Pathogenesis, diagnostics, and therapeutics for Alzheimer's disease: Breaking the memory barrier

Alzheimer's disease (AD) is the most common cause of dementia and accounts for 60-70% of all cases. It affects millions of people worldwide. AD poses a substantial economic burden on societies and healthcare systems. AD is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. As the prevalence of AD continues to increase, understanding its pathogenesis, improving diagnostic methods, and developing effective therapeutics have become paramount. This comprehensive review delves into the intricate mechanisms underlying AD, explores the current state of diagnostic techniques, and examines emerging therapeutic strategies. By revealing the complexities of AD, this review aims to contribute to the growing body of knowledge surrounding this devastating disease.


Introduction
Alzheimer's disease (AD) is the most common form of dementia and accounts for approximately 60-80 % of all dementia cases.It is a progressive neurodegenerative disorder that primarily affects older adults, although early-onset forms of the disease can occur (Dementia vs, 2024).AD is characterized by the gradual loss of cognitive function, including memory decline, impaired thinking, and changes in behavior.These symptoms significantly impact an individual's ability to carry out daily activities and eventually lead to a complete loss of independence (Deture and Dickson, 2019).AD poses a significant global health challenge for both individuals and society as a whole.The prevalence of AD is rapidly increasing, driven by aging populations and longer life expectancies.According to the World Alzheimer Report 2019, approximately 50 million people worldwide are currently living with dementia, and this number is projected to triple by 2050 (Aranda et al., 2021).The impact of AD extends beyond the affected individuals to their families, caregivers, and healthcare systems.Caring for individuals with AD places a tremendous emotional, physical, and financial burden on families, often requiring long-term care and support.The economic costs associated with AD are substantial and include healthcare expenses, lost productivity, and social care services (Aranda et al., 2021).Understanding the underlying pathogenesis of AD is crucial for the development of effective diagnostic tools and therapeutic interventions.Advancements in these areas can lead to earlier and more accurate diagnoses, enabling individuals to access appropriate care and support promptly.Pathologically AD is characterized by accumulation of Amyloid beta (Aβ) plaques and neurofibrillary tangles in the regions connected to cognition (Murakami and Lacayo, 2022).AD is a multifactorial disease with genetics, ageing and environmental factors playing a key role in disease pathogenesis.Several genes like APP, PSEN1, PSEN2 mutations were identified to increase Aβ aggregation in AD.In addition, cardiovascular diseases, obesity, diabetes and certain lifestyle factors also increase the risk of AD (Wang et al., 2021).Various mechanisms like accumulation of Aβ plaques and neurofibrillary tangles, oxidative stress, neuroinflammation, mitochondrial dysfunction, synaptic dysfunction are implicated in AD pathogenesis (Ratan et al., 2023).The diagnosis of AD uses various cognitive tests and behavioral tests, blood and CSF tests, neurological examination and brain imaging.CSF levels of Aβ40/42 and p-tau181/Aβ42 are the two most commonly used biomarkers for the diagnosis of AD.CSF analysis is highly invasive.Hence, recently, research has focused on identifying non-or minimally invasive biomarkers for early diagnosis of AD (Barthélemy et al., 2024;Hansson et al., 2023a).In addition, various radiolabelled tracers are also being developed for neuroimaging techniques to study cerebral hypoperfusion, hypometabolism, neuroinflammation, amyloid beta Fig. 1.Alzheimer's disease and its pathology.(A) Characteristic symptoms at various stages of AD.In the mild stage, neuronal damage is initiated in entorhinal cortex and hippocampus and the patient experiences memory loss, speech difficulties, mood changes.As the disease progresses to other cortical areas, learning ability and daily activities are impaired.In the severe/ late stage, the motor activities of the patient are impaired making them bedridden (B) Causative factors and hallmarks of AD.Several pathological mechanisms like neuroinflammation, mitochondrial dysfunction, oxidative stress, blood brain barrier disruption, protein aggregation play role in AD progression.Hallmarks include the presence of pathological proteins such as Aβ plaques, p-tau, neurofibrillary tangles (NFTs) and anatomical changes like enlarged ventricles, cortical atrophy, shrunken hippocampus.deposition (Bao et al., 2021).Current therapy of AD is majorly directed at the alleviation of symptoms.The development of disease-modifying treatments that can slow or halt disease progression is a major research goal (van der Flier et al., 2023;Porsteinsson et al., 2021).Several novel therapeutic strategies are being developed that target and prevent the aggregation of Aβ and tau, suppress neuroinflammation, improve mitochondrial function and improve neurogenesis and synaptic function.These include immunotherapy, vaccines, stem cell therapy, gene therapy, hormonal therapy, and probiotics.Recently, FDA gave accelerated approval for two monoclonal antibodies aducanumab, lecanemab that target Aβ plaques.These novel therapeutics can significantly reduce disease burden and improve cognition in AD patients.Many of these are in clinical trials and show promising results.Lecanemab was granted license by Medicines and health products regulatory agency (MHRA) for the treatment of early stage AD in adult patients (Burns et al., 2022; FDA Grants Accelerated Approval for Alzheimer's Disease Treatment | FDA [Internet], 2024; FDA Grants Accelerated Approval for Alzheimer's Drug | FDA [Internet], 2024; Lecanemab licensed for adult patients in the early stages of Alzheimer's disease -GOV.UK [Internet], 2024).In addition, lifestyle and dietary modification also play role in AD management.Insights gained from AD research could have implications for the development of treatments for these related disorders as well.Advancing our knowledge of the disease pathogenesis, improving diagnostic techniques, and developing effective therapeutic strategies are essential for addressing this urgent medical need.This review provides a comprehensive discussion on various pathogenic mechanisms involved in AD, diagnostic techniques with a special focus on blood biomarkers and novel therapeutic strategies that are active in clinical trials for the effective management of AD.

Pathogenesis of Alzheimer's Disease
Alzheimer's disease occurs due to the accumulation of Amyloid β and neurofibrillary tangles in the hippocampus.Amyloid disease can be broadly classified as familial AD (FAD) and Sproadic AD (SAD).The occurrence of FAD is attributed to gene mutations in APP, PSEN1 and PSEN2, however SAD etiology is a complex interplay of aging, genetics, metabolic and environmental factors (Piaceri et al., 2013).Understanding AD pathology is important to develop efficient treatment strategies.Several hypotheses have been put forth and mechanisms studied to understand AD pathology.Complex interplay of various pathological mechanisms in AD are shown in Fig. 1.Major mechanisms are discussed in the following sections.

Amyloid beta hypothesis
The amyloid beta (Aβ) hypothesis, proposed by John Hardy and David Allsop has been a leading theory in Alzheimer's disease (AD) research for several decades (Murphy and Levine, 2010).According to the Aβ hypothesis, Aβ deposition is central to AD followed by neurofibrillary tangles, cell death, vascular damage and dementia (Hardy and Higgins, 1992).Aβ peptide is formed by abnormal cleavage of a larger Amyloid precursor protein (APP).APP is a transmembrane protein that is normally cleaved by enzymes called secretases to produce various peptide fragments essential for neuronal functions.В-site APP cleavage enzyme (BACE) cleaves APP at N-terminal domain to release sAPPβ peptide fragment leaving the carboxy terminal CTF99/89 fragment.γ-secretase cleaves CTF99/89 fragment resulting in various Aβ peptides of which Aβ40 and Aβ42 are the most common.Long species (Aβ42) are more prone to aggregation than short species (Suzuki et al., 2023).Aβ oligomers, which are smaller aggregates of Aβ peptides, are considered particularly toxic to neurons and synapses (Chen et al., 2017;Meyer-Luehmann et al., 2008).The causes for Aβ aggregation is not clear.Genetic mutations in the genes encoding APP and secretases, such as the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes have been linked to rare cases of early-onset familial AD, providing further support for the Aβ hypothesis.These mutations increase the production of longer and more aggregation-prone forms of Aβ, leading to accelerated disease progression (Lanoiselée et al., 2017) as shown in Fig. 2. Mutations in the APP gene on chromosome 21 can lead to an overproduction of Aβ peptides, specifically the longer, more amyloidogenic forms, increasing the likelihood of Aβ aggregation and the formation of amyloid plaques in the brain.About 25 mutations were identified as pathogenic causing autosomal dominant AD.These mutations determine Aβ42/Aβ40 ratio and distinct aggregation propensity and morphology due to differences in cleavage (Li et al., 2019;Hatami et al., 2017).D7H mutation in APP increases Aβ42 oligomer formation (Chen et al., 2024).Mutations in the PSEN1 gene on chromosome 14 and in the PSEN2 gene on chromosome 1 result in abnormal processing of the APP protein and subsequent increased Aβ production (Tcw and Goate, 2017;Petit et al., 2022).Another gene associated with AD is the apolipoprotein E (APOE) gene, which is located on chromosome 19.The APOE gene has three common alleles: ε2, ε3, and ε4.The APOE ε4 allele is the strongest genetic risk factor for late-onset AD and is the most common form of this disease.
Possessing one copy of the APOE ε4 allele increases the risk of developing AD, while having two copies significantly increases the risk (Liu et al., 2013).It is associated with increased Aβ aggregation and reduced clearance, leading to the accumulation of Aβ plaques.Furthermore, APOE ε4 carriers often exhibit increased neuroinflammation and neuronal damage compared to noncarriers (Kim et al., 2009;Schmechel et al., 1993).
The accumulation of Aβ peptides is believed to trigger a cascade of events that ultimately lead to neurodegeneration.Aβ aggregation promotes tau phosphorylation by activating kinases like GSKβ, CDK-5 (Hernandez et al., 2009;Terwel et al., 2008).APOE ε4 allele also increases the activity of GSKβ and promote tau pathology (Medina and Avila, 2012).Aβ peptides can activate microglial cells via amylin receptors, activate NLRP3 inflammasome pathway and induce neuroinflammation (Fu et al., 2017).Mitochondria targeted Aβ 1-42 accumulation results in severe morphological changes in the mitochondria, eventually causing mitochondrial dysfunction and activation of apoptosis pathway (Cha et al., 2012).They also cause synaptic damage by modulating NMDA receptor signaling pathway.The oligomers associate with the synaptic densities and cause excitatory synaptic loss (Koffie et al., 2009;Shankar et al., 2007) However, the Aβ hypothesis has faced challenges and criticisms over the years.Some clinical trials investigating Aβ-targeting agents have failed to show significant benefits, raising questions about the underlying mechanism and timing of intervention.This has prompted researchers to explore alternative or complementary mechanisms involved in AD pathogenesis, including tau protein pathology, inflammation, vascular factors, and network dysfunction (Liu et al., 2019).Nonetheless, the Aβ hypothesis continues to guide research and drug development efforts in AD.Strategies aimed at reducing Aβ production, enhancing Aβ clearance, or targeting Aβ aggregation are being actively investigated.These include approaches such as secretase inhibitors, immunotherapies, and anti-aggregation agents (Jeremic et al., 2021).While this hypothesis has faced challenges, it remains a significant focus of research and therapeutic development in the quest to understand and combat this devastating neurodegenerative disorder.

