Unraveling the molecular links: Alzheimer's disease-induced mechanisms of memory impairment: A narrative review

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive memory impairment and cognitive decline, significantly impacting the quality of life for millions worldwide. Understanding the intricate molecular pathways linking AD pathology to memory dysfunction is crucial for developing effective therapies. This narrative review aims to elucidate the key molecular mechanisms underlying memory impairment in AD. We conducted a comprehensive literature search across major scientific databases (e.g., PubMed, Scopus, Web of Science) focusing on peer-reviewed studies (original research, reviews) exploring the molecular links between AD pathology and memory deficits. The review identifies and details several interconnected molecular pathways driving memory impairment in AD: (1) Synaptic dysfunction and neuronal loss triggered by amyloid-β (Aβ) peptide accumulation and aggregation; (2) Intracellular transport disruption and neurodegeneration caused by tau protein hyperphosphorylation and aggregation; (3) Exacerbation of cognitive deficits by neuroinflammation, mediated through activated microglia and pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6); (4) Impairment of synaptic plasticity and cognitive function due to dysregulation of neurotrophic factors, particularly brain-derived neurotrophic factor; (5) Contributory roles of oxidative stress, mitochondrial dysfunction, disrupted neurotransmission (e.g., acetylcholine, GABA), and apoptotic pathways. This review comprehensively unravels the critical molecular links between AD pathology and memory impairment, emphasizing the interplay of Aβ, tau, neuroinflammation, neurotrophic factor dysregulation, and other mechanisms. Targeting these interconnected pathways represents a promising strategic approach for developing therapies to mitigate cognitive decline and improve outcomes in AD patients.

Graphical abstract

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Keywords

Alzheimer's disease amyloid-beta BDNF memory impairment molecular mechanisms neurodegeneration neuroinflammation oxidative stress synaptic dysfunction tau protein

Introduction

Alzheimer's disease (AD) is the leading cause of dementia, profoundly affecting cognitive function and quality of life for millions worldwide.¹ Characterized primarily by memory impairment, AD presents a complex interplay of environmental factors that contribute to its pathogenesis.² The hallmark pathological features of AD include the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein.³ These abnormalities lead to synaptic dysfunction and neuronal loss, particularly in brain regions essential for memory processing, such as the hippocampus and the medial temporal lobe.⁴ As these pathological changes progress, they disrupt the intricate neural networks responsible for memory formation and retrieval, leading to the characteristic memory impairments observed in patients.⁵ Recent research has illuminated the multifactorial nature of memory impairment in AD.⁶ While the toxic effects of Aβ and tau pathology are well-documented, emerging studies indicate that neuroinflammatory processes and oxidative stress also play crucial roles in exacerbating cognitive decline.⁷

Furthermore, the understanding of how AD-induced memory impairment relates to other neurodegenerative diseases is a burgeoning area of research. Conditions such as Parkinson's disease, Lewy body dementia, and frontotemporal dementia share overlapping features, including memory deficits, albeit with distinct pathophysiological mechanisms.⁸ Exploring the commonalities and differences in memory impairment across these disorders offers a broader perspective on the neurobiological underpinnings of cognitive decline and may inform more comprehensive treatment approaches. By integrating findings from various studies, this review seeks to provide a comprehensive understanding of how several mechanisms interact to produce memory deficits in AD and their implications for other neurodegenerative conditions.

Rationale for selection of specific pathophysiological mechanisms

The selection of Aβ accumulation, tau protein hyperphosphorylation, neuroinflammation, and neurotrophic factor dysregulation (specifically brain derived neurotrophic factor (BDNF)) as the focal mechanisms in this review, out of the myriad potential contributors to AD-related memory impairment, was driven by a confluence of factors emphasizing their established centrality, interconnectedness, and therapeutic relevance. These pathways represent the most robustly validated and intensely researched core pathological hallmarks of AD, forming the foundation of the prevailing “amyloid cascade” and “tau propagation” hypotheses, which are strongly supported by extensive genetic, neuropathological, biochemical, and biomarker evidence linking them directly to synaptic dysfunction, neuronal loss, and the clinical manifestation of cognitive decline, including memory deficits. Prioritizing Aβ and tau pathology is justified by their status as defining neuropathological lesions of AD (as per diagnostic criteria) and their initiation of downstream events.^9,10 Neuroinflammation was included as a critical amplifier mechanism, consistently documented in AD brains through activated microglia, astrogliosis, and elevated pro-inflammatory cytokines, known to exacerbate Aβ and tau toxicity, impair synaptic plasticity, and directly damage neurons, thereby significantly contributing to progressive memory impairment.¹¹ The focus on neurotrophic factors, particularly BDNF, stems from its vital, well-documented role in maintaining synaptic plasticity, neuronal survival, and learning and memory processes; its significant downregulation in AD brains and serum/cerebrospinal fluid (CSF) correlates strongly with cognitive impairment severity and represents a crucial convergence point where upstream pathologies (Aβ, tau, inflammation) disrupt essential maintenance and repair mechanisms.^12,13 While acknowledging the potential contributions of other mechanisms like oxidative stress, mitochondrial dysfunction, or specific neurotransmitter deficits, the chosen quartet provides a comprehensive yet focused framework that captures the primary, interdependent drivers of AD pathogenesis.^14–16 This targeted approach allows for a deeper, more cohesive exploration of how these specific, dominant pathways interact to disrupt the neural substrates of memory, aligning with the primary goal of elucidating the principal molecular links underlying memory loss in AD and reflecting the current dominant focus of both mechanistic research and therapeutic development aimed at modifying core AD pathology and preserving cognitive function.

AD and memory disorders

AD is primarily defined by its progressive cognitive decline, with memory disorders being among the earliest and most debilitating symptoms.¹⁷ As a neurodegenerative condition, AD is characterized by a gradual deterioration of mental functions, which significantly impacts the ability to remember, learn, and process information.¹⁸ As neuronal death and synaptic loss occur, the capacity for memory encoding and retrieval diminishes, leading to significant deficits in both short-term and long-term memory.⁵ In the early stages of AD, individuals may experience mild cognitive impairment (MCI), where memory lapses and difficulties in retaining new information become noticeable.¹⁹ This stage often presents a window for early intervention, as patients may still retain a degree of independence.¹⁹ However, as the disease progresses, the memory deficits become more pronounced and pervasive. Memory disorders in AD primarily affect episodic memory, which involves the recall of personal experiences and specific events.²⁰ Patients often struggle to remember recent conversations, appointments, or the names of familiar individuals. This loss of episodic memory not only impacts daily functioning but also significantly affects the individual's sense of identity and continuity of self.²¹

The mechanisms underlying memory impairment in several diseases and AD are complex and multifactorial. Neuroinflammation, oxidative stress, and synaptic dysfunction play critical roles in the progression of memory disorders.^22–24 Neuroinflammation, for instance, is a prominent feature of AD and can contribute to synaptic loss and neuronal death.²² Studies have shown that pro-inflammatory cytokines can interfere with neurotransmitter systems, further exacerbating memory deficits.²⁵ Additionally, the dysregulation of synaptic plasticity, particularly long-term potentiation (LTP), has been implicated in the impaired ability to form new memories.²⁶ LTP is a process that strengthens synapses and is crucial for learning, and its disruption due to Aβ toxicity highlights the direct relationship between AD pathology and memory impairment.²⁷ Furthermore, the role of tau protein in neurodegeneration cannot be overlooked. The hyperphosphorylation of tau leads to the formation of NFTs, which correlate strongly with cognitive decline.²⁸

Animal studies

Animal studies have emerged as a vital tool in AD research, providing insights into the pathophysiological changes associated with the disease and their impact on memory function.²⁹ In these studies, various animal models, such as transgenic mice, have been developed to mimic the hallmark features of AD, including Aβ plaque accumulation, NFTs, and neuroinflammation.^30,31 Memory impairment in AD is often examined through behavioral assessments that evaluate learning and memory capabilities, such as the Morris water maze and the novel object recognition test.^24,32 These assessments reveal that animals with AD-like pathology exhibit significant deficits in both spatial and non-spatial memory tasks and also in both short-term and long-term memory.^31,33,34 The observed impairments are often linked to disruptions in synaptic plasticity, which is essential for memory formation and retrieval.³⁵ Studies have shown that the changes in neurotransmitter systems, particularly those involving acetylcholine (ACh) and glutamate, significantly contribute to the observed cognitive deficits.³⁶ The presence of Aβ oligomers disrupts synaptic transmission and impairs LTP memory.³⁷ Additionally, neuroinflammatory responses triggered by the accumulation of amyloid plaques can further exacerbate cognitive deficits by promoting an environment detrimental to neuronal health.³⁸ The activation of glial cells and the release of pro-inflammatory cytokines can alter neuronal function and synaptic integrity, further impeding memory processes.³⁹ As researchers continue to explore these intricate relationships, animal models provide a critical platform for testing potential treatments aimed at ameliorating memory deficits and restoring cognitive function.⁴⁰ Furthermore, changes in the levels of neurotrophic factors, such as BDNF, have been observed in animal models of AD, indicating a potential link between neurotrophic signaling and memory impairment.⁴¹

