Neuroinflammation in Alzheimer's Disease: Molecular Mechanisms and Therapeutic Opportunities

Figure 1. Structural brain changes in Alzheimer’s Disease

The global burden of AD has increased markedly over recent decades owing to demographic aging and increasing life expectancy. According to the World Health Organization, more than 55 million people are currently living with dementia worldwide, with projections indicating that this number may exceed 139 million by 2050 if effective preventive and therapeutic strategies are not implemented [2]. AD constitutes the largest proportion of these cases and has emerged as a major public health concern across both developed and developing nations. Epidemiological studies indicate that disease prevalence rises exponentially with advancing age, particularly after 65 years, making population aging a principal driver of future disease incidence [1,2]. Beyond its clinical implications, AD imposes a profound socioeconomic burden on patients, caregivers, healthcare systems, and society. The global cost associated with dementia care exceeds one trillion US dollars annually and continues to rise substantially with increasing disease prevalence [3]. In addition to direct healthcare expenditures, indirect costs related to long-term institutional care, productivity loss, and informal caregiving contribute significantly to the overall economic impact. Furthermore, caregivers frequently experience psychological distress, physical exhaustion, and reduced quality of life, highlighting the extensive societal consequences of the disease [4].

1.2 Classical Hallmarks of Alzheimer's Disease

Figure 2: Pathological Hallmarks of Alzheimer’s Disease and Neuroinflammatory Cascade

Table 1. Classical Neuropathological Hallmarks of Alzheimer's Disease and Their Clinical Significance[5-8]

1.3 Emergence of Neuroinflammation as a Central Pathological Feature

Although AD has historically been viewed primarily as a disorder of protein aggregation, accumulating evidence suggests that neuroinflammation plays a fundamental role in disease initiation and progression [9,10]. Contemporary research indicates that inflammatory processes are not merely secondary responses to amyloid and tau pathology but active contributors to neurodegeneration. Microglia, the resident immune cells of the central nervous system, have emerged as critical regulators of AD pathogenesis. In the early stages of disease, microglia contribute to the clearance of amyloid deposits and cellular debris; however, chronic activation results in sustained production of pro-inflammatory cytokines, chemokines, reactive oxygen species, and other neurotoxic mediators that exacerbate neuronal injury [9,10]. The importance of innate immunity in AD is further supported by genome-wide association studies identifying several disease-associated risk genes, including triggering receptor expressed on myeloid cells 2 (TREM2), which is predominantly expressed in microglial populations [11].

Astrocytes also participate actively in neuroinflammatory responses through reactive astrogliosis, altered metabolic support, and dysregulated secretion of inflammatory mediators. Furthermore, growing evidence implicates inflammasome activation, particularly the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, in amplifying neuroinflammatory signaling and promoting disease progression [12]. These findings have led to a paradigm shift in AD research, emphasizing complex interactions among amyloid pathology, tau aggregation, neuroimmune responses, and neuronal dysfunction.

1.4 Scope and Objectives of the Review

Given the growing recognition of neuroinflammation as a critical component of AD pathogenesis, a comprehensive understanding of the underlying inflammatory mechanisms has become increasingly important. This review aims to critically examine current knowledge regarding the role of neuroinflammation in AD, with particular emphasis on microglial and astrocytic activation, inflammatory signaling pathways, cytokine networks, inflammasome-mediated responses, and neuroimmune interactions. In addition, emerging therapeutic strategies targeting neuroinflammatory pathways and their translational potential will be discussed. By integrating evidence from experimental, translational, and clinical studies, this review seeks to provide a comprehensive perspective on the contribution of neuroinflammation to AD progression and its implications for future disease-modifying interventions.