Tau protein and neurofibrillary tangles
In addition to the accumulation of amyloid-beta plaques, another hallmark pathology of AD is the presence of neurofibrillary tangles (NFTs) composed of abnormal aggregates of tau protein.Tau is a microtubule-associated protein that plays a crucial role in maintaining the stability and integrity of neuronal microtubules and is essential for proper cellular functioning and nutrient transport within neurons (Moloney et al., 2021;Rajmohan and Reddy, 2017).In healthy neurons, tau protein is regulated and phosphorylated in a controlled manner, allowing it to bind to microtubules and promote their assembly (Weingarten et al., 1975).However, in AD, tau undergoes abnormal posttranslational modifications, such as hyperphosphorylation, which disrupts its normal function (LeBoeuf et al., 2008).Hyperphosphorylated tau molecules become prone to self-aggregation and form insoluble paired helical filaments (PHFs) and straight filaments (SFs).These aggregated tau structures are the major components of NFTs observed in the brains of AD patients (Liu et al., 2020a;Del et al., 1996).Additionally, Amyloid beta fibrils also induce Tau pathology (Vasconcelos et al., 2016).The formation and accumulation of NFTs disrupt neuronal function and contribute to neurodegeneration in several ways.First, various PTMs, Lysine succinylation, lysine acetylation, and tyrosine phosphorylation in the microtubule-binding region of Tau disrupt its interaction with Microtubules.A reduction in acetylated a-tubulin has been identified due to NFT accumulation in neuronal population (Hempen and Brion, 1996;Acosta et al., 2022).Second, the accumulation of NFTs triggers inflammatory responses within the brain.Microglia are more sensitive to NFTs than Amyloid plaques and become hypertrophied and ramified in NFT-rich regions of the brain (Ohm et al., 2021).Interestingly other studies show an inverse relation: NFT levels and stages of NFT formation were proportional to microglial density and activated IL-1 overexpressing microglia and S100B overexpressing astrocytes (Sheng et al., 1997;Sheffield et al., 2000).This sustained inflammatory state exacerbates neuronal damage and promotes the spread of tau pathology (Novoa et al., 2022).Third, recent research has suggested that tau aggregates might have prion-like properties, enabling their propagation and spread throughout the brain.It is hypothesized that abnormal tau species can induce the misfolding of normal tau in neighboring neurons, leading to the progressive spread of tau pathology across different brain regions.This spreading phenomenon is thought to contribute to the progressive nature of AD and the worsening of cognitive decline observed in affected individuals (Clavaguera et al., 2015).Targeting abnormal tau aggregation and its associated downstream consequences is a promising avenue for potential disease-modifying treatments (Congdon and Sigurdsson, 2018).

Neuroinflammation
Inflammatory processes play a significant role in the pathogenesis of AD.Chronic inflammation within the brain, often referred to as neuroinflammation, is a prominent feature observed in AD patients and has been implicated in disease progression (Kinney et al., 2018).Inflammation in AD is characterized by the activation of various immune cells, including microglia and astrocytes, as well as the release of proinflammatory molecules such as cytokines, chemokines, and reactive oxygen species (Wang et al., 2015).While these immune responses are initially intended to protect the brain and clear harmful substances, chronic and dysregulated inflammation can contribute to neuronal damage and exacerbate the disease process (Passaro et al., 2021).In AD, microglia are activated by Aβ plaques via various cell surface receptors like CD14, TLR4-TLR6 heterodimer, CD36-CD47-α6β1-integrin complex, and scavenger receptors (Stewart et al., 2009;Bamberger et al., 2024;Liu et al., 2005;Paresce et al., 1996).Microglia also release cardiolipin which in turn promotes the uptake of Aβ plaques (Wenzel et al., 2023).Initial response to Aβ plaques is aimed at clearance of the plaques but sustained exposure results in chronic activation to majorly to M1 phenotype and secretion of proinflammatory cytokines TNF-α and interleukin 1β (Wang et al., 2023a).ApoE4, which was identified as the Fig. 2. Pathogenesis of AD.Several factors, such as genetic mutations, epigenetic changes, aging, and lifestyle, contribute to pathology of AD.Mutations in APP, PSEN1/2, APOE genes increase the risk of amyloid β-plaque formation.In addition, hyperphosphorylation of tau leads to its aggregation and neurofibrillary tangles.These pathologic protein forms can be transmitted across the cells, damage the neurons.Various risk genes such as PLCG2, CD33, Aβ plaques activate the microglia resulting in cytokine release and further promote neurodegeneration.
key factor in the development of FAD, binds with TREM2 receptors on the microglia and activates them resulting in the production of inflammatory cytokines like IL-1, IL-6, TNF-α, IFN-γ that damage the neurons (Li et al., 2015;Krasemann et al., 2017).In addition, the binding of APOE and APOJ to TREM2 promotes the uptake of amyloid beta by microglia (Yeh et al., 2016).Astrocytes are other inflammatory cells implicated in AD.They migrate towards the Aβ plaques in response to the monocyte chemoattractant protein-1 (MCP-1) present in the plaques and degrade them (Wyss-Coray et al., 2003).They also augment neuroinflammation in concert with microglia.They secrete glypican-4 which promotes hyperphosphorylation of tau ( (Saroja et al., 2022).Activation of complement component 3 (C3) on astrocytes by NFTs promotes neuroinflammation and neuronal damage (Litvinchuk et al., 2018).In addition, peripheral mononuclear cells are also involved in AD pathology further exacerbating the situation (Simard et al., 2006).
Furthermore, peripheral inflammation and systemic diseases have been implicated in AD pathogenesis.Chronic systemic inflammation, such as that observed in conditions such as diabetes, obesity, and cardiovascular diseases, can contribute to neuroinflammation and increase the risk of developing AD (Cummings et al., 2022;Rohm et al., 2022).Systemic inflammation can affect blood-brain barrier integrity, allowing the entry of peripheral immune cells and inflammatory molecules into the brain, further exacerbating neuroinflammation (Galea, 2021).

Oxidative stress and mitochondrial dysfunction
Oxidative stress refers to an imbalance between the production of reactive oxygen species (ROS) and the ability of the body's antioxidant defense mechanisms to neutralize them (Pizzino et al., 2017).In the context of AD, oxidative stress plays a significant role in the pathogenesis and progression of the disease.Mitochondria, the cellular powerhouses responsible for energy production, are particularly susceptible to oxidative damage due to their high metabolic activity and generation of ROS as natural byproducts of oxidative phosphorylation (Misrani et al., 2021;Guo et al., 2013).Mitochondrial abnormalities, including impaired energy metabolism, altered dynamics, reduced antioxidant capacity, and increased ROS production, have been observed in both animal models and human AD brains (Bhatti et al., 2017).Furthermore, dysregulation of cellular antioxidant defense mechanisms contributes to oxidative stress in AD.Antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, are crucial for neutralizing ROS.However, in AD, these antioxidant systems are often compromised, leading to increased oxidative stress (Singh et al., 2019).
Several mechanisms contribute to mitochondrial dysfunction and oxidative stress in AD.First, the accumulation of Aβ peptides, a hallmark of AD, has been shown to directly impair mitochondrial function (Averchuk et al., 2023).Aβ can accumulate within inter mitochondrial membrane space and disrupt their normal function, leading to reduced ATP production and increased ROS generation.Moreover, Aβ-induced mitochondrial damage can trigger a vicious cycle, as impaired mitochondrial function further promotes Aβ production and aggregation (Anandatheerthavarada et al., 2003).Second, the tau protein, another key player in AD pathology, has been implicated in mitochondrial dysfunction.Abnormal phosphorylation and aggregation of tau can impair mitochondrial transport along neuronal axons, leading to local energy deficits and oxidative stress (Shahpasand et al., 2012).Additionally, tau pathology disrupts mitochondrial dynamics, impairing fission and fusion processes necessary for maintaining a healthy mitochondrial network (Li et al., 2016).Conversely mitochondrial dysfunction and oxidative stress results in formation of tau aggregates (Du et al., 2022).They promote neuronal damage and death, disrupt synaptic function and plasticity, and trigger neuroinflammation, further exacerbating disease progression.Oxidative stress can also contribute to the formation and accumulation of Aβ plaques and neurofibrillary tangles, thereby amplifying neurodegenerative processes (Roy et al., 2023).
Given the role of oxidative stress and mitochondrial dysfunction in AD, targeting these processes has emerged as a potential therapeutic strategy.Antioxidant therapies, either through dietary interventions or pharmacological agents, aim to restore redox balance and mitigate oxidative damage (Kurutas, 2016).Additionally, compounds targeting mitochondrial function and dynamics hold promise for preserving neuronal health and alleviating AD-related symptoms (Singh et al., 2021).