Clinical studies

The hallmark symptoms of AD include memory loss, particularly in the domains of episodic and working memory, which severely impacts daily functioning and quality of life.¹⁹ Understanding the effects of AD on memory impairment through clinical studies is essential for developing effective diagnostic tools and therapeutic interventions. Clinical research has consistently demonstrated that memory impairment in AD is not merely a consequence of aging but is intricately linked to specific pathological changes in the brain.⁴² Clinically, the assessment of memory disorders in AD patients often involves a combination of neuropsychological testing and imaging techniques.⁴³ Neuroimaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), have provided valuable insights into the structural and functional changes occurring in the brains of individuals with AD, revealing patterns of atrophy in regions critical for memory processing, such as the hippocampus and entorhinal cortex.^44–47 These findings correlate with the severity of memory impairment, illustrating a clear link between the biological underpinnings of the disease and its cognitive manifestations.⁴⁸ Moreover, clinical studies have highlighted the heterogeneity of memory impairment in AD, with variations in the onset and progression of symptoms among individuals.⁴⁹ While some patients may experience early and pronounced deficits in episodic memory, others may retain certain cognitive functions for longer periods.⁵⁰ This variability underscores the importance of early diagnosis and personalized treatment approaches, as interventions may need to be tailored to the specific cognitive profiles of patients. Additionally, clinical trials investigating pharmacological and non-pharmacological interventions have provided insights into potential strategies for mitigating memory impairment in AD. These studies have explored the efficacy of cholinesterase inhibitors, amyloid-targeting therapies, and cognitive training programs, revealing varying degrees of success in improving or stabilizing cognitive function in patients.^51,52

In this regard, numerous clinical studies have been conducted to examine how AD influences different types of memory, ranging from short-term recall to long-term memory formation.^53,54 One of the foundational studies in this area utilized standardized neuropsychological assessments to evaluate the memory capabilities of patients diagnosed with AD.⁵⁵ These assessments often include tests like the Mini-Mental State Examination (MMSE) and the Wechsler Memory Scale (WMS), which measure various aspects of cognitive function, including immediate and delayed memory recall.^56,57 Findings consistently indicate that patients with AD exhibit significant deficits in both verbal and visual memory tasks when compared to age-matched control groups.⁵⁸ These deficits often become more pronounced as the disease progresses, reflecting the gradual erosion of cognitive abilities.⁵⁸

In addition to cross-sectional studies, longitudinal research has provided valuable insights into the trajectory of memory impairment in AD patients.⁵⁹ For instance, studies have shown that memory decline can be observed even in the early stages of the disease, sometimes before a formal diagnosis of AD is made.⁶⁰ This early decline is often characterized by subtle difficulties in recalling recent events or learning new information, which may be overlooked in routine assessments.⁶¹ Such findings underscore the importance of early detection and intervention, emphasizing that memory impairment is not merely a late-stage symptom but rather an integral feature of the disease from its onset.

Moreover, some studies have explored the differential impact of AD on various types of memory, such as episodic, procedural, and semantic memory.⁶² Research has shown that individuals may struggle to remember recent events or the context in which they occurred, while their procedural memory, related to skills and tasks they have learned, may remain relatively intact until later stages of the disease.⁶³ Understanding these differences can help tailor interventions and support strategies for those living with AD.

Specific and temporal role of Aβ

Aβ accumulation represents an early pathogenic event. Soluble Aβ oligomers, emerging long before frank plaque deposition, exert acute toxicity by binding to synaptic receptors (e.g., NMDA-R, PrPC).⁶⁴ This interaction specifically disrupts LTP, the synaptic basis of memory formation, by impairing glutamate receptor trafficking and calcium (Ca2+) homeostasis.⁶⁵ Temporally, this synaptic dysfunction precedes significant neuronal loss and correlates with early cognitive deficits observed in MCI.⁶⁶ As Aβ aggregates progress to insoluble plaques, they further trigger chronic microglial activation and astrocyte reactivity, establishing a pro-inflammatory milieu that specifically damages surrounding synapses and neurons over time, exacerbating memory decline.^27,67

Specific and temporal role of tau pathology

While Aβ initiates the cascade, hyperphosphorylated tau follows a distinct spatiotemporal progression. In the early stages, soluble hyperphosphorylated tau species (not yet aggregated into NFTs) specifically impair mitochondrial function and axonal transport within neurons, disrupting synaptic vesicle recycling and neurotransmitter release, which are crucial for memory encoding.⁶⁸ Later in the disease course, tau aggregation into NFTs directly causes neuronal death, particularly in memory-critical regions like the hippocampus and entorhinal cortex.⁶⁹ Crucially, misfolded tau exhibits prion-like propagation along neural networks, specifically facilitating the spread of pathology from limbic areas to the neocortex, which temporally correlates with the progression from MCI to full dementia and the worsening of global amnesia.⁷⁰ Furthermore, hyperphosphorylated tau specifically downregulates the expression of critical neurotrophic factors like BDNF, thereby independently impairing synaptic plasticity and resilience.⁷¹ This integrated view highlights how Aβ primarily initiates synaptic dysfunction early, while tau pathology propagates neuronal dysfunction and loss later, both converging on pathways essential for memory.

Aβ seeds tau pathology in AD

Aβ and hyperphosphorylated tau operate through distinct temporal mechanisms to drive AD progression. In the earliest preclinical stages, soluble Aβ oligomers initiate synaptic dysfunction by binding to NMDA receptors, disrupting calcium homeostasis, and impairing LTP.⁷² This Aβ-mediated disruption concurrently triggers microglial activation via TLR4/NF-κB signaling, leading to sustained release of neurotoxic cytokines such as TNF-α and IL-6 that exacerbate neuronal stress.⁷³ As the disease transitions to MCI, these accumulating Aβ aggregates directly activate kinases such as glycogen synthase kinase-3β (GSK-3β), which phosphorylates tau at specific residues (Ser202/Thr205), initiating its dissociation from microtubules and subsequent misfolding.⁷⁴ This hyperphosphorylated tau then propagates trans-synaptically, disrupting mitochondrial trafficking and elevating oxidative stress markers such as malondialdehyde in affected neurons.⁷⁵ By the clinical dementia stage, Aβ plaques and NFTs jointly amplify neurodegeneration through synergistic pathways: Aβ sustains neuroinflammation that accelerates tau spread, while phosphorylated tau sequesters synaptic proteins such as PSD-95 and suppresses BDNF transcription, crippling synaptic resilience.⁷⁶ Critically, Aβ also cleaves TrkB receptors, further disabling neurotrophic support essential for memory consolidation.⁷⁷ This cascade culminates in a self-reinforcing cycle where microglial reactive oxygen species (ROS), activated by Aβ, directly oxidize tau, promoting its aggregation and neuronal toxicity.⁷⁸

Mechanism of memory impairment in AD

Aβ peptide accumulation and aggregation

Among the various pathological features associated with AD, the accumulation and aggregation of Aβ peptide in the brain tissues stand out as one of the most critical hallmarks of the disease.⁷⁹ The Aβ peptide, derived from the cleavage of amyloid-β protein precursor (AβPP), plays a central role in the development and progression of AD pathology.⁸⁰ Understanding how Aβ accumulation and aggregation contribute to neurodegeneration is essential for unraveling the complexities of AD and developing effective therapeutic strategies. In healthy individuals, Aβ is produced and cleared in a balanced manner; however, in AD, this equilibrium is disrupted, leading to an excess of the peptide.⁸¹ This excess can result from increased production, reduced clearance, or a combination of both factors.⁸¹ The accumulation of Aβ peptides is observed predominantly in the form of soluble oligomers and insoluble fibrils, which aggregate to form amyloid plaques.⁸² These plaques are typically found in the extracellular space of the brain, particularly in regions associated with memory and cognition, such as the hippocampus and cortex.⁸³ The aggregation of Aβ is particularly concerning due to its neurotoxic properties.⁸⁴ Soluble oligomers of Aβ have been shown to interfere with synaptic function, disrupt neurotransmitter release, and impair synaptic plasticity, ultimately leading to neuronal dysfunction and cell death.⁸⁵ Moreover, the presence of amyloid plaques triggers a cascade of neuroinflammatory responses, involving the activation of glial cells and the release of pro-inflammatory cytokines.⁸⁶ This neuroinflammatory environment further exacerbates neuronal damage and contributes to the cognitive decline observed in individuals with AD.³⁸