2. Overview of Neuroinflammation in Alzheimer's Disease

2.1 Definition of Neuroinflammation

Neuroinflammation refers to the coordinated immune response within the central nervous system (CNS) mediated primarily by microglia, astrocytes, endothelial cells, perivascular macrophages, and infiltrating peripheral immune cells. Under physiological conditions, these cellular components maintain tissue homeostasis through pathogen surveillance, debris clearance, synaptic remodeling, and neurotrophic support. However, sustained activation of innate immune signaling pathways results in a chronic inflammatory milieu characterized by excessive production of cytokines, chemokines, reactive oxygen species (ROS), complement proteins, and other inflammatory mediators that contribute to neuronal dysfunction and degeneration [13,14,15].

2.2 Physiological versus Pathological Neuroinflammatory Responses

Physiological neuroinflammation is an adaptive and tightly regulated process essential for maintaining CNS integrity. Resting microglia continuously survey the neural environment and rapidly respond to tissue injury or infection. Following activation, microglia facilitate phagocytosis of cellular debris, secrete neuroprotective growth factors, and coordinate repair mechanisms that promote restoration of homeostasis [16]. Similarly, astrocytes contribute to blood-brain barrier (BBB) maintenance, metabolic support, and regulation of synaptic transmission. In contrast, pathological neuroinflammation is characterized by prolonged and dysregulated activation of glial cells. Chronic exposure to Aβ oligomers, fibrillar plaques, hyperphosphorylated tau aggregates, and damage-associated molecular patterns (DAMPs) promotes persistent activation of pattern-recognition receptors including Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), and triggering receptor expressed on myeloid cells 2 (TREM2)-associated signaling pathways [17,18]. Activated microglia subsequently release pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), while astrocytes undergo reactive transformation and amplify inflammatory cascades. Although acute inflammatory responses may initially facilitate Aβ clearance, prolonged activation leads to impaired phagocytic capacity, oxidative stress, synaptic dysfunction, and neuronal injury. This transition from protective to detrimental inflammation represents a critical feature of AD pathogenesis and may explain why inflammatory responses become self-perpetuating during disease progression [19].

2.3 Evidence Supporting Neuroinflammation in Alzheimer's Disease

Table 2. Evidence Supporting Neuroinflammation in Alzheimer's Disease.[20-22]

2.4 Neuroinflammation as a Driver Rather Than a Consequence

Historically, neuroinflammation was considered a secondary reaction to amyloid deposition and neuronal death. However, accumulating evidence challenges this view. The identification of immune-related genetic risk factors suggests that dysregulated inflammatory signaling may precede overt pathology and influence disease initiation [23]. Furthermore, experimental studies demonstrate that inflammatory mediators can directly enhance amyloidogenic APP processing, promote tau phosphorylation, impair synaptic function, and disrupt BBB integrity, thereby accelerating neurodegeneration [27].

3. Cellular Mediators of Neuroinflammation in Alzheimer's Disease

Fig 3. Neuroinflammatory cascade in Alzheimer’s disease

Neuroinflammation in Alzheimer's disease (AD) is mediated by a coordinated network of resident glial cells and infiltrating peripheral immune cells that collectively influence disease onset and progression. Among these cellular mediators, microglia and astrocytes represent the principal regulators of innate immune responses within the central nervous system (CNS), while oligodendrocytes and peripheral immune populations contribute to disease-associated inflammatory cascades. Although neuroinflammatory mechanisms may initially exert protective effects through the clearance of pathological proteins and maintenance of tissue homeostasis, chronic activation of these pathways promotes synaptic dysfunction, neuronal injury, and cognitive decline. Recent advances in transcriptomics, genetics, and neuroimaging have established neuroinflammation as a central pathogenic process rather than merely a secondary consequence of neurodegeneration [33].