Vascular contributions
Cerebral blood vessels play a crucial role in maintaining the brain's energy supply and delivering the oxygen and nutrients necessary for proper neuronal function.Vascular dysfunction can disrupt this supply, leading to hypoperfusion and reduced oxygen and nutrient delivery to the brain.Vascular aging is considered to be one of the key triggers for AD pathology.Cerebral atherosclerosis, arteriosclerosis and cardiovascular diseases were found to increase the risk of AD (Arvanitakis et al., 2016;Kuller et al., 2016).Chronic hypoperfusion of the brain results in neuronal death.Chronic hypoperfusion and cerebral hypoxia can promote the accumulation of Aβ peptides, a hallmark of AD.Reduced blood flow also impairs the clearance of Aβ from the brain, further exacerbating its accumulation and aggregation (Rajeev et al., 2022).Vascular risk factors, such as hypertension, diabetes, hypercholesterolemia, and smoking, have been associated with an increased risk of AD.These risk factors contribute to endothelial dysfunction, oxidative stress, inflammation, and the development of atherosclerosis, which can negatively impact cerebral blood flow and vascular health.Atherosclerosis and small vessel disease can lead to cerebral infarcts, white matter lesions, and microhemorrhages, collectively known as cerebrovascular pathology.These vascular lesions can contribute to cognitive impairment and accelerate AD-related neurodegeneration (Gireud-Goss et al., 2021).Cerebral amyloid angiopathy (CAA) is another vascular pathology associated with AD.CAA involves the deposition of Aβ peptides in the walls of cerebral blood vessels, particularly in small vessels and capillaries.CAAs can impair blood flow regulation and compromise the integrity of the blood-brain barrier, leading to increased neuroinflammation and neuronal damage (Cechetto et al., 2008).Hypoperfusion also leads to mitochondrial dysfunction and the generation of reactive oxygen species.

Synaptic dysfunction and neurotransmitter alterations
Synaptic dysfunction and alterations in neurotransmitter systems are key features of AD pathology.Synapses are crucial for communication between neurons and play a fundamental role in cognitive processes, including learning and memory (Mecca et al., 2022).In AD, synaptic dysfunction occurs early and contributes to the cognitive decline observed in affected individuals.The accumulation of Aβ peptides and the formation of neurofibrillary tangles (composed of hyperphosphorylated tau protein) lead to synaptic damage and loss (Karisetty et al., 2020).Aβ aggregates disrupt synaptic function by impairing neurotransmitter release, reducing synaptic density, and interfering with synaptic plasticity, which is the ability of synapses to adapt and strengthen connections in response to stimuli (Sciaccaluga et al., 2021).In AD, there is a significant reduction in the levels of neurotransmitters, including acetylcholine, which plays a crucial role in memory and cognition.Degeneration of cholinergic neurons in the basal forebrain, which project to the hippocampus and neocortex, leads to a deficiency in acetylcholine signalling.This deficiency contributes to memory impairment and cognitive decline in AD (Sabandal et al., 2022).Other neurotransmitter systems are also affected in AD.Dysfunction in glutamate neurotransmission, the main excitatory neurotransmitter in the brain, contributes to excitotoxicity, which is the excessive activation of glutamate receptors, leading to neuronal damage and cell death.Alterations in the dopaminergic, serotonergic, and noradrenergic systems have also been observed in AD, impacting mood, behavior, and cognitive function (Huber et al., 2021;Gautam et al., 2023).Furthermore, synaptic dysfunction in AD involves the disruption of proteins involved in synaptic structure and function.These include synaptic vesicle proteins, postsynaptic density proteins, and cell adhesion molecules, among others.Impaired signalling between pre-and postsynaptic components hinders the transmission of neuronal signals and compromises the stability and plasticity of synapses (Jha et al., 2017).

Diagnostic approaches for Alzheimer's disease
Accurate and early diagnosis of AD is essential for providing appropriate care, managing symptoms, and developing targeted interventions.Diagnostic approaches for AD encompass a combination of clinical assessments, cognitive screening, and advanced neuroimaging techniques (Assunção et al., 2022).A stepwise approach in the diagnosis and management of AD is represented in Fig. 3.   (Harvey, 2019).These tests provide valuable information about an individual's cognitive functioning and help distinguish AD from other forms of dementia.These assessments help identify cognitive impairments and establish a baseline for monitoring disease progression (Wang et al., 2022).The MMSE is a pen-and-paper test used to evaluate orientation, concentration, attention, verbal memory, naming, and visuospatial skills, with a maximum score of 30.The total score decreased faster for patients with dementia of Alzheimer's type (Meyer et al., 2002).Belleville et al. showed that episodic memory tests have good sensitivity and specificity for assessing MCI progression to AD. Various episodic memory tests, including the free and cued selective reminder test (FCSRT) and the consortium, were used to establish a registry for Alzheimer's disease (CERAD-WL, Rey auditory verbal learning test [RAVLT]) (Daou et al., 2023).Several studies have been conducted to compare the effectiveness of neurocognitive tests and biomarkers for predicting AD progression.According to these authors, the predictive accuracy of the trail marking test-B is comparable to that of the right entorhinal cortex thickness (Ewers et al., 2012).Similarly, a decrease in the MMSE score below 24 was associated with 33 % increased progression, whereas a 2 % increased risk was associated with every 1 ng/l above 40 ng/L pNFL (Darmanthé et al., 2021).Currently, these tests are used in combination with other biomarkers to improve the effectiveness of early diagnosis of AD.Several routine tests that are in use, in addition to the abovementioned tests, include the shortness test, which evaluates orientation, memory and concentration (Carpenter et al., 2011).The clock drawing test is yet another examination that assesses visual-spatial assessment, memory, concentration and information processing (Aprahamian et al., 2009).In addition.There are questionnaire-based tests, such as the Neuropsychiatric Inventory and Alzheimer's Disease 8 (AD-8) test, for caretakers or informants to distinguish healthy people from dementia and to evaluate risk.

Neuroimaging techniques
Neuroimaging techniques provide valuable insights into the structural, functional, and molecular changes that occur in the brains of individuals with AD.These techniques aid in confirming the diagnosis, assessing disease severity, and differentiating AD from other causes of dementia.Neuroimaging techniques can be classified into structural and functional imaging methods.Structural imaging techniques include CT and structural Magnetic resonance imaging (sMRI) whereas positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional MRI (fMRI) are functional neuroimaging techniques (Varghese et al., 2013a).

Structural magnetic resonance imaging (sMRI)
MRI is a noninvasive imaging technique in which magnetic fields and radio waves are used to generate detailed images of the brain's structure (Vemuri and Jack, 2010).Brain atrophy is an inevitable consequence of neuronal loss.It directly correlates with the Braak neurofibrillary tangle (NFT) staging.sMRI allows for the visualization of anatomical changes in brain like brain atrophy (Vemuri et al., 2008).MRI studies show that the hippocampus and entorhinal cortex are atrophied in early AD followed by trophy in temporal, parietal and neocortices, thus useful for early diagnosis and identify the progression from mild cognitive impairment (MCI) to AD (Devanand et al., 2007).Diffusion tensor imaging (DTI) is an advanced MRI technique that can detect microstructural alterations like the integrity of the fiber tract which can be used as AD biomarker (Vasconcelos et al., 2009).MRI can also help identify other causes of cognitive impairment, such as vascular lesions or tumors, and is valuable for ruling out alternative diagnoses (Knight et al., 2016).MRI also helps to monitor disease progression, therapeutic effect of drugs (Jack et al., 2003;Hashimoto et al., 2005;Fox and Freeborough, 1997)

Computed tomography (CT)
CT reveals the features of late AD, like diffuse cerebral atrophy, Enlarged ventricles and cortical sulci.It is also used for differential diagnosis of dementia by ruling out other possible causes of dementia (Varghese et al., 2013b).Wu et al. studied intraorbital optic nerve CT density a grouo of AD patients and found that it corresponds to the AB deposition in the occipital cortex (Wu et al., 2022).Kavkova at all showed that contrast-enhanced micro-CT imaging can detect AB plaque deposition in brain in a preclinical study (Kavkova et al., 2021).

Positron emission tomography (PET)
PET imaging involves injecting a radioactive tracer into the bloodstream, which binds to specific molecular targets in the brain.This tracer emits positrons, and the subsequent detection of these particles allows the creation of three-dimensional images that reflect the distribution of the tracer (Crișan et al., 2022).PET imaging in AD can detect Aβ plaques and tau pathology, glucose utilization, neuroinflammation.It often employs radiotracers that are specific to proteins of interest. 11C-labelled Pittsburgh compound B ([ 11 C]PIB) binds to and detects Aβ plaques.18 F-labelled Aβ tracers are also available (Klunk et al., 2004).[ 18 F] Flortaucipir is approved by FDA for tau tracing (Xia et al., 2013).Translocator protein (TSPO) acts as a switch to microglial activation in response to various stressful stimuli.[ 11 C]PK11195 and other 11 C -labelled compounds are used as TSPO tracers (Cagnin et al., 2001).18 F-fluorodeoxyglucose (FDG) is a major radio tracer used in AD diagnosis.It identified hypometabolism in the AD brains.The sensitivity for AD diagnosis of FDG-PET is 78.7 % whereas that of PIB-PET is 93.5 % (Zhang et al., 2012)

Single-photon emission computed tomography (SPECT)
SPECT imaging utilizes radioactive tracers similar to PET imaging but with different tracer characteristics.SPECT measures the gamma radiation emitted by the tracer, providing information about cerebral blood flow and metabolic activity.In AD, SPECT scans can reveal reduced blood flow and functional abnormalities in specific brain regions, aiding in the diagnosis and evaluation of disease progression (Ferrando and Damian, 2021).Since glucose metabolism correlates with cerebral perfusion, FDG-PET or SPECT can be used to study them in AD.Technetium-99 m-hexamethyl propylene amine oxime (99 mTc-HMPAO) or Technetium-99 m-ethyl cysteinate diethylester (99mTc-ECD) are two radiolabelled tracers used to study cerebral perfusion using SPECT (Valotassiou et al., 2012(Valotassiou et al., , 2015)).Even though SPECT does not have as much specificity as FDG-PET, it is equally sensitive.It is also cost-effective and can be used an alternative to FDG-PET which is relatively costly (Valotassiou et al., 2020).