Clinical and preclinical studies have provided substantial evidence linking Aβ accumulation to the clinical manifestations of AD.⁸⁷ Furthermore, genetic studies have identified several risk factors for AD, including mutations in genes related to Aβ production and clearance, reinforcing the importance of this peptide in the disease's pathophysiology.⁸⁸ Understanding how Aβ accumulation leads to neuronal dysfunction involves exploring several interconnected molecular pathways. Initially, Aβ is produced from the cleavage of AβPP by enzymes known as secretases.^89,90 In a healthy brain, this process is tightly regulated, and Aβ is efficiently cleared. However, in AD, various factors disrupt this balance. Genetic predispositions, such as mutations in the APP or presenilin genes, can lead to increased production of Aβ.^91,92 Additionally, age-related changes in cellular mechanisms may impede the clearance of Aβ, leading to its accumulation.⁹¹

As Aβ levels rise, they begin to aggregate into soluble oligomers and, eventually, insoluble fibrils. These aggregates are particularly toxic to neurons.⁸² Soluble Aβ oligomers can interfere with synaptic signaling by disrupting the function of neurotransmitter receptors, such as NMDA receptors.⁹³ This disruption hinders synaptic plasticity, a critical mechanism for learning and memory.⁹⁴ When synapses fail to function properly, the ability to form and retrieve memories is significantly impaired.⁹⁴ In addition to synaptic disturbances, Aβ accumulation also affects intracellular pathways. The aggregation of Aβ can lead to the formation of NFTs and neuronal cell death.^95,96 Furthermore, the Aβ-induced dysregulation of calcium homeostasis in neurons plays a significant role in memory impairment.⁹⁷ Elevated levels of Aβ can cause calcium influx through various channels, leading to excitotoxicity and apoptosis. This disruption in calcium signaling has direct implications for synaptic function and memory processes.^98,99 The models, such as the APP/PS1 and 5xFAD mice, develop Aβ plaques and exhibit cognitive deficits that parallel human symptoms.^100,101 Studies utilizing these models have consistently demonstrated that increased Aβ accumulation correlates with deteriorating performance in memory tasks, such as the Morris Water Maze and Novel Object Recognition tests.^32,102 For instance, in a study by Dodart et al., APP transgenic mice showed significant memory impairments that were directly linked to the presence of soluble Aβ oligomers, highlighting the detrimental effects of Aβ accumulation on synaptic integrity and cognitive function.¹⁰³

Human studies have also provided compelling evidence of the relationship between Aβ and memory impairment. Postmortem analyses of brain tissues from individuals diagnosed with AD reveal extensive Aβ plaque deposition, particularly in the hippocampus and cortex.¹⁰⁴ Research by Selkoe emphasized that the density of amyloid plaques in these areas correlates with the severity of cognitive decline, suggesting that the spatial distribution of Aβ aggregates plays a crucial role in memory impairment.¹⁰⁴ Research has shown that soluble Aβ oligomers disrupt synaptic function by interfering with neurotransmitter receptor signaling, particularly NMDA receptors. For example, a study by Shankar et al. highlighted how oligomeric Aβ could inhibit LTP.¹⁰⁵ This disruption in synaptic plasticity has been implicated in the early stages of cognitive decline associated with AD. Research by Heneka et al. demonstrated that the inflammatory response triggered by Aβ plaques exacerbates synaptic dysfunction and promotes the progression of neurodegeneration.¹⁰⁶

Tau protein hyperphosphorylation and aggregation

Among AD's various pathological features, the hyperphosphorylation and aggregation of tau protein have emerged as critical components in the disease's progression. Tau, a microtubule-associated protein, plays a vital role in maintaining the stability of neuronal microtubules, essential for intracellular transport and overall neuronal health.¹⁰⁷ In a healthy brain, tau is predominantly in a dephosphorylated state, allowing for effective microtubule assembly and function. However, in AD, tau undergoes abnormal hyperphosphorylation, resulting in the formation of NFTs, which are a hallmark of AD pathology.^108,109 The process of tau hyperphosphorylation is influenced by various kinases and phosphatases, which regulate its phosphorylation state.²⁸ In AD, the dysregulation of these enzymes leads to an increased phosphorylation of tau, disrupting its normal function.¹¹⁰ This hyperphosphorylated tau tends to aggregate, forming paired helical filaments that contribute to the formation of NFTs within neurons. These tangles disrupt the microtubule network, impairing axonal transport and ultimately leading to neuronal dysfunction and cell death.^111,112

Research has shown that tau pathology is closely linked to the severity of cognitive impairment in AD. Studies indicate that the extent of tau tangles in specific brain regions, particularly the entorhinal cortex and hippocampus, correlates with the degree of memory loss and cognitive decline.¹¹³ NFTs are often found in the brains of individuals with AD even in the early stages of the disease, suggesting that tau aggregation may precede significant Aβ deposition and serve as a better predictor of cognitive decline.¹¹⁴ Furthermore, the interaction between tau protein and Aβ has garnered significant interest in understanding AD pathology. While Aβ plaques are considered an early feature of the disease, emerging evidence suggests that tau hyperphosphorylation may be the primary driver of neurodegeneration.¹¹⁵ The presence of Aβ can exacerbate tau pathology by promoting its hyperphosphorylation and facilitating its aggregation, thereby contributing to a cycle of neurotoxicity.^95,116

Studies have shown that the process of tau hyperphosphorylation in AD is influenced by several molecular pathways. One significant factor is the dysregulation of kinases and phosphatases, the enzymes responsible for adding and removing phosphate groups from tau, respectively.¹¹⁷ In AD, certain kinases, such as GSK-3β and cyclin-dependent kinase 5 (CDK5), become overactive, leading to excessive phosphorylation of tau.¹¹⁸ As tau aggregates accumulate, they can also trigger neuroinflammatory responses, further exacerbating neuronal damage. Activated microglia and astrocytes release pro-inflammatory cytokines, which can lead to additional neuronal stress and death.¹¹⁹ The disruption of synaptic function due to tau pathology impairs LTP, a process that strengthens synapses and is crucial for learning and memory.^120,121 Researchers have consistently found that the density of NFTs, which are composed of hyperphosphorylated tau, correlates strongly with the degree of cognitive impairment observed in patients.¹²² For instance, a seminal study by Braak established a staging system for tau pathology, demonstrating that the progression of NFTs follows a predictable pattern that aligns with the clinical severity of dementia.¹²³ Their findings indicated that tangles first appear in the entorhinal cortex and hippocampus before spreading to other areas of the brain.¹²⁴

In addition to postmortem analyses, neuroimaging studies have provided further evidence of the impact of tau hyperphosphorylation on memory function.¹²⁵ For example, studies using tau-specific PET tracers have shown that higher levels of tau accumulation in the brain are associated with greater memory deficits, even in individuals with MCI, a precursor to AD.^126,127 Studies have shown that mice with tau pathology exhibit deficits in LTP.¹²⁸ Moreover, Studies investigating tau-targeting therapies, such as tau aggregation inhibitors and immunotherapies, have shown promise in reducing tau levels and improving cognitive outcomes in preclinical models.¹²⁹

Elaborating on the specific and temporal roles of Aβ and tau pathology in AD mechanisms