Table 3. Cellular mediators of neuroinflammation in Alzheimer’s disease

3.1 Microglia

3.1.1 Microglial Physiology

Microglia are the resident immune cells of the CNS and originate from primitive yolk-sac macrophages during embryonic development. Under physiological conditions, they continuously survey the neural microenvironment through highly motile processes and participate in synaptic remodeling, neurogenesis, debris clearance, and maintenance of neuronal homeostasis [35,36]. Homeostatic microglia express characteristic markers such as P2RY12, TMEM119, and CX3CR1, which facilitate communication with neurons and other glial cells. Neuronal signaling molecules including fractalkine (CX3CL1) and CD200 contribute to the maintenance of a quiescent microglial phenotype and prevent excessive inflammatory activation [36].

3.1.2 Microglial Activation in AD

Microglial activation is among the earliest pathological alterations observed in AD. Amyloid-β (Aβ) oligomers and fibrils activate microglia through pattern-recognition receptors, including Toll-like receptors, scavenger receptors, and triggering receptor expressed on myeloid cells-2 (TREM2). Activation of these receptors initiates intracellular signaling pathways involving nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases, and the NLRP3 inflammasome, resulting in the production of pro-inflammatory mediators [10,37].

Accumulating evidence indicates that microglia also respond to pathological tau species. Activated microglia contribute to tau propagation through the release of inflammatory mediators and extracellular vesicles, thereby linking innate immune activation with the spread of neurofibrillary pathology [38]. Furthermore, genome-wide association studies have identified several AD risk genes associated with microglial function, including TREM2, CD33, CR1, and PLCG2, highlighting the importance of innate immune dysregulation in disease susceptibility [15].

3.1.3 Protective Functions

Amyloid Clearance

Microglia play an important protective role during the early stages of AD by facilitating the recognition and removal of Aβ deposits. Through receptor-mediated mechanisms involving TREM2 and scavenger receptors, microglia internalize and degrade amyloid aggregates, thereby limiting plaque accumulation and associated neurotoxicity [18]. Experimental studies have demonstrated that functional TREM2 signaling promotes microglial migration toward amyloid plaques and enhances plaque compaction, reducing local neuronal damage [39].

Phagocytosis

In addition to amyloid clearance, microglia remove apoptotic cells, damaged synapses, and cellular debris through phagocytosis. This process is essential for maintaining CNS homeostasis and preventing the accumulation of potentially neurotoxic materials. However, aging and sustained inflammatory stimulation impair microglial phagocytic capacity, leading to reduced clearance efficiency and progressive accumulation of pathological substrates [10,18].

3.1.4 Detrimental Effects

Chronic Activation

Although acute microglial activation can be beneficial, persistent stimulation by Aβ and tau promotes a chronic inflammatory state characterized by metabolic dysfunction, oxidative stress, and exaggerated immune responses. Aging-associated microglial priming further enhances susceptibility to sustained activation, amplifying neuroinflammatory signaling and accelerating neuronal damage [9,40].

Cytokine Release

Chronically activated microglia release a broad range of pro-inflammatory cytokines and chemokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and CCL2. These inflammatory mediators disrupt synaptic transmission, impair neuronal plasticity, alter blood-brain barrier integrity, and promote recruitment of additional immune cells into the CNS. Elevated levels of these cytokines have been consistently detected in AD brains and biological fluids, supporting their role in disease progression [9,17].

Synaptic Pruning

Recent studies have revealed that aberrant complement-mediated synaptic elimination represents a critical mechanism linking neuroinflammation to cognitive decline. Complement proteins C1q and C3 accumulate on vulnerable synapses, marking them for removal by microglia. Excessive synaptic pruning results in substantial synapse loss, which correlates strongly with cognitive impairment in AD [41,42].

3.1.5 Disease-Associated Microglia (DAM)

Single-cell transcriptomic studies have identified a specialized microglial phenotype termed disease-associated microglia (DAM). These cells exhibit reduced expression of homeostatic genes and increased expression of genes associated with lipid metabolism, phagocytosis, and inflammatory responses, including APOE, TREM2, TYROBP, and CST7 [43]. DAM appear to emerge in response to neurodegeneration and may initially contribute to amyloid containment and debris clearance. However, persistent DAM activation may promote chronic neuroinflammation and neurotoxicity, suggesting a dual role during disease progression [43,44].