Functional MRI (fMRI)
fMRI is a novel techniques which measures various aspects of brain function.It's a non-invasive technique and can be useful in measuring brain functions in clinical trials.Various types of fMRI like BOLD fMRI, task fMRI can be used in AD diagnosis.BOLD fMRI measures the changes in blood oxygen level dependent (BOLD) MR signals that reflect neuronal activity.Task MRI studies the activation of various brain regions while performing different tasks (Cummings, 2019;Maji et al., 2010).The function of mediotemporal lobe is decreased in MCI patients (Andersen et al., 2021).
These neuroimaging techniques, in combination with clinical assessments and cognitive screening, enhance the accuracy of AD diagnosis.They enable clinicians to detect structural, functional, and molecular changes associated with AD pathology, aiding in early detection, differential diagnosis, and personalized treatment planning.However, it is important to note that these neuroimaging techniques are often used in conjunction with other diagnostic criteria, including clinical evaluations and biomarker assessments, to achieve a more comprehensive diagnosis of AD.

Biomarkers
Biomarkers are measurable indicators that can provide valuable information about the presence, progression, and underlying pathological processes of a disease.In AD, biomarkers play a crucial role in improving diagnostic accuracy, monitoring disease progression, and assessing treatment response.Biomarkers for AD can be categorized into different types, including cerebrospinal fluid (CSF) markers and blood-based biomarkers (Cummings, 2019) and are depicted in Fig. 4.

CSF markers
CSF is the fluid that surrounds the brain and spinal cord.Analysis of CSF biomarkers can provide insights into the biochemical changes associated with AD pathology (Maji et al., 2010).The most well-established CSF markers for AD include the following: 3.3.1.1.Aβ peptides.Aβ, which is the major component of amyloid plaques, has two important C-terminal variants, Aβ40 and Aβ42.Aβ40 is the predominant form; however, Aβ42 is more prone to oligomer and fibril formation in the extracellular space (Andersen et al., 2021).Aβ42 is the most commonly used marker, and its level is negatively correlated with the number of Aβ plaques in the brain.The lower the Aβ42 concentration is, the greater the number of Aβ plaques.In addition, the Aβ42/Aβ40 ratio is used to assess the risk of progression of AD and has good diagnostic performance (Hansson et al., 2019;Gunes et al., 2022).

Tau proteins.
Elevated levels of total tau in CSF were the first possible biomarker reported in 1993 (Klyucherev et al., 2022).The tau protein is essential for microtubule stabilization and is indicative of the intensity of neuronal damage.It is abnormally hyperphosphorylated (p-tau) in AD and is a major component of neurofibrillary tangles.Several p-tau biomarkers, including p-tau181, p-tau217, and p-tau231, have been found.These markers help in the differential diagnosis and staging of AD (Wattmo et al., 2020;Schraen-Maschke et al., 2008).
The combination of the Aβ42/Aβ40 ratio, total tau and p-tau is a more accurate single CSF marker for predicting AD pathology, as each component indicates the unique pathophysiologic features of Aβ42/ Aβ40 for amyloidosis, t-tau for neurodegeneration and p-tau for neurofibrillary tangles.These markers were found to be expressed several years before the disease started to develop (Dumurgier et al., 2015).McDade et al. reported changes in Aβ and p-tau levels in the CSF 25 and 10 years before disease onset in patients with dominantly inherited AD (McDade et al., 2018;Lleó et al., 2019).
Other emerging CSF markers include markers of microglial (TREM-2, TSPO) and astrocyte (YKL-40) activation (Bradburn et al., 2019).Even though CSF biomarkers provide information that is reflective of disease pathology, CSF analysis is highly invasive and places a burden on patients.Hence, research is more focused on identifying non-invasive or minimally invasive biomarkers that can be used for the early diagnosis of AD (Hansson et al., 2023b;Fortea et al., 2014).Several body fluids, such as blood, saliva, tears, and urine, are being explored to identify biomarkers.

Blood-based biomarkers
Blood-based biomarkers are particularly attractive for AD diagnosis and monitoring due to their non-invasive nature and ease of accessibility.Although blood-based biomarkers are still being actively researched and developed, several promising candidates have emerged (Varesi et al., 2022), including the following: 3.3.2.1.Plasma Aβ42/40 ratio.Similar to CSF biomarkers, plasma Aβ and tau protein levels have been investigated as potential biomarkers for AD.The reduction in the Aβ42/40 ratio in plasma is only 10-15 % when compared to the 50 % reduction in the CSF ratio.However, the utility of these methods is still under investigation, and additional research is needed to establish their diagnostic accuracy (Grothe et al., 2021).

Phosphorylated
Tau. Similar to CSF pTau levels, plasma pTau levels are also increased in AD patients.Phosphorylation at threonine 231 occurs in the early stage of AD, followed by increased phosphorylation at threonine 217, threonine 218 and threonine 205 (Leuzy et al., 2022).(NfL).Elevated levels of NfL, a protein released into the bloodstream following neuronal damage, have been associated with neurodegeneration and cognitive decline in AD (Sami Abed et al., 2023).Blood NfL levels were found to be 2.61 times greater in AD patients than in controls, but the difference in plasma NfL levels was not significant (Hampel et al., 2023). 3.3.2.4. Glial Fibrillary Acidic Protein (GFAP).Glial fibrillary acid protein III (GFAP) is an intermediate filament III protein found in astrocytes.Several studies have shown that plasma GFAP levels increase with AD progression.It is high in individuals with preclinical-AD and symptomatic-AD and can be used as an early biomarker (Forgrave et al., 2019).

Artificial intelligence in AD diagnosis
Artificial intelligence (AI) techniques, such as machine learning and deep learning algorithms, are being increasingly utilized in AD diagnosis and prediction.AI models can analyse complex datasets, including neuroimaging data, genetic information, and biomarker profiles, to identify patterns and make accurate predictions (Fabrizio et al., 2021a).Neuroimaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), generate vast amounts of data that can be analysed using artificial intelligence (AI) algorithms to detect structural and functional brain changes associated with AD.AI algorithms can also incorporate biomarker data, genetic information, and cognitive test results to develop predictive models for AD risk assessment (Mirkin and Albensi, 2023).The integration of AI in AD diagnosis holds great potential for improving accuracy and efficiency.AI models can aid clinicians in making more informed diagnostic decisions, facilitating early detection of AD, and enabling personalized treatment approaches based on individual risk profiles (Vora et al., 2023).However, while AI shows promise, further validation and standardization are needed before widespread clinical implementation of these AI-based diagnostic approaches in AD patients (Fabrizio et al., 2021b).
Overall, the use of biomarkers, cognitive testing, and AI techniques in AD diagnosis and assessment offers valuable tools for improving early detection, providing accurate diagnoses, and monitoring disease progression, ultimately facilitating timely interventions and personalized care for individuals with AD as represented in Fig. 5.

Therapeutic strategies for Alzheimer's disease
AD is a complex neurodegenerative disorder, and the development of effective therapeutic strategies is crucial for managing symptoms, slowing disease progression, and improving quality of life in individuals with AD.Therapeutic approaches for AD encompass both pharmacological and nonpharmacological interventions.In particular, nonpharmacological interventions play an essential role in comprehensive AD care.

Cholinesterase inhibitors
Cognitive dysfunctions in Alzheimer's disease are explained by the loss of cholinergic neurons Thus, acetylcholinesterase (AChE) inhibitors are used as interventions to prevent the hydrolysis of acetylcholine by the enzyme acetylcholinesterase, which leads to increased acetylcholine levels in the synaptic cleft and improved neurotransmission.By increasing acetylcholine levels, cholinesterase inhibitors help to improve cognitive function and alleviate some of the symptoms associated with AD, particularly in the early stages of the disease (Grossberg, 2003).Rivastigmine, donepezil and galantamine are prescribed for the treatment of mild to moderate AD.There are differences in the pharmacokinetic and pharmacodynamic properties of these three drugs, but they have no variable differences in their efficacy.Patient compliance with AChE inhibitors has been found to be good, although adverse events such as diarrhea, vomiting, nausea and anorexia can be observed (Kumar et al., 2015a).The new molecule Huperizine A, which is a natural alkaloid that has been found to be associated with neuroprotection and has an effect on APP metabolism, was found in the Chinese moss shrub Huperzia serrata.According to previous reports, M1 receptor agonists play a role in the metabolic processes of APP, which further affects tau phosphorylation, as the elimination of M1 AChRs results in an increase in the formation of Aβ oligomers.A few recent studies have highlighted the use of the nicotine metabolite "cotinine" for its cognitive strength, as it modulates α7 nicotinic AChRs (Vaz and Silvestre, 2020a).

N-Methyl-D-aspartate (NMDA) receptor antagonists
Synaptic plasticity, neuronal growth and differentiation, cognition, learning, and memory are all governed by glutamatergic neurons (Kumar et al., 2015b).Cholinergic neurons are most likely involved early in this disease, but glutamatergic system damage and excitotoxic degradation eventually occur late in disease progression.Memantine is a noncompetitive NMDA receptor antagonist approved by the FDA for the treatment of moderate to severe AD.In AD, the excitotoxic effect on neurons is exerted by the overexpression of NMDA receptors.The excitatory neurotoxic effect of glutamate is blocked by memantine, thereby protecting neurons from excitotoxicity and potentially slowing disease progression.The safety and efficacy of memantine have been found to be tolerable for treating moderate to severe AD.Memantine therapy enhances spatial learning in animal models of Alzheimer's disease and protects neurons against Aβ.It reduces apoptosis and free radical-mediated damage and restores synaptic degeneration (Hellweg et al., 2012).

