirectional neuroimmune interactions152,153. Increased expression of inhibitory immune checkpoint molecules such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may further attenuate immune surveillance and limit effective clearance of pathogenic aggregates153. Notably, emerging mechanistic evidence suggests that age-related epigenetic remodeling including DNA methylation changes at immune regulatory loci such as PDCD1 and histone modifications influencing microglial genes like TREM2 may contribute to sustained immune dysfunction and chronic neuroinflammatory signaling, thereby linking Immunosenescence with persistent neurodegenerative vulnerability154.

The increasing focus on neuroimmune biomarkers reflects their potential to capture early pathophysiological alterations preceding clinical symptom onset. Peripheral and central markers including soluble checkpoint molecules, monocyte activation markers, and glial-derived proteins have shown associations with disease progression in observational and translational studies155. However, their clinical applicability remains constrained by several critical limitations. Many immune biomarkers lack disease specificity and may be influenced by comorbid inflammatory conditions, infections, or metabolic disorders. In addition, variability in assay platforms, lack of standardized protocols, and limited reproducibility across cohorts pose significant barriers to clinical translation155,156. These challenges are particularly pronounced in low- and middle-income countries, where access to advanced diagnostics such as cerebrospinal fluid analysis and molecular neuroimaging is limited. Furthermore, high background levels of systemic inflammation in such settings may increase the risk of false-positive interpretations, thereby complicating population-level screening strategies156. Consequently, while neuroimmune biomarkers hold promise for early risk stratification, their integration into routine clinical practice will require rigorous validation, harmonization of methodologies, and cost-effective implementation frameworks.

From a therapeutic perspective, the shift toward immune-directed strategies represents a conceptual departure from traditional amyloid-centric approaches. Monoclonal antibodies targeting amyloid-β, including Aducanumab and Lecanemab, have demonstrated reductions in amyloid burden but have yielded modest and sometimes inconsistent clinical benefits, and are associated with adverse effects such as amyloid-related imaging abnormalities (ARIA)157. These limitations underscore the need for alternative or complementary strategies. In contrast, immune-modulatory approaches including checkpoint pathway modulation, microglial reprogramming via TREM2 signaling, and targeting cellular senescence aim to restore immune homeostasis rather than directly eliminate pathological aggregates. While preclinical findings are promising, these approaches remain in early translational stages, and their safety profiles require careful evaluation given the potential risks of excessive immune activation and the unique immunological constraints of the CNS157.

Beyond pharmacological interventions, broader determinants of immune function including metabolic health, environmental exposures, and microbiome composition are increasingly recognized as modulators of neurodegenerative risk. Interactions between systemic inflammation and epigenetic regulation may influence disease susceptibility across the lifespan, further emphasizing the complexity of neuroimmune dynamics154,156. Importantly, much of the current evidence base is derived from high-income populations, raising concerns regarding generalizability. Variations in environmental exposures, infectious disease burden, and healthcare infrastructure across global settings may shape neuroimmune trajectories differently, underscoring the need for geographically diverse and population-specific research156.

From a public health and translational perspective, the integration of neuroimmune insights into early detection and prevention strategies presents both opportunities and challenges. While multi-omic and immune-based profiling approaches may enhance risk stratification, their implementation raises critical considerations related to cost, accessibility, assay standardization, and ethical implications particularly in the absence of definitive disease-modifying therapies155,156,157. These constraints highlight the importance of aligning scientific advances with health system capacity and policy frameworks to ensure equitable and responsible translation.

In summary, the conceptualization of AD as a disorder involving neuroimmune dysregulation provides a valuable framework for understanding early disease mechanisms and identifying potential intervention points. Nevertheless, substantial gaps remain in defining causal relationships, validating biomarkers across diverse populations, and establishing the long-term safety and efficacy of immune-targeted therapies. Future progress will depend on integrating mechanistic insights with longitudinal human studies and implementation science approaches to determine whether modulation of the neuroimmune axis can meaningfully alter disease trajectories150,151,152,153,154,155,156,157.

FUTURE DIRECTIONS

The reconceptualization of Alzheimer’s Disease (AD) as an immune-mediated disorder offers a powerful foundation for advancing both diagnostic and therapeutic paradigms. Immune checkpoint molecules such as PD-1, PD-L1, CTLA-4, and LAG-3 are emerging as dual-purpose tools: not only as therapeutic targets but also as dynamic biomarkers for tracking disease onset and progression. Their expression profiles in both central and peripheral compartments may reflect evolving immune exhaustion, synaptic dysfunction, and early-stage neuroinflammation enabling multi-dimensional stratification of at-risk individuals158,159 (Figure 3).