3.2 Astrocytes

3.2.1 Normal Astrocytic Functions

Astrocytes are the most abundant glial cells in the CNS and perform numerous homeostatic functions. They regulate neurotransmitter recycling, maintain ion balance, support neuronal metabolism, preserve blood-brain barrier integrity, and participate in synaptic modulation. Astrocytes also secrete neurotrophic factors that promote neuronal survival and synaptic plasticity [45].

3.2.2 Reactive Astrogliosis

In AD, astrocytes undergo reactive astrogliosis, a process characterized by cellular hypertrophy, proliferation, and increased expression of glial fibrillary acidic protein (GFAP). Reactive astrocytes are frequently observed surrounding amyloid plaques and exhibit profound transcriptional and metabolic alterations [46]. Emerging evidence indicates that reactive astrocytes comprise heterogeneous populations with distinct functional properties. Some astrocytic phenotypes may retain protective functions, whereas others contribute directly to neurodegeneration through impaired metabolic support and enhanced inflammatory signaling [47].

3.2.3 Cytokine Production

Activated astrocytes produce a wide range of inflammatory mediators, including IL-1β, IL-6, TNF-α, transforming growth factor-β, and complement proteins. These molecules amplify local inflammatory responses and contribute to neuronal dysfunction. Notably, astrocytic production of complement component C3 has been associated with synaptic degeneration and cognitive decline in experimental models of AD [47,48].

3.2.4 Astrocyte-Microglia Crosstalk

Astrocytes and microglia engage in extensive bidirectional communication that regulates neuroinflammatory responses. Activated microglia release IL-1α, TNF-α, and C1q, which induce neurotoxic reactive astrocytes. In turn, astrocytes secrete cytokines and chemokines capable of further stimulating microglial activation. This reciprocal amplification loop contributes to chronic inflammation, synaptic dysfunction, and progressive neurodegeneration [47,49].

3.3 Oligodendrocytes and Myelin Dysfunction

Although less extensively studied than microglia and astrocytes, oligodendrocyte dysfunction has emerged as an important contributor to AD pathology. Oligodendrocytes are responsible for myelin formation and metabolic support of axons. Neuroimaging and neuropathological studies have demonstrated widespread white matter abnormalities and myelin degeneration in AD patients [50]. Inflammatory cytokines, oxidative stress, and amyloid-associated toxicity impair oligodendrocyte survival and remyelination capacity. Moreover, myelin debris can activate microglia and further exacerbate neuroinflammatory responses, establishing a self-perpetuating cycle of white matter damage and inflammation [50,51].

3.4 Peripheral Immune Cell Infiltration

Increasing evidence suggests that disruption of blood-brain barrier integrity during AD facilitates infiltration of peripheral immune cells into the CNS. These cells contribute to both protective and detrimental immune responses depending on disease stage and microenvironmental conditions [52].

Monocytes and Macrophages

Circulating monocytes are recruited into the CNS through chemokine-mediated pathways, particularly the CCL2-CCR2 axis. Following infiltration, these cells may differentiate into macrophages capable of phagocytosing Aβ deposits. However, prolonged recruitment can also enhance inflammatory signaling and tissue damage through cytokine production and antigen presentation [52].

T Lymphocytes

T lymphocytes have been identified in both the cerebrospinal fluid and brain parenchyma of AD patients. Recent studies have demonstrated expansion of clonally related cytotoxic CD8+ T-cell populations within the AD brain, suggesting active adaptive immune responses. These cells may influence disease progression through cytokine secretion and interactions with microglia and neurons [53].