Novel drug targets and disease-modifying therapies
Researchers are actively exploring novel drug targets and diseasemodifying therapies aimed at addressing the underlying pathology of AD.These approaches aim to target Aβ accumulation, tau pathology, neuroinflammation, and synaptic dysfunction, among other mechanisms (Parums, 2021).The various small molecules and monoclonal antibodies used in clinical trials are listed in Table 1.

Anti-amyloid therapies
Aβ deposition is considered to be the initial step in treating Alzheimer's disease.Aβ plaques are the major pathological hallmark of AD.These plaques are composed of Aβ peptides, which are generated by the abnormal cleavage of APP by β-secretase and γ-secretase (an enzymatic complex of presenilin, nicarstin, anterior pharynx defective I and presenilin enhancer 2).Several studies have shown that reducing Aβ accumulation significantly reduces neurotoxicity and could be a potential therapeutic strategy for managing AD (Aisen, 2005).Three strategies have been explored: 1) decreasing the production of Aβ using secretase inhibitors, 2) inhibiting Aβ aggregation and 3) administering Aβ immunotherapy to enhance Aβ clearance.

Secretase inhibitors.
Secretase inhibitors are aimed at targeting β-and γ-secretases, which cause abnormal cleavage of APP to form pathological Aβ peptides.β-secretase inhibitors and γ-secretase modulators, aim to reduce the production of Aβ peptides.Several BACE1 inhibitors were developed but were terminated in phase III clinical trials due to a lack of efficacy and deterioration of cognition.Recently, γ-secretase inhibitors such as semagacestat and avagacestat were found to cause deterioration of cognitive function and severe adverse effects such as transient bowel obstruction in patients with mild cognitive impairment (MCI) and mild to moderate AD (Coric et al., 2015;Doody et al., 2013;Kumar et al., 2018).This is probably due to the nonselective nature of these inhibitors for accessing APP, which results in the inhibition of notch signalling as well.The γ-secretase modulator Tarenflurbil was also discontinued in phase III clinical trials due to a lack of efficacy and adverse reactions (Green et al., 2009).(Ramanan and Day, 2023;Cummings, 2023).Aducanumab selectively targets 3-7 aminoacids at the N-terminal of Aβ aggregates and promotes their clearance.It has >10,000 times affinity to Aβ aggregates than Aβ monomers (Haddad et al., 2022;Decourt et al., 2021;Arndt et al., 2018).Lecanemab acts similarly to Aducanumab and has a higher binding affinity to large soluble Aβ aggregates (Tucker et al., 2015).Donanemab specifically targets pyroglutamate modified Aβ peptides in the Amyloid plaques and facilitates their clearance (Lowe et al., 2021).

Others.
Experimental evidence suggests that plasminogen activator inhibitor 1 (PA1) inhibitors reduce plasma and brain Aβ oligomer levels in transgenic animals (Kumar et al., 2015b).A previous study revealed that the peptide hormone somatostatin modulates Aβ oligomer clearance by activating neprilysin.Colostrinin (CLN), also known as a proline-rich polypeptide complex, was initially isolated from ovine colostrum.It significantly inhibits Aβ peptide aggregation and dissolves preformed fibrils (Kumar et al., 2015b).

Anti-tau therapies
The spread and accumulation of tau aggregates are associated with neuronal loss and clinical impairment in AD.In this sense, tau aggregation inhibition is a legitimate method for treating AD disease (Vaz and Silvestre, 2020b).Several approaches are being explored, including tau immunotherapies, small molecule inhibitors, and tau aggregation inhibitors, to prevent or reduce tau pathology.GSK3β is the kinase that is majorly involved in tau phosphorylation.Study reports show that the administration of valproate and lithium reduces the phosphorylation of tau by inhibiting GSK3β.Methylene blue (methylthioninium chloride) has also been shown to decrease tau interactions, improve electron transport, reduce oxidative stress, prevent mitochondrial damage, regulate autophagy, and inhibit acetylcholinesterase (Schelter et al., 2019;Hashmi et al., 2023a) and is in Phase 2 clinical trials.Some medications, such as astemizole and lansoprazole, have a high affinity for tau protein and indirectly inhibit the tau-tau interaction (Rojo et al., 2010).APNmAb005, JNJ-63733657 are two humanized monoclonal antibodies that target synaptic tau oligomers and microtubule-binding region of tau respectively, and are in clinical trials (Tau Antibody Therapy, 2024;Tai et al., 2023).OLX-07010 is a small molecule that inhibits tau self-association (Davidowitz et al., 2023).NIO752 is an antisense oligonucleotide to tau mRNA and prevents the translation of tau mRNA (Study Details, 2024a).Another small molecule LY3372689 indirectly inhibits tau aggregation by inbiting O-GlcNAcase enzyme and preventing O-GlcNAcylation (Kielbasa et al., 2021).

Anti-inflammatory therapies
Neuroinflammation plays a significant role in AD progression.Therapies targeting inflammatory processes in the brain, such as nonsteroidal anti-inflammatory drugs (NSAIDs), immune-modulating agents, and anti-inflammatory biologics, are being investigated for their potential to slow disease progression.NSAIDs are used to treat neuroinflammation associated with disease processes, and they have therapeutic effects through a range of pathways other than COX inhibition, such as maintaining Ca2 + homeostasis and targeting γ-secretase, Rho-GTPases, and PPAR.NSAIDs control several AD-related events, such as axon development, tau phosphorylation, and astrocyte motility, via the Rho-GTPases pathway (Choi et al., 2013;Nicolakakis et al., 2008).

Microglia modulators.
One of the characteristics of neuroinflammation is microglial activation.In the pathophysiology of AD, microglia interact with tau and Aβ (Kaur et al., 2019).Toll-like receptor (TLR), colony-stimulating factor-1 receptor (CSF1R), and receptor expressed on myeloid cells 2 (TREM2) are all activated by glial activation through the apolipoprotein E (ApoE) signalling pathway (Yu et al., 2021).TREM2 and ApoE mutations are regarded as major AD risk factors (Shi and Holtzman, 2018).In the early stages of AD, TREM2 impairment reduces plaque deposition, but in the later stages, it increases amyloid-β pathology (Jay et al., 2017).AL002 is a humanized monoclonal antibody that activates TREM2 and increases microglial proliferation and enhances amyloid and tau clearance.It is in clinical trial Phase 2 (Ward et al., 2021).Several TLR pathways, particularly the TLR4 and TLR2 pathways, react to the accumulation of Aβ and cause neuronal damage in the pathophysiology of AD.In animal models of AD, many TLR4 inhibitors, such as thymoquinone, ethyl pyruvate, and TAK-242, ameliorate cognitive abnormalities (Zhou et al., 2020).Regarding AD therapy, none of these medicines have advanced to clinical trials.

Insulin resistance management.
One of the features of Alzheimer's disease is impaired utilization of cerebral glucose with accelerated cognitive impairment (Kandimalla et al., 2017).Insulin resistance, insulin deficiency, and insulin-like growth factor 1 (IGF-1) deficiency are shortcomings in cerebral glucose utilization in human AD.Insulin resistance increases toxic Aβ levels, oxidative stress, and inflammation, and it also phosphorylates tau (De la Monte, 2017).The application of insulin therapy for the treatment of AD has been demonstrated with an intranasal device.Intranasal insulin therapy was shown to improve memory impairment in AD and MCI patients in a double-blind randomized controlled trial (RCT).For four months, the subjects received 40 IU of normal intranasal insulin daily (Craft et al., 2017).
Insulin production is stimulated by gut-derived hormones called incretins, which include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).To treat AD, a double-blind RCT of liraglutide was performed.Compared to that in the placebo group, the 12-month period of liraglutide treatment postponed cognitive decline in the treated group (Gejl et al., 2016).Patients with moderate AD are currently enrolled in a second phase II double-blind liraglutide RCT (Femminella et al., 2019).Semaglutide is being tested for its beneficial role in AD in clinical trials.Metformin was studied in nondiabetic, overweight (BMI above 25) MCI populations.Daily, the treatment group received 500-2000 mg of metformin.In comparison to the placebo group, the treated group indicated a decrease in recall memory deterioration following a 12-month intervention (Luchsinger et al., 2016).Metabolic pathways and anti-inflammatory processes are activated by peroxisome proliferator activator receptors (PPARs) (Iglesias et al., 2017).In an intracerebral streptozotocin (STZ) animal model of AD, neuroinflammation was alleviated by the hybrid PPAR-δ and PPAR-γ agonist T3D-959 (Reich et al., 2018).

Microbiome therapy
The gut microbiota framework influences brain function and the gutbrain connection by producing different neurotransmitters and neuromodulators (Megur et al., 2020).The composition of gut microbiota in altered in AD patients and is associated with changes in Aβ levels (Dissanayaka et al., 2024).Permeability to the blood brain barrier is increased due to the overproduction of LPS in the gut, which is a consequence of gut microbiota dysbiosis (Sochocka et al., 2019).In addition, gut dysbiosis also alters synaptic plasticity (Bairamian et al., 2022).The marine-derived oligosaccharide sodium oligomannate (GV-971) inhibits dysbiosis of the gut microbiota, modulates neuroinflammation, and disassembles Aβ aggregates (Wang et al., 2019).Improved cognition has been observed in patients with mild to moderate AD in phase III double-blind trials of sodium oligomannate (Wang et al., 2020).In November 2019, China approved the use of sodium oligomannate for the treatment of mild to moderate AD (Syed, 2020).