To fully realize this potential, investment in longitudinal, ethnically diverse cohorts with serial immune, imaging, and cognitive data is critical. Most current biomarker frameworks are derived from predominantly white, high-income populations, limiting translational equity. Building population-specific reference ranges, especially in low- and middle-income countries (LMICs), must become a priority within international dementia research consortia160. The integration of immune biomarkers into digital health platforms and AI-guided risk prediction tools also demands scalable public health infrastructure that bridges geriatric medicine, immunology, and informatics161 (Figure 3). Positioning neuroimmune dysregulation as a modifiable axis reframes cognitive decline not as an inevitable consequence of aging but as an intervenable trajectory. Therapeutic strategies including checkpoint recalibration, TREM2 activation, senolytics clearance, and anti-inflammatory diets have the potential to reprogram immune tone, delay pathology, and extend cognitive health span162. A global call to action must now converge immunology, geriatrics, and public health into a unified front against dementia. This requires cross-sector coordination, ethical frameworks for preclinical detection, and the political will to fund preventive neurology at scale. As immune signatures become the harbingers of neurodegeneration, the future of AD prevention lies in decoding and correcting the language of immune aging166.

CONCLUSION

The evolving understanding of Alzheimer’s Disease (AD) as a disorder influenced by neuroimmune interactions provides an expanded framework for interpreting early disease mechanisms and identifying potential points of intervention. Accumulating evidence suggests that neuroimmune dysregulation including microglial priming, immune checkpoint signaling, and systemic inflammaging may contribute to both the initiation and progression of neurodegenerative processes, although the precise causal relationships remain to be fully established. Advances in biomarker research, including soluble immune mediators, glial activation markers, and neuroinflammation-targeted imaging approaches, offer promising avenues for detecting early pathophysiological changes associated with preclinical AD. However, the clinical applicability of these biomarkers is currently limited by issues related to specificity, reproducibility, and standardization across populations and platforms. Similarly, emerging therapeutic strategies targeting immune pathways such as checkpoint modulation, microglial signaling pathways, and cellular senescence have demonstrated encouraging results in preclinical and early translational studies, but require rigorous clinical validation to establish safety, efficacy, and long-term outcomes. Beyond targeted therapies, broader determinants of immune function, including metabolic health, environmental exposures, and lifestyle factors, may influence neurodegenerative risk and represent additional areas for preventive investigation. Nevertheless, translating these insights into clinical and public health practice remains challenging. Barriers related to cost, infrastructure, and population heterogeneity are particularly relevant in low- and middle-income countries, where the burden of dementia is rapidly increasing and access to advanced diagnostic technologies is limited. In this context, future progress will depend on integrating mechanistic insights from neuroimmunology with longitudinal clinical studies, biomarker validation efforts, and implementation science approaches. A more comprehensive understanding of how immune dysregulation interacts with neurodegenerative pathways may ultimately inform more precise and equitable strategies for early detection and intervention. While the neuroimmune paradigm represents a promising direction, its successful translation into clinical practice will require careful evaluation, interdisciplinary collaboration, and alignment with global health priorities.

ABBREVIATIONS

AA: Accelerated Aging; AD: Alzheimer’s Disease; AUC: Area Under the Curve; CD14: Cluster of Differentiation 14; CNS: Central Nervous System; CRP: C-Reactive Protein; CSF: Cerebrospinal Fluid; CTLA-4: Cytotoxic T-Lymphocyte Antigen 4; DAMPs: Damage-Associated Molecular Patterns; EHR: Electronic Health Record; IFN-γ: Interferon-gamma; IL-6: Interleukin-6; ICPs: Immune Checkpoint Pathways; IS: Immunosenescence; LAG-3: Lymphocyte Activation Gene-3; LMICs: Low- and Middle-Income Countries; mTOR: Mechanistic Target of Rapamycin; MRI: Magnetic Resonance Imaging; NDDs: Neurodegenerative Diseases; NID: Neuroimmune Dysregulation; PD-1: Programmed Cell Death Protein 1; PD-L1: Programmed Death-Ligand 1; PAMPs: Pathogen-Associated Molecular Patterns; PET: Positron Emission Tomography; PHI: Public Health Intervention; PMI: Precision Medicine Initiative; PPH: Precision Public Health; SASP: Senescence-Associated Secretory Phenotype; sCD14: Soluble CD14; sPD-L1: Soluble Programmed Death-Ligand 1; TIM-3: T-cell Immunoglobulin and Mucin-Domain Containing-3; TLRs: Toll-Like Receptors; TME: Tissue Microenvironment; TNF-α: Tumor Necrosis Factor-alpha; TSPO: Translocator Protein (18kDa); WHO: World Health Organization; YKL-40: Chitinase-3-Like Protein 1.

Acknowledgments

None.

Author’s contributions

Dr. Arpita Mukherjee conceived the study, designed the methodology, conducted the research, created all figures and illustrations, analyzed the data, and wrote the manuscript. Dr. Arpita Mukherjee takes full responsibility for the integrity, accuracy, and completeness of the work.

Funding

None.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Declaration of generative AI and AI-assisted technologies in the writing process

The authors declare that they have not used generative AI (a type of artificial intelligence technology that can produce various types of content including text, imagery, audio and synthetic data).

Competing interests

The authors declare that they have no competing interests.