Natural Killer Cells

Natural killer (NK) cells represent another peripheral immune population implicated in AD. Alterations in NK-cell phenotype and activity have been reported in affected individuals. Although their precise role remains incompletely understood, NK cells may modulate neuroinflammation through production of interferon-γ and interactions with resident immune cells [54]. Collectively, resident glial cells and infiltrating peripheral immune populations constitute a highly interconnected inflammatory network that influences virtually every stage of AD pathogenesis. Understanding the dynamic interplay among these cellular mediators is critical for the development of targeted immunomodulatory therapies aimed at limiting neuroinflammation while preserving essential homeostatic functions.

4. Molecular Mechanisms Underlying Neuroinflammation

4.1 Amyloid-β-Induced Inflammatory Signaling

Accumulation and aggregation of amyloid-β (Aβ) peptides represent one of the earliest pathological events associated with Alzheimer's disease (AD) and constitute a major trigger of innate immune activation within the central nervous system (CNS). Aβ is generated through sequential cleavage of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase, yielding peptides with varying lengths, among which Aβ42 exhibits the greatest propensity for oligomerization and fibrillization. Although soluble Aβ oligomers are increasingly recognized as the most neurotoxic species, insoluble fibrillar aggregates deposited as extracellular plaques also contribute significantly to chronic neuroinflammatory responses [55,56,]. Microglia recognize aggregated Aβ through multiple pattern-recognition receptors (PRRs), including toll-like receptors (TLRs), scavenger receptors, receptor for advanced glycation end products (RAGE), CD36, and triggering receptor expressed on myeloid cells 2 (TREM2). Binding of Aβ to these receptors initiates intracellular signaling cascades that activate transcription factors such as nuclear factor-kappa B (NF-κB), resulting in increased production of inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and reactive oxygen species (ROS) [9,33].

Initially, microglial activation promotes Aβ phagocytosis and clearance, constituting a protective response aimed at restoring tissue homeostasis [57]. However, persistent exposure to aggregated Aβ drives chronic activation of microglia, resulting in a shift toward a pro-inflammatory phenotype characterized by impaired phagocytic capacity and sustained cytokine production [9,18]. This maladaptive immune response establishes a self-perpetuating cycle in which neuroinflammation accelerates Aβ deposition, while increasing Aβ burden further amplifies inflammatory signaling [56]. Genetic studies identifying risk variants in immune-related genes such as TREM2, CD33, and CR1 further support the central role of immune dysfunction in Aβ-driven AD pathogenesis [15].

4.2 Tau-Mediated Neuroinflammation

While Aβ pathology is often considered the initiating event in AD, neurofibrillary pathology composed of hyperphosphorylated tau correlates more closely with neuronal dysfunction and cognitive decline. Tau is a microtubule-associated protein that normally stabilizes neuronal cytoskeletal architecture. Under pathological conditions, abnormal phosphorylation, truncation, and aggregation promote the formation of intracellular neurofibrillary tangles (NFTs) [58,59]. Emerging evidence indicates that pathological tau actively participates in neuroinflammatory processes rather than serving solely as a downstream consequence of disease progression. Extracellular tau released from damaged neurons can be recognized by microglial PRRs, including TLR2 and TLR4, stimulating inflammatory signaling pathways and cytokine secretion. Activated microglia subsequently release inflammatory mediators that enhance tau kinase activity, including glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5), thereby promoting further tau hyperphosphorylation [59,60].

Tau pathology also exhibits prion-like propagation between anatomically connected brain regions [61]. Microglia appear to facilitate this process through uptake and release of tau-containing extracellular vesicles, contributing to the spread of pathology throughout neural networks [62]. Experimental studies demonstrate that suppression of microglial activation reduces tau propagation and mitigates neurodegeneration, highlighting a bidirectional relationship between tau pathology and innate immune activation [38].

4.3 Cytokine and Chemokine Networks

Table 4. Major Cytokines Involved in Neuroinflammation in Alzheimer's Disease[63-66]

4.4 NLRP3 Inflammasome Activation

The NLRP3 inflammasome is a multiprotein complex consisting of NLRP3, ASC, and pro-caspase-1. Assembly of this complex results in activation of caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their biologically active forms [67,28].