This section elaborates on the distinct and temporal roles of Aβ and tau pathologies in the mechanisms underlying memory impairment in AD. Aβ accumulation, which manifests early in the disease course, serves as a primary instigator of synaptic toxicity.¹³⁰ Specifically, soluble Aβ oligomers bind with high affinity to postsynaptic sites, disrupting glutamate receptor trafficking (particularly NMDAR and AMPAR) and inducing LTP deficits within hours to days of exposure. This acute synaptic dysfunction precedes overt neuronal loss and is a direct contributor to early cognitive deficits observed in preclinical AD models and potentially in humans.¹³¹ Concurrently, Aβ deposition in the extracellular space initiates a cascade of neuroinflammatory responses. Microglia, activated within days by fibrillar Aβ plaques via receptors like TREM2, release pro-inflammatory cytokines (e.g., IL-1β, TNF-α). This chronic neuroinflammation, sustained over months to years, not only fails to clear Aβ effectively but also directly damages surrounding neurons and synapses, amplifying cognitive decline.^11,132 Furthermore, Aβ oligomers induce oxidative stress within neurons within minutes to hours by promoting mitochondrial ROS production and impairing antioxidant defenses, leading to lipid peroxidation and protein oxidation that further compromise synaptic function.¹³³ Tau pathology, while potentially triggered by Aβ in its initiation, follows a distinct temporal and spatial pattern.⁹⁵ Intracellular hyperphosphorylation of tau (at sites like Ser202/Thr205 recognized by AT8 antibody) leads to its dissociation from microtubules, occurring over weeks to months.¹³⁴ This loss of microtubule stability directly impairs axonal transport of mitochondria and synaptic vesicles, depriving synapses of energy and neurotransmitters critical for plasticity.^135,136 Crucially, the misfolded tau propagates trans-synaptically in a prion-like manner along connected neuronal circuits, correlating temporally and topographically with the progression of clinical symptoms from medial temporal lobe structures (early memory loss) to neocortical regions (global cognitive decline).^137,138 The accumulation of NFTs, the endpoint of tau aggregation, is strongly associated with neuronal death occurring over years. This neuronal loss, particularly in the hippocampus and entorhinal cortex, directly underpins severe and irreversible memory impairment in later AD stages.^139,140 Tau pathology also exacerbates Aβ-induced neuroinflammation, as dying neurons releasing tau aggregates further activate microglia.¹⁴¹ Additionally, both Aβ and tau synergistically disrupt neurotrophic signaling; Aβ downregulates BDNF expression acutely, while tau pathology impairs the retrograde transport of TrkB receptors over time, collectively diminishing synaptic resilience and plasticity essential for memory consolidation.^132,142 Collectively, Aβ acts predominantly as an early instigator of synaptic dysfunction, oxidative stress, and neuroinflammation, while tau pathology drives progressive neuronal dysfunction, transport failure, and eventual cell death, with their interplay evolving throughout the AD continuum to orchestrate the multifaceted cognitive decline.

Oxidative stress

Another critical pathological feature of AD is the presence of oxidative stress, which plays a pivotal role in the neurodegenerative disease's progression and the associated.¹⁴³ Oxidative stress refers to an imbalance between the production of ROS and the brain's ability to detoxify these harmful compounds or repair the resulting damage.¹⁴⁴ In the context of AD, this imbalance is exacerbated by various factors, including the accumulation of Aβ plaques and NFTs.¹⁴⁵ Research has shown that oxidative stress is implicated in the pathology of several disorders and in multiple aspects of AD.^146–148 Elevated levels of ROS can lead to lipid peroxidation, protein oxidation, and DNA damage, all of which contribute to neuronal dysfunction and cell death.¹⁴⁶ The brain, being highly metabolically active and rich in lipids, is particularly vulnerable to oxidative damage.¹⁴⁹ Furthermore, the presence of Aβ peptides has been shown to enhance oxidative stress by promoting the generation of free radicals, thereby creating a vicious cycle that exacerbates neuronal injury.¹⁵⁰ This oxidative damage not only affects neuronal cells but also disrupts the function of glial cells, which play essential roles in maintaining homeostasis and supporting neuronal health.¹⁵¹ Moreover, oxidative stress has been linked to the dysregulation of various signaling pathways involved in neuroinflammation and apoptosis, further complicating the disease process.¹⁵² The interplay between oxidative stress and neuroinflammatory responses can lead to a detrimental environment that accelerates neurodegeneration.¹⁵³

By elucidating the mechanisms through which oxidative stress contributes to the pathophysiology of AD, researchers can pave the way for the development of novel therapeutic strategies aimed at reducing oxidative damage and preserving cognitive function in affected individuals. In the context of AD, it has been shown that AD has a profound impact on oxidative stress, which in turn contributes to memory impairment through a complex interplay of molecular pathways. Several factors contribute to increased oxidative stress, including the accumulation of Aβ plaques and tau hyperphosphorylation. These hallmark features of AD not only disrupt normal cellular functions but also trigger an overproduction of ROS, leading to cellular damage.¹⁵²

The presence of Aβ in the brain has been shown to promote the generation of ROS through various mechanisms, including the activation of microglia.¹⁵⁴ When microglia encounter Aβ, they become activated and release pro-inflammatory cytokines and ROS, creating a neuroinflammatory environment that exacerbates oxidative stress. overproduction of ROS directly affects various cellular components, including lipids, proteins, and DNA.¹⁵⁴ For instance, lipid peroxidation, caused by ROS, can lead to the formation of toxic byproducts that further damage cellular membranes and disrupt neuronal signaling pathways. This damage can compromise synaptic integrity and function, which are crucial for memory formation and retrieval.¹⁵⁴

Furthermore, at a molecular level, oxidative stress can impair the function of key proteins involved in synaptic plasticity, such as BDNF. BDNF is essential for the survival and growth of neurons and is heavily involved in learning and memory processes. Oxidative damage can inhibit BDNF signaling, leading to reduced synaptic plasticity and diminished capacity for memory formation.¹⁵⁵ Additionally, oxidative stress can disrupt the balance of calcium ions within neurons, which is vital for neurotransmitter release and synaptic signaling.¹⁵⁵ Dysregulation of calcium homeostasis can further impair cognitive functions, contributing to the memory deficits observed in AD.¹⁵⁵

Another critical aspect of oxidative stress in AD is its role in promoting tau hyperphosphorylation. Hyperphosphorylated tau disrupts cellular processes and impairs mitochondrial function. Mitochondria are critical for energy production and play a vital role in regulating oxidative stress. When mitochondrial function is compromised, it leads to increased ROS production and decreased ATP (adenosine triphosphate) levels, further exacerbating oxidative damage to neurons.¹⁵⁶ Elevated oxidative stress can activate various kinases, such as GSK-3β, which are responsible for adding phosphate groups to tau protein. This hyperphosphorylation leads to tau aggregation and contributes to cognitive decline.¹⁵⁷

Moreover, oxidative stress can disrupt signaling pathways involved in synaptic plasticity, the process by which synapses strengthen or weaken over time in response to activity. This disruption can impair LTP. When oxidative stress interferes with LTP, it hinders the brain's ability to form new memories and retrieve existing ones, leading to the characteristic memory deficits observed in AD patients.¹⁵⁸

In this regard, many studies have investigated the relationship between AD, oxidative stress markers in brain tissue, and memory impairment.^154,157 One of the foundational approaches in this area has been the examination of oxidative stress markers in postmortem brain tissue from individuals diagnosed with AD. Research has consistently shown elevated levels of oxidative stress markers, such as malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and protein carbonyls, in the brains of AD patients compared to age-matched controls.¹⁵⁹ For instance, a study by Sultana et al. demonstrated significantly increased levels of MDA, a byproduct of lipid peroxidation, in the hippocampus and frontal cortex of AD patients.¹⁶⁰ This finding correlates with the degree of cognitive impairment, suggesting that oxidative damage to lipids is a contributing factor to memory deficits in AD.¹⁴ In addition to lipid peroxidation markers, studies have also focused on the role of antioxidant defenses in AD. Research has shown that levels of key antioxidants, such as glutathione and superoxide dismutase (SOD), are often reduced in the brains of individuals with AD.¹⁶⁰ A study by Butterfield et al. found decreased glutathione levels in the brains of AD patients, which impairs the brain's ability to counteract oxidative stress.¹⁶⁰ This reduction in antioxidant capacity further exacerbates oxidative damage and contributes to neuronal dysfunction, ultimately impacting memory and cognitive function. A study by Oddo et al. demonstrated that APP transgenic mice exhibited increased oxidative stress markers, such as elevated levels of ROS and lipid peroxidation products, alongside significant memory deficits in behavioral tests.¹⁶⁰ Furthermore, clinical studies have explored the relationship between oxidative stress markers and cognitive performance in individuals with MCI and AD. Research has shown that higher levels of oxidative stress markers in the blood and CSF are associated with worse cognitive performance and increased risk of progression from MCI to AD.¹⁶¹ For instance, a study by Montine et al. found that elevated levels of oxidative stress markers in CSF were predictive of cognitive decline in individuals with MCI, highlighting the potential of these markers as early indicators of AD progression.¹⁶² Table 1 shows the oxidative status in different parts of the brain in some models of AD.

Table 1.

The oxidative status in different parts of the brain in some models of Alzheimer's disease.

Model	Tissue	Aβ	P tau	SOD	GPx	CAT	GSH	MDA	Crb	Species	Ref.
Scopolamine	Hippocampus	↑	↑	↓		↓	↓	↑		Rat	^163,164
STZ	Hippocampus						↓	↑		Rat	¹⁶⁵
	Cortex						↓	↑		Rat	¹⁶⁵
	Kidney			↓		↓		↑		Mouse	¹⁶⁶
	Hippocampus and cortex	↑			↓			↑	↑	Rat	¹⁶⁷
LPS	Brain	↑	↑							Rat	¹⁶⁸
Aβ	Brain			↑				↑		Rat	¹⁶⁹
	Hippocampus			↓			↓	↑		Rat	¹⁷⁰
	Hippocampus			↓	↓	↓	↓	↑	↑	Rat	¹⁷¹

Aβ: amyloid-β peptide; P tau: phosphorylated tau; SOD: superoxide dismutase; GPx: glutathione peroxidase; MDA: malondialdehyde; Crb: carbonylated proteins; CAT: catalase; GSH: reduced glutathione; ↓: decrease; ↑: increase.