Neuroprotective and synaptic therapies
Various neuroprotective strategies aim to promote neuronal health and synaptic function.These include drugs targeting oxidative stress, mitochondrial dysfunction, and neurotrophic factors.Additionally, approaches focused on enhancing synaptic plasticity and neuronal communication are being explored.Several hormones, including testosterone, estrogen, and progesterone, are known to have neuroprotective effects.It is widely known that the level of these cytokines decreases with age, and luteinizing hormone (LH) promotes the illness process, but the concentration increases with age (Barron et al., 2006).Another recent study revealed that low-dose estrogen therapy reduces the risk of Alzheimer's disease.Similarly, the male hormone testosterone has been shown to significantly enhance cognition and quality of life in men, with both protective and therapeutic effects.The principal female hormone estrogen and the primary male hormone testosterone have several preventive effects on the brain that are related to the prevention of Alzheimer's disease, such as increasing neuron survival, decreasing Aβ buildup, and alleviating tau hyperphosphorylation (Yue et al., 2007;Lu et al., 2006).Various neuroprotective small molecules are clinical trials as shown in Table 1.ABBV-552 is a small molecule that modulates synaptic vesicle glycoprotein and improves synaptic plasticity and function in AD (Study Details, 2024b).ANAVEX2-73 or Blarcamesine is a sigma-R1 and muscarinin receptor agonist.It exerts neuroprotective effect by blocking hyperphosphorylation of tau and AB generation in AD (Study Details, 2024c).Guanfacine is a noradrenergic receptor agonist which is being tested as an add-on therapy in AD to enhance neuronal functioning.ATH-1017, a small molecule that activates hepatocyte growth factor receptor (HGFR) improves neurogenesis and enhances synaptic plasticity (Hua et al., 2022).SAGE-718 is an NMDA receptor activator is found to improve cognitive function in AD (Hill et al., 2022).Allopregnanolone, a GABA-A receptor modulator improves cognition by enhancing neurogenesis (Hernandez et al., 2020).L-Serine, a non-essential aminoacid is found to have neuroprotective effect in dementia and is in phase 2 clinical trials (Le Douce et al., 2020).

Immunotherapy and vaccination
Immunotherapy approaches involve targeting and removing abnormal protein aggregates in the brain, such as beta-amyloid plaques or tau tangles, which are characteristic of AD pathology.Monoclonal antibodies designed to bind to and clear these protein aggregates have been developed.These antibodies can either enhance the clearance of beta-amyloid or prevent its accumulation (Song et al., 2022;Sigurdsson, 2008).Some immunotherapeutic agents have shown promise in early clinical trials, demonstrating a reduction in the beta-amyloid burden and potential cognitive benefits and are discussed under above sections Vaccination strategies aim to stimulate the immune system to generate an immune response against beta-amyloid.Active immunization involves administering beta-amyloid fragments or proteins to trigger an immune response, while passive immunization utilizes preformed antibodies targeting beta-amyloid.Although initial clinical trials of vaccination approaches faced challenges due to adverse effects, ongoing research is focused on refining the techniques and exploring safer and more effective immunotherapeutic and vaccination strategies for AD (Agadjanyan et al., 2015).

Gene therapy
Gene therapy aims to replace deficient genes, remove/silence pathologic genes, and regulate abnormal genes.Based on their physiological functions, the molecular targets against which gene therapy is designed can be classified into four categories: 1) neurotrophins, such as NGF and BDNF; 2) enzymes involved in the degradation of Aβ, such as neprilysin, cathepsin B, and ECE; and 3) AB burden-associated factor (APOE), 4) proteins involved in Aβ generation (BACE1 and APP).Putative targets tested in several preclinical trials include NGF and BDNF (Nilsson et al., 2010).
Mark H Tuszynski initiated a clinical trial of AAV-mediated delivery of NGF as an intervention in AD.NGF therapy improved neuronal signalling in degenerating neurons from 2 patients.The delivery of gene therapy is equally important as the therapy itself.Sanjay Arora showed that the use of surface functionalized liposomes with mannose and cellpenetrating peptides enhanced the delivery of BDNF, enhanced its expression twofold and significantly reduced the amount of toxic Aβ peptides (Arora et al., 2022).
The development of AD is closely associated with cholesterol metabolism.ACAT plays an important role in cholesterol homeostasis, and its downregulation was found to be beneficial in AD (Lennon et al., 2021).Stephanie Murphy showed that knocking down Acyl-CoA-cholesterol acyltransferase 1 (Acat1) using AAVs decreased Aβ in an AD mouse model (Murphy et al., 2013).CYP46A1 encodes neuronal cholesterol 24-hydroxylase, which converts cholesterol to 24S-hydroxycholesterol, which is a more exportable form.Eloise Hudry et al. showed that increasing 24S-hydroxycholesterol levels via AAV-mediated delivery of CYP46A1 reduced the number of amyloid plaques in the hippocampus of amyloid precursor protein/presenilin 1 (APP/PS) mice (Hudry et al., 2010).

Stem cell therapy
Stem cell therapy involves the transplantation of stem cells or their derivatives into the brain to promote tissue repair and regeneration.Researchers are exploring the potential of stem cells to replace damaged neurons, enhance neuroplasticity, and modulate the inflammatory response associated with AD.Different types of stem cells, including embryonic stem cells, induced pluripotent stem cells (iPSCs), and adult stem cells, are being investigated for their therapeutic potential in AD (Sivandzade and Cucullo, 2021).Preclinical studies have shown promising results in animal models, but additional research is needed to optimize transplantation protocols, address safety concerns, and determine the long-term effects of stem cell therapy in human AD patients.The depleted neural circuitry could be repopulated and restored with the use of exogenous stem cells.In addition to removing aberrant protein degradation and neurofibrillary tangles, stem cell therapy can enhance cognition by promoting mitochondrial transport (Kim et al., 2020a).To gain a solid understanding of how stem cell therapy works in AD, various types of stem cells, such as 1) neural stem cells, 2) mesenchymal stem cells, 3) embryonic stem cells, and 4) induced pluripotent stem cells, have been explored (Hosseini et al., 2018).

Neural stem cells.
It is essential to establish experimental models that accurately depict a particular cellular phase of AD and to thoroughly analyse the cellular pathogenic pathways to develop treatments for AD (Cosacak et al., 2020).In 2018, McGinley et al. discovered that transplanting human neural stem cells (NSCs) improved the understanding of AD in a mouse model known as APP/PS1 (mice with mutant presenilin 1 and amyloid precursor protein).By targeting the fimbria fornix, transplantation considerably enhanced cognition in hippocampus-dependent memory tasks at 4 and 16 weeks posttransplantation (McGinley et al., 2018).In 2021, Apodaca et al. reported that extracellular vesicles formed from hNSCs can ameliorate the symptoms of AD.These authors injected hNSC-derived extracellular vesicles (EVs) into 5-month-old 5 × AD mice.In all age groups, NSC therapy significantly reduced the accumulation of dense core amyloid-β plaques, demonstrating neuroprotective effects for the treatment of AD neuropathologies (Apodaca et al., 2021).

Mesenchymal stem cells.
Considering their great accessibility and broad range of differentiation potential, mesenchymal stem cells (MSCs) are the type of stem cell that has been explored the most in stem cell therapy for AD (Guo et al., 2020).In recent years, a number of preclinical research trials have yielded noteworthy outcomes.Zaldivar et al. have reported that MSC-exos can improve cognitive impairment and boost neuronal plasticity.The subventricular zone was shown to have increased neurogenesis as a result of MSC-exos administration in Aβ 1-42 induced AD mice model (Reza-Zaldivar et al., 2019).In the hippocampus, ESC-derived mesenchymal stem cells markedly reduced Aβ-induced cell death and enhanced Aβ autophagolysosomal clearance in an AD mice model (Kim et al., 2020b).In a phase I clinical trial, Kim et al. performed an experiment in which human umbilical cord blood MSCs (hUCB-MSCs) were administered intracerebroventricularly to 9 patients with mild to moderate AD.Within 36 hours, all the adverse events were found to decrease, and their AD symptoms decreased (Kim et al., 2021).Taken together, these findings suggest that MSC therapy lowers neuroinflammation by eliminating amyloid-β and neurofibrillary tangle activity and causing abnormal degradation of proteins.MSC therapy controls acetylcholine levels, enhances brain cognition and supports blood-brain barrier integrity and autophagy-related restoration (Kim et al., 2020a). 4.2.8.3.Embryonic stem cells.Short-term therapeutic application of embryonic stem cell (ESC)-based therapy may not be feasible due to ethical and immunogenic constraints on the use of ESCs in AD treatment.Nonetheless, a small number of preclinical investigations have demonstrated advancements in the modelling of AD pathology utilizing ESCs (Kim et al., 2020a). 4.2.8.4.Induced pluripotent stem cells.Through the use of induced pluripotent stem cell (iPSC) technology, somatic cells are reprogrammed to become pluripotent stem cells, producing an ideal, medically accurate model while preserving the genetic identity of the donor.The ability of iPSCs to self-renew indefinitely and differentiate into diverse cell types offers hope for modelling and treating AD (Duan et al., 2023).Neural precursors produced from iPSCs improved memory and rectified synaptic defects in a mouse model of AD.The mouse hippocampus was stereotaxically injected with mouse iPSC-derived neural precursors (iPSC-NPCs).Mice with an iPSC-NPC transplant showed improved synaptic plasticity and less brain pathology associated with AD, including a decrease in amyloid and tangle deposits (Armijo et al., 2021).