Activation of the NLRP3 inflammasome generally requires two signals. The priming signal is mediated through NF-κB activation following stimulation of TLRs or cytokine receptors, resulting in increased expression of NLRP3 and pro-inflammatory cytokines. A second activation signal is subsequently triggered by cellular stressors such as mitochondrial dysfunction, lysosomal rupture, potassium efflux, ROS generation, and aggregated Aβ [67,28].

Aβ fibrils promote NLRP3 activation following microglial phagocytosis and lysosomal destabilization. Activated inflammasomes increase IL-1β and IL-18 secretion, amplify neuroinflammation, and impair Aβ clearance mechanisms [67,68]. Studies in transgenic AD mouse models demonstrate that genetic deletion of NLRP3 or caspase-1 reduces amyloid burden, attenuates neuroinflammation, and improves cognitive performance [37].

Recent evidence further suggests that NLRP3 activation contributes to tau hyperphosphorylation and aggregation, thereby linking the two major pathological hallmarks of AD [,68]. Given its central role in neuroinflammatory amplification, NLRP3 has emerged as an attractive therapeutic target. Several experimental inhibitors have demonstrated efficacy in reducing neuroinflammation and improving cognitive outcomes in preclinical models [67,68].

4.6 Toll-Like Receptor Signaling

Toll-like receptors represent a major family of PRRs involved in recognition of pathogen-associated molecular patterns and damage-associated molecular patterns. In AD, endogenous danger signals such as Aβ and tau activate multiple TLR pathways [9]. TLR2 expression is increased in microglia surrounding amyloid plaques. Binding of aggregated Aβ to TLR2 initiates MyD88-dependent signaling, promoting production of inflammatory cytokines and chemokines. TLR4 similarly recognizes Aβ aggregates and contributes to activation of innate immune responses. Although TLR4-mediated signaling may facilitate Aβ clearance during early disease stages, chronic activation promotes neurotoxicity through excessive cytokine production and oxidative stress. Both TLR2 and TLR4 converge upon NF-κB signaling pathways, resulting in transcriptional upregulation of inflammatory genes including TNF-α, IL-1β, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) [9,33,31].

4.7 Oxidative Stress and Neuroinflammation

Oxidative stress is both a consequence and a driver of neuroinflammatory responses in AD. Activated microglia and astrocytes generate substantial amounts of ROS through NADPH oxidase activity, mitochondrial dysfunction, and inflammatory signaling pathways. Mitochondrial impairment is particularly important because neurons possess high energetic demands and limited antioxidant capacity. Aβ and tau pathology disrupt mitochondrial respiration, increase electron leakage, and enhance ROS generation. Excessive ROS damage proteins, lipids, and nucleic acids, leading to progressive cellular dysfunction and neuronal death.

Importantly, oxidative stress amplifies inflammatory signaling by activating NF-κB and NLRP3 inflammasome pathways. In turn, inflammatory cytokines further increase ROS production, establishing a vicious cycle that accelerates neurodegeneration[67,69].

4.8 Blood-Brain Barrier Dysfunction

The blood-brain barrier (BBB) is a specialized interface that maintains CNS homeostasis through selective regulation of molecular and cellular trafficking. Increasing evidence indicates that BBB dysfunction occurs early in AD and contributes directly to neuroinflammation. Aβ accumulation, oxidative stress, and chronic inflammation induce endothelial damage, leading to disruption of tight junction proteins such as claudin-5, occludin, and zonula occludens-1. Loss of BBB integrity permits leakage of plasma proteins and neurotoxic molecules into the brain parenchyma. Compromised BBB function also facilitates immune cell infiltration, including monocytes, macrophages, and lymphocytes. These infiltrating cells release cytokines, chemokines, and ROS that further exacerbate local inflammatory responses.