Neuroinflammation

As the AD progresses, a complex interplay of pathological processes occurs within the brain, one of the most significant being neuroinflammation. Neuroinflammation refers to the inflammatory response within the central nervous system (CNS), primarily mediated by glial cells, including microglia and astrocytes.¹⁷² In the context of AD, neuroinflammation is not merely a byproduct of neuronal degeneration but rather plays a pivotal role in the disease's pathophysiology, contributing to both the progression of neurodegeneration and the associated cognitive decline.¹⁷³ Research has shown that the accumulation of Aβ plaques and NFTs triggers an inflammatory response in the brain. Microglia, the resident immune cells of the CNS, become activated in response to these pathological changes.¹⁷² Aβ peptides and hyperphosphorylated tau protein activate microglia, through their binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and CD14. This activation leads to the production of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), which in turn activate astrocytes, another type of glial cell, to produce pro-inflammatory mediators.^154,174,175 Additionally, hyperphosphorylated tau protein also activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which regulates the expression of pro-inflammatory genes.¹⁷⁴ The activation of microglia also leads to the production of ROS and nitric oxide (NO), which contribute to the oxidative stress and damage to neurons.¹⁷⁶ The inflammatory milieu can disrupt synaptic plasticity, impair neurotransmitter signaling, and promote neuronal apoptosis, all of which are critical for maintaining cognitive function.⁸⁶ The chronic activation of microglia leads to the release of pro-inflammatory cytokines, which in turn activate astrocytes to produce pro-inflammatory mediators.⁸⁶ This creates a self-perpetuating cycle of inflammation, which contributes to the progression of the disease.¹⁷⁷ Additionally, neuroinflammation also disrupts the blood-brain barrier, allowing the entry of peripheral immune cells and toxins into the brain, further exacerbating the inflammatory response.¹⁷⁸ Studies have shown that anti-inflammatory therapies, such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, can reduce the levels of pro-inflammatory cytokines and slow the progression of AD.¹⁷⁹ Additionally, immunotherapies, such as vaccines and antibodies, targeting Aβ peptides and tau protein, have also shown promise in reducing neuroinflammation and slowing disease progression.¹⁸⁰

The activation of microglia and astrocytes leads to the production of pro-inflammatory cytokines, which in turn activate the innate immune response. The innate immune response is mediated by the activation of various signaling pathways, including the NF-κB pathway. The activation of the innate immune response leads to the production of pro-inflammatory mediators and adhesion molecules, which contribute to the recruitment of immune cells to the site of inflammation.¹¹⁹ Furthermore, in this regard, many sherds of evidence have investigated the presence and levels of pro-inflammatory cytokines in the brains of individuals with AD. These inflammatory markers correlate with the severity of neurodegeneration and Aβ plaque deposition, suggesting that chronic inflammation may exacerbate the underlying pathology of the disease. For example, a study by Heneka et al. demonstrated that elevated levels of these cytokines were associated not only with greater amyloid burden but also with significant cognitive impairment in patients.¹¹

A study conducted by Streit et al. highlighted that microglial activation is often observed in proximity to amyloid plaques, indicating a localized inflammatory response.¹⁸¹ This activation is characterized by morphological changes and the release of neurotoxic substances, which can further damage neurons and synapses, leading to memory deficits.¹⁸¹ The correlation between microglial activation and cognitive decline has been reinforced by imaging studies that utilize PET to visualize neuroinflammation in living patients.¹⁸² Research by Edison et al. revealed that individuals with MCI exhibited increased microglial activation, which was associated with poorer cognitive performance.¹⁸³ A study by Sofroniew emphasized the dual role of astrocytes in AD, where they can either promote neuroprotection or contribute to neurotoxicity, depending on their activation state. This highlights the complexity of inflammation in the AD brain and its implications for memory function.¹⁸⁴ A notable study by Calsolaro and Edison found that anti-inflammatory treatments could mitigate synaptic loss and improve cognitive outcomes, suggesting that targeting neuroinflammation may offer therapeutic benefits.¹⁸⁵ Studies have demonstrated that higher levels of inflammatory cytokines correlate with deficits in episodic memory, which is often one of the first cognitive domains affected by AD. For example, a longitudinal study by Yaffe et al. tracked cognitive decline in older adults and found that elevated levels of inflammatory markers in the blood were associated with a faster rate of memory decline over time.¹⁸⁶ Table 2 shows the neuroinflammation status in different parts of the brain of different models of AD.

Table 2.

Neuroinflammation status in different parts of the brain of different models of Alzheimer's disease.

Model	Tissue	TNF-α	NF-kB	IL-6	IL-1β	IFN-γ	IL-10	Species	Ref.
Scopolamine	Hippocampus	↑		↑	↑	↑	↓	Rat	^163,164
STZ	Brain	↑		↑				Mouse
	Hippocampus	↑			↑			Rat	¹⁶⁵
	Cortex	↑			↑			Rat	¹⁶⁵
Aβ	Brain	↑			↑			Rat	¹⁶⁹
Aβ	Hippocampus	↑	↑		↑			Mouse	¹⁸⁷
LPS	Brain			↑			↓	Rat	¹⁶⁸
TMT	Hippocampus	↑		↑	↑			Rat	¹⁸⁸
Alcl3 + d-gal	Hippocampus	↑	↑	↑	↑			Rat	¹⁸⁹

STZ: streptozotocin; LPS: lipopolysaccharides; Aβ: amyloid-β peptide; TNF-α: tumor necrosis factor-alpha; NF-kB: nuclear factor k B; IL-6: interleukin-6; IL-1β: interleukin-1β; IL-10: interleukin-10; IFN-γ: Interferon gamma; ↓: decrease; ↑: increase.

Disruption of synaptic plasticity and neurotransmission

Many studies have demonstrated that central to the cognitive deficits observed in AD is the disruption of synaptic plasticity and neurotransmission, which are two fundamental processes that underpin learning and memory.¹⁹⁰ Synaptic plasticity refers to the ability of synapses—the connections between neurons—to strengthen or weaken in response to activity, while neurotransmission involves the release and reception of neurotransmitters that facilitate communication between neurons.¹⁹⁰ As described, the pathophysiology of AD is characterized by the accumulation of Aβ plaques and NFTs composed of hyperphosphorylated tau protein. These pathological features are believed to initiate a cascade of neurobiological changes that ultimately lead to synaptic dysfunction.¹⁹¹ Aβ oligomers, in particular, have been shown to interfere with synaptic signaling, impairing LTP and long-term depression (LTD), which are critical for the encoding and retrieval of memories.¹⁹² LTP is characterized by a sustained increase in synaptic strength following high-frequency stimulation, while LTD involves a decrease in synaptic efficacy in response to low-frequency stimulation.¹⁹³ The inhibition of N-methyl-D-aspartate (NMDA) receptors by Aβ oligomers disrupts calcium influx, a key event necessary for the activation of intracellular signaling pathways that promote synaptic strengthening.¹⁹³ Also, this inhibition leads to a reduction in the phosphorylation of key proteins involved in synaptic plasticity, such as calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase B (Akt). The downstream effects of this disruption include decreased expression of BDNF.^194,195

Moreover, the neuroinflammatory response associated with AD further exacerbates synaptic dysfunction. Activated microglia release pro-inflammatory cytokines that can alter the function of glutamate receptors, leading to excitotoxicity, a process where excessive glutamate signaling results in neuronal injury and death. This inflammatory milieu not only disrupts neurotransmission but also contributes to the overall neurodegenerative process, creating a vicious cycle that accelerates cognitive decline.¹⁹⁶ Activated microglia release ROS as part of their immune response. Elevated ROS levels can cause oxidative damage to cellular components, including lipids, proteins, and DNA. This oxidative stress can disrupt the integrity of synapses, impairing neurotransmitter release and receptor function. For example, oxidative stress can lead to the oxidation of proteins involved in neurotransmitter release, reducing the efficacy of synaptic transmission.¹⁹⁷ The presence of Aβ can activate stress-related pathways, such as the c-Jun N-terminal kinase (JNK) pathway, which can result in the phosphorylation of key proteins involved in synaptic plasticity. This phosphorylation cascade can ultimately lead to the downregulation of BDNF.¹⁹⁸