Repurposing existing drugs
Repurposing existing drugs for AD treatment offers a cost-effective and time-efficient approach to identifying potential therapeutic options.Numerous drugs approved for other conditions have shown potential for repurposing in AD treatment based on their mechanisms of action.For example, drugs targeting inflammation, oxidative stress, or neurotransmitter systems have been explored for their potential benefits in AD.Repurposing existing drugs allows for expedited clinical trials, as safety profiles and dosing regimens are already established.However, careful evaluation is necessary to determine the efficacy and safety of repurposed drugs specifically for AD treatment.GLP-1 agonist, semaglutide, Lamivudine, valacyclovir, escitalopram, methylene blue, atorvastatin are being repurposed for AD and are in clinical trials.Semaglutide exerts multiple actions ultimately reducing neuroinflammation, improving cognition by enhancing glucose metabolism through GLP-1 receptors (Wang et al., 2023b).Lamivudine, a reverse transcriptase inhibitor decreases the RNA signatures of inflammation in the Hippocampus.Viral infections increase the risk of AD (Vallés-Saiz et al., 2023).Valacyclovir is used in HSV-1 seropositive AD patients in the early stage to improve cognition (Weidung et al., 2022).Escitalopram, piromelatine are beneficial in reducing agitation and sleep disturbances respectively in AD patients (Ehrhardt et al., 2019;Piromelatine for Mild Alzheimer's Disease ReCOGNITION Internet, 2024).Methylene blue reduces amyloid toxicity and also reduces oxidative stress by an unclear mechanism but plays role in improving cognition.Atherosclerosis is a risk factor for AD (Hashmi et al., 2023b).Atorvastatin, a HMG-CoA reductase inhibitor reduces LDL cholesterol and improves cognition in mild to moderate AD patients (Sparks et al., 2005).
These emerging therapeutic approaches hold significant potential for advancing AD treatment.However, these strategies are still in various stages of development, and additional research is needed to establish their safety, efficacy, and long-term effects.AD is a complex and multifactorial disease, and a combination of approaches, including pharmacological and nonpharmacological interventions, may be required for effective management and treatment.

Combination therapies
Given the complex nature of AD pathology, combination therapies that target multiple aspects of the disease are being investigated.Combinations of drugs with different mechanisms of action may have synergistic effects and provide greater therapeutic benefits.Combination therapy is another recent method recommended by certain authors.Given the complicated etiology of AD and the possible synergistic effects of Aβ and tau, combining these therapies may be more beneficial than monotherapy (Vaz and Silvestre, 2020b).Because of the complexity of the mechanisms involved in AD, compounds with multiple potential targets (multitarget-directed ligands) interact via different mechanisms and thus provide symptomatic and disease-modifying benefits; for example, compounds with dual AChE and BACE inhibition or AChEIs with antioxidant properties.Ladostigil is a multifunctional drug that works by inhibiting monoamine oxidase (MAO)-A and B and thereby increasing cholinergic neurotransmission.It slows the production of amyloidogenic APP.It has neuroprotective and neurorestorative properties and reduces apoptosis.Ladostigil, a prospective treatment for Alzheimer's dementia and Lewy body disease, combines the neuroprotective benefits of rasagiline, a selective MAO-B inhibitor, with the ChE-inhibiting action of rivastigmine as a single molecule (Weinreb et al., 2008).
It is important to note that while there have been advancements in these areas, many of these novel drug targets and disease-modifying therapies are still under investigation in clinical trials and require further research and validation before they can be widely implemented in clinical practice.
In addition to pharmacological interventions, non-pharmacological approaches such as cognitive stimulation, physical exercise, and lifestyle modifications (e.g., a healthy diet, social engagement) are also recognized as important components of comprehensive AD management.These interventions can help improve cognitive function, promote overall well-being, and potentially delay cognitive decline in individuals with AD.

Nonpharmacological interventions
Nonpharmacological interventions for AD focus on enhancing cognitive function, promoting overall well-being, and managing behavioral and psychological symptoms of the disease.These interventions have shown promise in improving cognitive abilities, delaying functional decline, and improving the quality of life for individuals with AD.Two key nonpharmacological interventions for AD include cognitive stimulation and rehabilitation, as well as physical exercise and lifestyle modifications.

Deep brain stimulation and vagal nerve stimulation
Deep brain stimulation (DBS) is a surgical technique used to stimulate a region of brain specific to a given disease through electrodes implanted in that region by a pulse generator.It is used in various neurological diseases like essential tremors, Parkinson's disease (PD) (Fariba and Gupta, 2023).Stimulation of entorhinal cortex or fornix modulate cognitive functions.In AD, DBS of cholinergic nucleus of meynert was explored in phase I clinical trials.DBS has shown to decrease cognitive decline in mild to moderate AD (Fontaine and Santucci, 2021;Ríos et al., 2022).
Vagal nerve stimulation (VNS) is used to stimulate the vagus nerve with a pulse generator and lead wire to stabilize irregular electrical activity in brain.In AD, vagal nerve stimulation increases catecholamine release in hippocampus and neocortex.This procedure enhances synaptic plasticity and reduce neuroinflammation.It also enhances cognition in AD patients (Merrill et al., 2006;Vargas-Caballero et al., 2022).Transcutaneous VNS is a non-invasive technique which can modulate gut-brain-microbiota axis and decrease the progression of AD (Yan et al., 2024).

Cognitive stimulation and rehabilitation
Neuronal plasticity forms the basis of cognitive enhancement therapy for AD.Neuromodulatory functioning is one of the systems in the brain that gradually decreases with age.However, the capacity of the nervous system to modify its structural organization in response to external stimuli is a relatively discovery (Mahncke et al., 2006).Cognitive stimulation and rehabilitation programs aim to engage individuals with AD in activities that stimulate cognitive function, promote social interaction, and maintain overall cognitive abilities.These interventions involve structured and individualized activities that target various cognitive domains, such as memory, attention, language, and executive function.Cognitive training, cognitive stimulation, and individualized cognitive rehabilitation are the three basic categories of cognitive-oriented therapies.In recent years, these therapies have drawn increased amounts of attention as potential preventive measures or ways to improve AD treatment (Bahar-Fuchs et al., 2013).
The theories and data in the Cochrane Review of Reality Orientation database serve as the foundation for the CST model (McAulay and Streater, 2020).To improve the overall cognitive and social performance of an individual, cognitive stimulation often refers to a broad range of group activities and conversations, such as recollection therapy and reality orientation treatment.Since the method was found to be at least as efficient as ChEIs at reducing cognitive decline in patients with mild-to-moderate dementia, the 2006 National Institute of Clinical Excellence (NICE) guideline suggested using it as a routine practice (Spector et al., 2003).Additionally, CST improves memory, orientation, language comprehension, coping and adaptation abilities; facilitates communication; ensures sustainability; lowers anxiety and sadness; and ultimately improves the quality of life (QoL) of individuals with dementia (Lok et al., 2020).Reminiscence therapy is a nonspecific stimulation treatment that helps people with dementia recall things from their past lives, either verbally or nonverbally, alone or in a group, by using all the senses as memory triggers, such as audiovisual materials (Stinson, 2009).The positive elements of reality orientation therapy are incorporated into CST.In both group and individual settings, this therapy involves repeated stimulation to person, time and place while providing patients with continuous memory and orientation information related to personal issues and the living environment.The person is encouraged to talk about current affairs, hobbies or everyday activities throughout each session (Spector et al., 2010).A randomized controlled trial (RCT) revealed that mindfulness stimulation was superior to muscle relaxation and comparable to cognitive stimulation in maintaining cognitive function in patients with AD receiving donepezil.As a result, mindfulness stimulation may be utilized as a nonpharmacological treatment for AD (Quintana-Hernandez et al., 2016).Another RCT revealed that while AChEIs alone did not enhance cognitive outcomes, a 6-month reality orientation in combination with AChEIs did (Camargo et al., 2015).
A personalized intervention program that targets certain functional issues and establishes attainable goals to support patients and their families in their everyday lives is known as cognitive rehabilitation.Individualized cognitive rehabilitation significantly reduced functional disability and delayed institutionalization in a parallel-group experiment comparing cognitive training, reminiscence therapy and individualized cognitive rehabilitation to routine care (Amieva et al., 2016).Furthermore, rather than improving cognitive skills, manual-guided cognitive rehabilitation intervention outperformed standardized cognitive training in noncognitive areas, including quality of life (Brueggen et al., 2017).

Physical exercise and lifestyle modifications
Regular physical activity has been shown to have many positive impacts on several systems of the body, such as the immune, digestive, cardiovascular and central nervous systems (Ruegsegger and Booth, 2018).Ageing plays crucial role in the onset and progression of AD (Liu et al., 2024).Physical activity has been demonstrated to improve memory and cognitive function; reverse the effects of ageing by reducing stress, anxiety and depression; and enhance brain health (Ross et al., 2023).Recent research has reported how exercise protects against dementia and cognitive decline in a number of populations.For example, a prospective cohort study conducted in Japan revealed that males who engaged in more moderate-to-intense physical exercise had a lower risk of developing dementia (Ihira et al., 2022).Exercise has been shown to improve cognitive ability, preserve memory and prevent neurodegenerative disorders in preclinical research.In AD model mice, regular exercise boosted synaptic activity and the expression of the glucose transporters GLUT1 and GLUT3 while lowering the levels of phosphorylated tau and amyloid-β (Pang et al., 2019).Short-term resistance training enhances cognitive function, decreases brain deposits of amyloid-β and hyperphosphorylated tau, and suppresses the production of the neuroinflammatory markers IL-1β and tumor necrosis factor alpha (TNF-α) (Liu et al., 2020b).Using human gene expression databases, bioinformatic techniques have been crucial for identifying significant biological and molecular pathways linked to cerebral physical activity.The expression of genes in the hippocampal region is inversely correlated with that in AD and aging individuals (Berchtold et al., 2019).The synthesis of mitochondrial energy and synaptic function were shown to be associated with these genes.Similarly, in the hippocampal regions of cognitively intact people, high levels of physical exercise promoted the expression of genes linked to neurogenesis (Sanfilippo et al., 2021).Research has shown that in cognitively intact individuals, physical activity causes significant transcriptional alterations in the hippocampus.Physical activity-induced gene expression patterns were shown to be inversely correlated with those of neurodegenerative disorders, such as AD (Santiago et al., 2022).
In triple transgenic AD mice (3xTg-AD), treadmill running reduced the amount of amyloid β and neuroinflammatory markers and enhanced mitochondrial function in the hippocampal and cerebral cortex (Kim et al., 2019), while extended voluntary wheel running decreased extracellular amyloid β buildup, enhanced dendritic spines, and enhanced spatial memory function (Xu et al., 2022).In the hippocampus of 5xFAD mice, sustained voluntary running enhanced astrocytic brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) staining and ameliorated cognitive impairment (Belaya et al., 2020).In APP/PS1 AD mice, exercise reduces neuroinflammation and cognitive impairment by upregulating miR-129-5p (Li et al., 2020).Enhancing the production of irisin, a myokine generated by exercise, restored memory and synaptic plasticity in APP/PS1 AD mice (Gronwald et al., 2019).
Sleep disturbances are linked to cognitive and neuropsychiatric issues and are prevalent in individuals with neurodegenerative diseases.Dysregulation of the sleep-wake cycle encourages the buildup of tau, synuclein and amyloid-β in the interstitial fluid of mice and human CSF (Holth et al., 2019).Remarkably, in human CSF, sleep deprivation elevates amyloid-β levels by 30 % and tau levels by 50 % (Lucey et al., 2018).Research using animal models has shown that prolonged sleep deprivation accelerates the spread of tau disease.In a long-term study utilizing information from 7959 participants and a 25-year follow-up, it was found that sleeping for less than 6 hours at 50, 60 and 70 years of age was linked to a 30 % higher risk of dementia (Sabia et al., 2021).
Smoking is a risk factor for dementia and Alzheimer's disease, and approximately 14 % of all cases of AD are likely related to this factor based on the global prevalence of smokers (27.4 %).Long-term alcohol abuse can cause cognitive issues ranging from Wernicke-Korsakoff syndrome to mild forms of memory and executive loss.Several nutrients and food items, including omega-3 polyunsaturated fatty acids and vitamins such as vitamin D, complex B vitamins (B6, B12, and folate), and antioxidants (A, C, and E), have been studied and found to be related to a decreased risk of cognitive impairment, dementia, and AD.Regular consumption of fish, fruits, vegetables, and nuts has been demonstrated to have a protective impact (Kivipelto et al., 2018).