At a broader level, AD is increasingly viewed as a disorder of the neurovascular unit, which comprises endothelial cells, pericytes, astrocytes, microglia, neurons, and extracellular matrix components [70,71]. Dysfunction of this integrated system impairs cerebral blood flow, reduces Aβ clearance, and promotes chronic inflammation.

5. Genetic Regulators of Neuroinflammation in Alzheimer's Disease

Table 5. Neuroinflammation-related genetic risk factors in Alzheimer’s disease.[72-76]

6. Neuroinflammation and Disease Progression

Neuroinflammation is now recognized as a central contributor to Alzheimer's disease (AD) progression, linking amyloid-β (Aβ) accumulation and tau pathology to synaptic dysfunction, neuronal loss, and cognitive decline. While innate immune responses may initially serve protective functions by facilitating the clearance of misfolded proteins, persistent activation of microglia and astrocytes promotes chronic inflammatory signaling that exacerbates neurodegeneration [9,34].

6.1 Synaptic Dysfunction

Synaptic impairment represents one of the earliest pathological events in AD and correlates more closely with cognitive decline than amyloid plaque burden alone. Activated microglia contribute to aberrant complement-mediated synaptic pruning, resulting in excessive elimination of functional synapses. Concurrently, inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) disrupt synaptic plasticity, impair long-term potentiation, and alter neurotransmitter homeostasis. Chronic neuroinflammation further enhances the synaptotoxic effects of Aβ oligomers and pathological tau species, thereby accelerating neuronal network dysfunction [9,10].

6.2 Neuronal Death

Persistent inflammatory activation contributes substantially to neuronal injury and death in AD. Activated glial cells generate reactive oxygen species, nitric oxide, and pro-inflammatory mediators that induce oxidative stress, mitochondrial dysfunction, and cellular damage. In addition, activation of inflammatory pathways such as the NLRP3 inflammasome promotes the release of IL-1β and IL-18, amplifying local immune responses and facilitating neurodegenerative processes. Neuroinflammation also promotes tau hyperphosphorylation and aggregation, creating a pathological feedback loop in which neuronal injury further stimulates inflammatory activation [9,33].

6.3 Cognitive Impairment

The combined effects of synaptic dysfunction and neuronal loss ultimately manifest as progressive cognitive impairment. Neuroinflammatory mediators disrupt communication within hippocampal and cortical networks responsible for memory, learning, and executive function. Clinical and experimental studies have demonstrated associations between increased microglial activation, elevated inflammatory biomarkers, and accelerated cognitive decline. Consequently, neuroinflammation is increasingly viewed not merely as a secondary response to pathology but as an active participant in the progression of cognitive deficits in AD [9,10].

6.4 Neuroinflammation Across Disease Stages

Neuroinflammatory responses evolve throughout the course of AD. During preclinical AD, microglia may initially exert protective effects by clearing Aβ deposits and maintaining tissue homeostasis. However, sustained exposure to accumulating pathological proteins gradually shifts microglia toward a pro-inflammatory phenotype. In mild cognitive impairment (MCI), increasing activation of microglia and astrocytes is associated with early synaptic dysfunction, propagation of tau pathology, and the emergence of measurable cognitive deficits. Inflammatory alterations at this stage are thought to contribute significantly to disease transition and progression [10,34].

In advanced AD, chronic neuroinflammation becomes widespread and self-perpetuating. Extensive gliosis, persistent cytokine production, complement activation, and inflammasome signaling amplify neurodegeneration and cognitive deterioration. These processes establish a vicious cycle in which inflammation promotes protein aggregation and neuronal damage, while accumulating pathology further sustains inflammatory responses [9].

7. Therapeutic Opportunities Targeting Neuroinflammation

Table 6. Current and emerging anti-inflammatory therapies in Alzheimer’s disease[77-96]