Similarly, hyperphosphorylated tau protein also plays a detrimental role in synaptic plasticity. The phosphorylation of tau disrupts its normal function in stabilizing microtubules, leading to their disintegration. This destabilization affects axonal transport, which is crucial for the delivery of neurotransmitters and essential cellular components to synapses. As tau pathology progresses, the resulting synaptic loss not only impairs neurotransmission but also diminishes the capacity for synaptic plasticity, further contributing to cognitive decline.³⁷

One of the earliest and most influential studies by Selkoe highlighted the role of Aβ in synaptic dysfunction.⁷² Research by Shankar et al. found that Aβ oligomers disrupt the function of NMDA receptors, which are essential for LTP.¹⁰⁵ This disruption is thought to be mediated by the loss of synaptic proteins, such as PSD-95, that anchor NMDA receptors to the postsynaptic membrane. The loss of these proteins diminishes the synaptic response to glutamate, the primary excitatory neurotransmitter in the brain, leading to impaired neurotransmission.¹⁰⁵

In addition to Aβ, hyperphosphorylated tau has been shown to play a critical role in synaptic dysfunction. A study by Ittner et al. demonstrated that tau pathology not only contributes to the formation of NFTs but also disrupts synaptic integrity. The researchers found that hyperphosphorylated tau interferes with the transport of essential synaptic proteins along axons, thereby impairing neurotransmitter release and synaptic communication. This effect on axonal transport can lead to synaptic loss, further exacerbating cognitive decline.¹⁹⁹ A notable study by Heneka et al. indicated that a chronic inflammatory environment not only contributes to neuronal toxicity but also disrupts the signaling pathways involved in synaptic plasticity, further impairing LTP and enhancing LTD.¹⁰⁶

Mitochondrial dysfunction and energy metabolism

While the hallmark features of AD, such as Aβ plaques and NFTs, have garnered considerable attention, emerging research has increasingly focused on the role of mitochondrial dysfunction and energy metabolism in the pathophysiology of AD. Mitochondria, often referred to as the powerhouses of the cell, are essential for producing adenosine triphosphate (ATP), the primary energy currency required for various cellular functions.¹⁵⁶ In the brain, where energy demands are particularly high due to the constant activity of neurons, efficient mitochondrial function is crucial for maintaining synaptic integrity, neurotransmission, and overall cognitive health.¹⁵⁶ Studies have shown that mitochondrial abnormalities in AD are characterized by impaired oxidative phosphorylation, increased production of ROS, and altered mitochondrial dynamics. These dysfunctions lead to a decrease in ATP production, which compromises the energy supply necessary for neuronal survival and function. Furthermore, the accumulation of ROS can result in oxidative stress, damaging cellular components such as lipids, proteins, and DNA, thereby exacerbating neuronal injury and contributing to the progression of cognitive decline.²⁰⁰ In addition to direct mitochondrial dysfunction, alterations in energy metabolism pathways have been observed in the brains of individuals with AD. For instance, impaired glucose metabolism has been documented, with studies indicating that reduced glucose uptake and utilization in the brain correlate with the severity of cognitive impairment. This metabolic dysregulation not only affects ATP production but also disrupts the balance of neurotransmitter synthesis and release, further impairing synaptic function and communication between neurons.²⁰¹ Previous studies have demonstrated that the molecular pathways through which AD impacts mitochondrial function are multifaceted and involve several interconnected mechanisms.

In addition to Aβ, hyperphosphorylated tau protein also plays a significant role in mitochondrial impairment. Hyperphosphorylated tau can disrupt mitochondrial transport along axonal microtubules, impairing the delivery of essential components necessary for mitochondrial function.²⁰² Research has indicated that tau pathology can lead to reduced mitochondrial biogenesis, a process critical for maintaining healthy mitochondrial populations within neurons. This impairment is partly mediated by a decrease in the activity of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis. When PGC-1α activity is reduced, the production of new mitochondria is hindered, further contributing to energy deficits in neurons.¹⁹²

Moreover, mitochondrial dysfunction in AD is associated with alterations in calcium homeostasis. Mitochondria play a crucial role in buffering intracellular calcium levels, and disturbances in this balance can lead to increased mitochondrial calcium uptake. Elevated calcium levels within mitochondria can trigger the opening of the mitochondrial permeability transition pore, leading to mitochondrial swelling, loss of membrane potential, and ultimately, cell death.²⁰³ This process is often exacerbated by the presence of Aβ, which can disrupt calcium signaling pathways, further compromising mitochondrial integrity.

Another significant pathway impacted by AD is the activation of inflammatory responses. Neuroinflammation, driven by the presence of Aβ and tau, can lead to the release of pro-inflammatory cytokines, which can adversely affect mitochondrial function. Inflammatory mediators can induce mitochondrial dysfunction by altering mitochondrial dynamics, such as fission and fusion processes that are essential for maintaining healthy mitochondria.²⁰⁴

Furthermore, the impairment of mitochondrial dynamics is closely tied to the regulation of mitophagy, the process by which damaged mitochondria are selectively degraded. In AD, impaired mitophagy can result in the accumulation of dysfunctional mitochondria, further exacerbating oxidative stress and energy deficits.²⁰⁵ The failure to clear damaged mitochondria leads to a buildup of dysfunctional organelles that contribute to neuronal cell death and cognitive decline.

Research by Du et al. highlights how Aβ oligomers disrupt mitochondrial respiration and increase the production of ROS, resulting in oxidative stress. This oxidative damage compromises ATP production, further exacerbating energy deficits in brain tissues critical for memory and cognitive functions.²⁰⁶ Wang et al. showed that hyperphosphorylated tau can inhibit mitochondrial transport within neurons, leading to localized energy shortages. This disruption in energy supply is particularly detrimental in areas of the brain responsible for memory, such as the hippocampus.¹⁵

A study by Culmsee et al. examined how activated microglia release pro-inflammatory cytokines that further impair mitochondrial function.²⁰⁷ The resulting inflammation not only exacerbates neuronal injury but also shifts energy metabolism from efficient oxidative phosphorylation to less effective glycolysis, leading to further cognitive decline.²⁰⁸ Interestingly, research has also begun to explore therapeutic approaches aimed at reversing mitochondrial dysfunction to improve memory. For example, the review by Bhatti et al. discusses various strategies, including pharmacological agents, dietary interventions, and lifestyle changes, that target mitochondrial function. Interventions that enhance mitochondrial biogenesis and promote oxidative phosphorylation have shown promise in preclinical models of AD.²⁰⁹ The shift in energy metabolism observed in AD also provides a critical insight into potential therapeutic targets. A study by Smith et al. emphasized that enhancing metabolic flexibility could mitigate cognitive decline. By promoting a return to oxidative metabolism or optimizing energy utilization, researchers are exploring how such strategies can translate into memory improvements in affected individuals.²¹⁰

Apoptosis and neuronal death

One of the critical mechanisms implicated in the progression of AD is apoptosis, a form of programmed cell death that plays a vital role in maintaining cellular homeostasis and normal brain function. In the context of AD, dysregulation of apoptotic pathways contributes significantly to the loss of neurons, particularly in regions crucial for memory and cognitive processing.²¹¹ Research has established that accumulation of Aβ plaques and NFTs, are closely associated with the activation of apoptotic pathways. Aβ can induce oxidative stress and inflammation, conditions that trigger signaling cascades leading to cell death.²¹²

The dysregulation of apoptosis in AD is not simply a consequence of neurodegeneration; it is also a contributing factor to the disease's progression. Studies have demonstrated that certain pro-apoptotic proteins, such as Bax and caspases, become upregulated in response to the neurotoxic environment created by Aβ and tau pathology. Conversely, anti-apoptotic factors like Bcl-2 may be downregulated, tipping the balance toward cell death.²¹³ This imbalance leads to increased neuronal loss and disrupts synaptic connections, further impairing cognitive function and memory.

When Aβ aggregates, it generates ROS, leading to oxidative stress. This oxidative stress activates stress response pathways that can trigger apoptosis.²¹⁴ Key players in this process include pro-apoptotic proteins, which promote mitochondrial outer membrane permeabilization. This event results in the release of cytochrome c from the mitochondria into the cytoplasm, activating caspases—proteolytic enzymes that orchestrate the cell death process.²¹⁵ These pro-inflammatory factors can sensitize neurons to apoptotic signals and disrupt neuronal signaling pathways.⁸⁶ They can also upregulate the expression of death receptors on neuronal surfaces, further promoting apoptosis in response to external ligands.