Complex pathology
The pathogenesis of AD involves multiple intertwined mechanisms, including the accumulation of amyloid-beta plaques, neurofibrillary tangles, neuroinflammation, synaptic dysfunction, and neuronal loss.The complex and multifactorial nature of AD poses challenges in developing therapies that can effectively target and modulate these diverse pathological processes (Ismail et al., 2020).

Limited understanding of disease mechanisms
Although significant progress has been made in understanding AD pathology, many aspects of the disease mechanisms remain unclear.There are ongoing debates and uncertainties regarding the primary causative factors and the precise sequence of events leading to neurodegeneration.This limited understanding hinders the development of targeted and disease-modifying therapies (Nichols et al., 2022).

Difficulty in early diagnosis
AD is often diagnosed at later stages when significant neurodegeneration has already occurred.Delayed diagnosis poses challenges in therapeutic development, as interventions aimed at preserving cognitive function and slowing disease progression may be less effective once extensive neuronal damage has occurred.Improving early and accurate diagnostic methods is crucial for identifying individuals at the earliest stages of AD, facilitating early interventions and clinical trials (Deture and Dickson, 2019).

Blood -Brain Barrier (BBB) and drug delivery
The BBB presents a challenge for delivering therapeutic agents to the brain.The BBB restricts the passage of molecules, including potential therapeutic compounds, from the bloodstream to the brain.The development of strategies to overcome the BBB and efficiently deliver drugs to the brain is a significant challenge in the field of AD therapeutics (Wu et al., 2023).

Heterogeneity of the disease
AD is a heterogeneous disease that presents with varying clinical symptoms, progression rates, and underlying molecular profiles This heterogeneity complicates therapeutic development, as interventions that may be effective for certain subtypes or stages of AD may not yield the same results as others.Precision medicine approaches, focusing on identifying specific subtypes or biomarker profiles, may help overcome this challenge (Duara and Barker, 2022).

Ethical considerations
AD research and therapeutic development also face ethical challenges.Clinical trials require the involvement of vulnerable people, such as individuals with cognitive impairments, and ethical considerations regarding informed consent, risk-benefit assessments, and participant autonomy need to be carefully addressed (Gordon, 2024).
Addressing these challenges requires continued research efforts, collaboration among scientists and clinicians, and innovative approaches in therapeutic development.Advancements in understanding disease mechanisms, early detection methods, targeted drug delivery systems, and the exploration of combination therapies and novel treatment modalities hold promise for overcoming these challenges and advancing AD therapeutics.

Ethical considerations and patient perspectives in Alzheimer's disease
Ethical considerations play a crucial role in the care and treatment of individuals with Alzheimer's disease (AD) and their families.It involves ensuring the autonomy, dignity, and well-being of the affected individuals while navigating the complex challenges posed by the disease.Several ethical issues arise throughout the disease course, and addressing these concerns is essential for providing patient-centered care (Chiong et al., 2021).Three important areas of ethical consideration in AD:

Informed consent and privacy
Informed consent is a fundamental ethical principle that respects an individual's right to make decisions about her own healthcare.In the context of AD, obtaining informed consent can be challenging due to progressive cognitive decline and loss of decision-making capacity.Healthcare professionals and caregivers must work closely with individuals with AD and their families to ensure that their preferences, values, and wishes are respected and incorporated into care decisions.Safeguarding privacy and confidentiality is also crucial, especially in regard to sharing sensitive health information and managing research participation (Shah et al., 2023).

Caregiver support and quality of life
AD not only affects the individuals diagnosed but also has a significant impact on their caregivers and families.Ethical considerations include ensuring adequate support, resources, and services for caregivers to prevent burnout and maintain their own well-being.Respecting their autonomy, providing education and training, and offering respite care are important aspects of ethical caregiving.Additionally, addressing the quality of life for individuals with AD involves promoting dignity, optimizing comfort, and incorporating their preferences into care decisions, even as the disease progresses (Reiss et al., 2023).

End-of-life decision making
End-of-life decision making in ADs raises ethical dilemmas, particularly regarding the use of advance directives and determining the goals of care.Individuals with AD may express their wishes regarding lifesustaining treatments, artificial nutrition and hydration, and other interventions while still having decision-making capacity.Healthcare professionals and families must honour these preferences and engage in ongoing discussions to ensure that care aligns with the individual's values.Ethical considerations also include providing appropriate palliative care and support for a dignified and comfortable end-of-life experience.It is important to acknowledge the diversity of perspectives and cultural values when addressing ethical considerations in AD.Engaging in shared decision making, promoting open communication, and respecting the autonomy and dignity of individuals with AD and their families are essential ethical principles in providing compassionate and person-centered care (McDarby et al., 2023;Rosen, 2024).

Conclusion
Alzheimer's Diseases is the most common and complex disease affecting millions of elderly population, debilitating them for rest of their lives due to memory impairment followed by motor impairment during the years expected to spend peacefully.It's a complex interplay of various pathological mechanisms and is characterised by the deposition of Aβ plaques and neurofibrillary tangles in several brain regions and cortical atrophy.Though there is significant development in understanding the disease mechanisms, challenges still exist in disease diagnosis and treatment.Research is focused on identifying novel biomarkers in various biological specimen to detect the disease in its early stages.Apart from the existing treatment options, other novel therapeutics both pharmacological and non-pharmacological are being developed to manage AD effectively.Immunotherapeutics that target Aβ plaques, gene therapy aimed at correcting the culprit gene, stem cell therapy intended to restore the neuronal functions show promising results as disease modifying therapies.However, several challenges like disease heterogeneity, drug delivery to brain and ethical considerations exist.Extensive research and use of technological tools like machine learning and artificial intelligence may help in overcoming the challenges.
Clinical assessment and cognitive screening are often the initial steps in evaluating individuals suspected of having AD.These steps involve gathering a comprehensive medical history, conducting physical examinations, and assessing cognitive function through various standardized tests.Some commonly used cognitive screening tools include the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) (Porsteinsson et al., 2021).
3.1.1.Cognitive and neuropsychological testing Cognitive and neuropsychological tests are essential components of AD diagnosis.These tests assess various cognitive domains, including memory, attention, language, and executive function.Commonly used cognitive tests for AD include the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog)

Fig. 3 .
Fig. 3.A stepwise approach in the management of AD.The steps involved in AD management can be divided into Identification, Evaluation, Diagnosis and Management.Various tests/tools involved in each step are shown under the respective column.Initially, cognitive changes and memory impairment is identified by the patient himself or his/her caretaker at home.In the healthcare setting, the physician evaluates the patient, his/her family history, medication status and refers him to the speciality setting.Neurocognitive tests such as MMSE, Mini-Cog, M-Cog, AD8, Imaging techniques such as MRI, Amyloid PET, Biomarkers like Aβ42/Aβ40, p-tau, various blood tests are used in diagnosis of AD.Upon diagnosis, both pharmacological and non-pharmacological treatment are used for the management of AD.

Fig. 4 .
Fig.4.Blood and CSF biomarkers for Alzheimer's Disease (AD).Among the biomarkers for AD, CSF biomarkers are the most widely used.The combination of Aβ42/Aβ40, total tau and p-tau is more accurate for predicting AD pathology.Other emerging CSF biomarkers include TREM2, TSPO, YKL-40.Since CSF collection is highly invasive, blood biomarkers are preferred and are in developmental stage.Aβ42/Aβ40, p-tau, NFL protein, GFAP are being studied as blood biomarkers for AD.

Fig. 5 .
Fig. 5. Integrating AI in Alzheimer's Disease (AD) Diagnosis and Treatment.The flowchart outlines the application of machine learning and deep learning techniques to diverse data types-including biological specimens, neuroimages, public databanks, cognitive tests, and genetic/omics data-to improve classification and clustering of disease patterns.This AI-driven approach utilizes data from CSF and blood biomarkers, patient subtypes, and disease progression to develop AIbased diagnostic tests, such as speech and neurocognitive tests, and AI-based image interpretation, culminating in enhanced AD diagnosis and treatment strategies.

Table 1
Therapeutic interventions that are active in clinical trials for the management of AD.