Tau pathology also contributes to neuronal death through its toxic effects. Hyperphosphorylated tau can disrupt microtubule stability, leading to impaired axonal transport and synaptic dysfunction.³⁷ This disruption can initiate apoptotic pathways, as the affected neurons struggle to maintain their metabolic and functional integrity. The accumulation of tau tangles further exacerbates oxidative stress and inflammation, creating a vicious cycle that accelerates neuronal loss.²¹⁶ Research by Ayala-Grosso et al. demonstrated that levels of pro-apoptotic proteins, such as Bax and caspase-3, were significantly elevated in the brain tissues of AD patients compared to age-matched controls. Conversely, anti-apoptotic markers like Bcl-2 showed reduced expression.²¹⁷ A study by Cheignon et al. highlighted that Aβ oligomers can activate apoptotic pathways in neurons, leading to increased levels of cleaved caspase-3.¹⁴⁵ Research by Leong et al. demonstrated that elevated levels of phosphorylated tau in brain tissue were associated with higher rates of apoptosis, as indicated by markers such as TUNEL staining, which detects DNA fragmentation characteristic of apoptotic cells.²¹³ Moreover, recent studies have explored therapeutic interventions aimed at modulating apoptotic pathways to improve cognitive outcomes in AD. For example, a study by Kumari et al. investigated the effects of potential neuroprotective agents on apoptosis markers in animal models of AD. The findings indicated that these agents could reduce the expression of pro-apoptotic markers and enhance the levels of anti-apoptotic factors, leading to decreased neuronal death and improved memory performance in treated subjects.²¹⁴ Table 3 shows the apoptosis status in different parts of the brain in some models of AD.

Table 3.

The apoptosis status in different parts of the brain in some models of Alzheimer's disease.

Model	Tissue	Bcl2	Bcl-xl	Bax	Caspase 9	Caspase 3	TLR4	Species	Ref.
Aβ	Hippocampus	↓		↑		↑		Rat	¹⁷⁰
	Hippocampus			↑		↑		Mouse	²¹⁸
	Hippocampus	↓		↑		↑	↑	Mouse	¹⁸⁷
	Hippocampus and cortex	↓		↑				Mouse	²¹⁹
	Brain	↓		↑				Mouse	²²⁰
	Hippocampus	↓		↑		↑		Rat	²⁰⁶
Aβ and APP/PS1	Hippocampus	↓	↓	↑	↑	↑		Mouse	^221,222
TMT	Hippocampus	↓		↑	↑			Rat	¹⁸⁸

Aβ: amyloid-β peptide; Bcl2: anti-apoptotic protein; Bcl-xl: anti-apoptotic protein; Bax: pro-apoptotic protein; Caspase 3 and caspase 9: pro-apoptotic enzyme; TrkB: tropomyosin receptor kinase B; TLR4: Toll-like receptor 4; ↓: decrease; ↑: increase.

Neurotrophic factors

One of the critical aspects of understanding the pathophysiology of AD lies in the examination of neurotrophic factors. Neurotrophic factors are crucial for synaptic plasticity, neurogenesis, and overall brain resilience, particularly in regions such as the hippocampus and cortex, which are significantly affected by AD. BDNF, for instance, is vital for promoting the survival of existing neurons and encouraging the growth of new neurons and synapses. It plays a pivotal role in learning and memory processes, making it particularly relevant in the context of cognitive decline associated with AD.²²³ Research has shown that levels of BDNF are often reduced in the brains of individuals with AD, correlating with the severity of cognitive impairment. This decline in BDNF affects neuronal survival and disrupts synaptic plasticity, further exacerbating memory deficits.⁴¹

Similarly, glial cell line-derived neurotrophic factor (GDNF) is another neurotrophic factor that has been implicated in the pathophysiology of AD. GDNF is primarily known for its protective effects on dopaminergic neurons and its role in promoting neuronal survival and differentiation. In the context of AD, GDNF has been shown to exert neuroprotective effects against Aβ toxicity.²²⁴ However, like BDNF, GDNF levels are often altered in AD patients, leading to impaired neuroprotection and increased vulnerability of neurons to degeneration. The interplay between neurotrophic factors and the pathological features of AD, such as Aβ accumulation and tau hyperphosphorylation, is complex and multifaceted. These pathological changes can lead to a detrimental cycle where reduced levels of neurotrophic factors contribute to neuronal dysfunction and death, which in turn exacerbates the cognitive decline characteristic of the disease.²²⁵

Aβ can induce neurotoxicity and inflammation, leading to reduced production and secretion of BDNF. Additionally, the presence of Aβ plaques can interfere with TrkB receptor signaling, impairing the activation of the phosphoinositide 3-kinase (PI3 K)/Akt pathway and mitogen-activated protein kinase (MAPK) pathways.²²⁶ Consequently, this disruption results in decreased neuronal survival and impaired cognitive functions, as the neuroprotective effects of BDNF are diminished. Furthermore, low levels of BDNF have been associated with increased levels of tau phosphorylation, exacerbating the neurodegenerative process.²²⁷

GDNF signals through the GDNF family receptor alpha (GFRα) and the Ret receptor tyrosine kinase. This signaling pathway activates downstream pathways, including the PI3 K/Akt pathway, which plays a role in cellular survival and growth.²²⁸ In AD, neuroinflammation, often driven by activated microglia, can lead to the downregulation of GDNF expression. Inflammatory cytokines, such as TNF-α and interleukin-1 beta (IL-1β), can inhibit GDNF production, thereby diminishing its neuroprotective effects and contributing to neuronal vulnerability.²²⁹

Moreover, Hyperphosphorylated tau can disrupt microtubule stability and impair axonal transport, which is essential for delivering neurotrophic factors and their signaling components to synapses.²³⁰

Furthermore, the dysregulation of neurotrophic factors in AD is closely tied to changes in metabolic pathways. Insulin resistance, commonly observed in individuals with AD, can impair the signaling required for BDNF expression.²³¹ Insulin has been shown to promote BDNF transcription, and when its signaling is disrupted, the production of this critical neurotrophic factor declines, further contributing to cognitive decline.

Moreover, Elevated levels of ROS can damage neuronal cells and disrupt GDNF signaling, leading to a cycle of increased neuronal death and loss of neurotrophic support. The interplay between oxidative stress and neuroinflammatory responses can create an environment where neurotrophic factors are not only reduced but their signaling pathways are impaired, exacerbating the cognitive decline associated with AD.²³²

An animal study showed that intracerebroventricular administration of BDNF in AD mouse models not only restored synaptic function but also improved performance in memory tasks.²³³ These findings suggest that therapeutic strategies aimed at increasing BDNF levels could offer a pathway to ameliorate cognitive deficits in AD patients. Similarly, A study reported that GDNF administration could counteract the effects of neuroinflammation and promote the survival of cholinergic neurons, which are critically involved in memory processes.²³⁴ Moreover, animal studies have demonstrated that GDNF can improve cognitive function when administered in various models of neurodegeneration.²³⁵ Some studies have suggested that a combination of neurotrophic factors may be more effective than targeting a single factor.²³⁴ For instance, research has shown that co-administration of both BDNF and GDNF can lead to synergistic effects, promoting enhanced neuroprotection and cognitive recovery in animal models.²³⁶ Table 4 shows the neurotrophic factors status in different parts of the brain of some models of AD.

Table 4.

The neurotrophic factors status in different parts of the brain of some models of Alzheimer's disease.

Model	Tissue	BDNF	GDNF	ProBDNF	P75 NTR	NGF	NT-3	Trkb	Species	Ref.
Scopolamine	Hippocampus	↓							Rat	^163,164
STZ	Brain	↓				↓			Rat	¹⁶⁸
AD Patients	Serum		↓						Human	²³⁷
AD Patients	Brain	↓		↑	↑				Human	²³⁸
TMT	Hippocampus	↓							Rat	¹⁸⁸
APP/PS1 And 3xtg	Hippocampus	↓	↓					↓	Mouse	^239,240
APP/PS1	Hippocampus	↓				↑	↓		Mouse	²⁴¹

STZ: streptozotocin; BDNF: brain-derived neurotrophic factor; GDNF: glial cell line-derived neurotrophic factor; NGF: nerve growth factor; NT-3: neurotrophin-3; ProBDNF: pro-brain-derived neurotrophic factor; P75NTR: P75 neurotrophin receptor; Trkb: tropomyosin receptor kinase B; ↓: decrease; ↑: increase.

Neurotransmitters

Neurotransmitters are the chemical messengers that facilitate the transmission of signals across synapses, enabling essential functions such as memory, learning, and emotional regulation.²⁴² In the context of AD, the disruption of these neurotransmitter systems is not only a hallmark of the condition but also correlates closely with the clinical symptoms observed in patients.³⁶ One of the most well-documented neurotransmitter deficits in AD is the decrease in ACh, a vital neurotransmitter involved in memory and learning. The loss of cholinergic neurons in the basal forebrain, which is associated with the degeneration of these neurons, leads to significant reductions in ACh levels in the cortex and hippocampus.²⁴³

Beyond ACh, other neurotransmitter systems are also affected by AD. For instance, alterations in glutamate, the primary excitatory neurotransmitter in the brain, are observed in AD pathology. Dysregulation of glutamatergic signaling can lead to excitotoxicity, where excessive stimulation of neurons results in cellular injury or death. This phenomenon is particularly concerning given the role of glutamate in synaptic plasticity and memory formation.²⁴⁴ Additionally, imbalances in gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter, have been implicated in the cognitive dysfunction seen in AD. Disruptions in the balance between excitatory and inhibitory signaling can lead to increased neuronal hyperactivity, further complicating the neurochemical landscape of the disease.²⁴⁵

The interplay between these neurotransmitter systems and the presence of Aβ plaques and NFTs adds another layer of complexity. These pathological changes can exacerbate neurotransmitter imbalances, leading to a vicious cycle of neurodegeneration and cognitive decline. Furthermore, neuroinflammation associated with AD can also influence neurotransmitter systems, as activated microglia release pro-inflammatory cytokines that can alter neurotransmitter synthesis and receptor function.¹⁹⁶

Numerous postmortem studies have consistently demonstrated a significant loss of cholinergic neurons in the basal forebrain, leading to reduced levels of ACh in cortical and hippocampal regions critical for memory.²⁴⁶ For instance, a pivotal study found that lower ACh levels correlated with the severity of cognitive impairment in patients with AD.²⁴⁷ This decline in ACh is thought to impair synaptic transmission, particularly in circuits involved in learning and memory, and has led to the development of acetylcholinesterase inhibitors as a therapeutic strategy. These medications aim to increase ACh availability, and clinical trials have shown modest improvements in cognitive function in some patients, further highlighting the relationship between ACh deficits and memory impairment.²⁴⁸

Research showed that elevated levels of glutamate were found in the CSF of AD patients, correlating with cognitive decline.²⁴⁹ The overactivation of NMDA receptors, a subtype of glutamate receptors, has been implicated in this excitotoxic process, leading to impaired synaptic plasticity, which is essential for learning and memory.²⁵⁰ A Research indicated that decreased GABA levels were associated with increased neuronal hyperactivity and cognitive dysfunction in AD models. This disruption in balance can exacerbate the cognitive impairments seen in patients, as the fine-tuning of neuronal circuits necessary for normal memory processing is compromised.²⁵¹ A study demonstrated that elevated levels of inflammatory markers were associated with decreased ACh and GABA levels in the brains of AD patients.²⁵² This suggests a feedback loop in which inflammation exacerbates neurotransmitter deficits, further contributing to cognitive decline. Table 5 shows the neurotransmitter status in different parts of the brain of some models of AD.

Table 5.

The neurotransmitter status in different parts of the brain in some models of Alzheimer's disease.

Model	Tissue	ACh	GABA	DA	5-HT	NE	Glu	Species	Ref.
SAMP8	Hippocampus And Cortex	↓		↓	↓	↓		Mouse	²⁵³
Aβ	Plasma	↓	↓	↓	↓	↓	↑	Rat	²⁵⁴
	Brain	↓	↓	↓	↓	↓		Rat	²⁵⁵
	Brain	↓		↓	↓			Rat	²⁵⁶
AD Patients	Plasma	↓			↓			Human	²⁵⁷
AD Patients	Brain		↑	↓	↓		↓	Human	¹⁶
Alcl3 + D-Gal	Hippocampus	↓	↓	↓			↑	Rat	²⁵⁸
D-Galactose And Aβ	Hippocampus And Cortex	↓	↓				↑	Rat	²⁵⁹
Aβpp-PS1	Hippocampus And Cortex		↓				↓	Mouse	²⁶⁰

AD: Alzheimer's disease; Aβ: amyloid-β; ACh: acetylcholine; GABA: gamma-aminobutyric acid; DA: dopamine; 5-HT: serotonin; NE: norepinephrine; Glu: glutamate; ↓: decrease; ↑: increase.

Aβ/tau biomarkers in anti-amyloid therapy

Pathological markers of Aβ and tau not only serve as diagnostic criteria but also play a pivotal role in guiding the development and assessment of targeted AD therapeutics. Emerging anti-amyloid therapies, such as the monoclonal antibodies aducanumab and lecanemab, directly focus on clearing cerebral Aβ plaques.²⁶¹ The efficacy of these treatments requires confirmation of Aβ pathology in patients, primarily evaluated through PET imaging with specific ligands (e.g., PiB or Flutemetamol) or measurement of CSF Aβ₄₂.²⁶² Clinical trials indicate that amyloid reduction with these agents correlates with slower cognitive decline, though effects are often modest and stage-dependent.²⁶³ Concurrently, tau pathology serves as a critical secondary biomarker. Tau-PET imaging, using ligands like Flortaucipir, tracks tau changes following anti-amyloid interventions, demonstrating that amyloid reduction may attenuate tau propagation in early-stage AD.²⁶⁴ These observations support the amyloid cascade hypothesis, wherein Aβ suppression may disrupt downstream tau spread. However, significant limitations persist: (1) current anti-amyloid therapies show greatest efficacy in preclinical or mild MCI stages, with diminished effects in advanced dementia; (2) tau biomarker changes often lag behind Aβ reduction; and (3) patient pathological heterogeneity (e.g., co-existing TDP-43 pathology or vascular injury) may modify treatment response. Notably, extensive concomitant tau pathology may reduce responsiveness to anti-amyloid therapies, underscoring the need for combination approaches targeting Aβ and tau simultaneously to optimize outcomes. Ongoing clinical trials are investigating anti-amyloid antibodies alongside anti-tau agents (e.g., tau aggregation inhibitors or vaccines) to address these challenges. Thus, integrated monitoring of Aβ and tau biomarkers is essential not only for selecting appropriate candidates for anti-amyloid therapies but also for evaluating treatment response and tracking underlying pathology progression.

Conclusion

In conclusion, this narrative review has highlighted the intricate molecular mechanisms that underlie memory impairment in AD (Figure 1). The interplay between Aβ accumulation, tau hyperphosphorylation, neuroinflammation, and neurotrophic factor dysregulation emerges as a complex web of pathological processes that collectively contribute to cognitive decline. Aβ plaques disrupt synaptic function and promote neurotoxicity, while tau tangles interfere with intracellular transport and neuronal integrity. Concurrently, the neuroinflammatory response, characterized by the activation of microglia and the release of pro-inflammatory cytokines, exacerbates neuronal damage and further impairs cognitive function. Moreover, the dysregulation of neurotrophic factors, particularly BDNF, plays a critical role in the loss of synaptic plasticity, which is essential for memory formation and retrieval. Understanding these molecular links not only enhances our comprehension of the pathophysiology of AD but also underscores the need for targeted therapeutic strategies that address these interconnected pathways. Future research should focus on developing interventions that can effectively modulate these mechanisms, potentially leading to improved outcomes for individuals affected by AD. By unraveling these complex molecular interactions, we can pave the way for innovative approaches to mitigate memory impairment and enhance the quality of life for those living with AD.

Figure 1.

A summary of all the key parameters in Alzheimer's disease (AD) pathogenesis. Aβ: amyloid-β; BDNF: brain derived neurotrophic factor; ACh: acetylcholine; GABA: gamma-aminobutyric acid; GDNF: glial cell line-derived neurotrophic factor; LTP: long-term potentiation; ROS: reactive oxygen species.

Footnotes

Acknowledgements

The authors used artificial intelligence (AI) tools, including ChatGPT, for the exclusive purpose of enhancing the language, grammar, and readability of the narrative review. All intellectual content, analysis, and conclusions in this manuscript are the sole product of the authors' work. Some major vector icons are from smart_servier.com and NIH BIOART sources.

ORCID iDs

Yousef Baghcheghi

Fateme Razazpour https://orcid.org/0000-0002-4889-0685

Mola Mohammadi

Habibeh Mashayekhi

Mahdiyeh Hedayati-Moghadam

Author contribution(s)

Yousef Baghcheghi: Conceptualization; Investigation; Project administration; Validation; Writing – original draft; Writing – review & editing.

Fateme Razazpour: Investigation; Project administration; Software; Writing – original draft; Writing – review & editing.

Mola Mohammadi: Investigation; Writing – original draft; Writing – review & editing.

Habibeh Mashayekhi: Investigation; Methodology; Software; Writing – original draft; Writing – review & editing.

Mahdiyeh Hedayati-Moghadam: Conceptualization; Investigation; Validation; Writing – original draft; Writing – review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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