Int J Curr Pharm Res, Vol 17, Issue 1, 1-10Review Article

ALZHEIMER'S DISEASE: COMPREHENSIVE INSIGHTS INTO RISK FACTORS, BIOMARKERS, AND ADVANCED TREATMENT APPROACHES

SURESH JANADRI*, SHREELAXMI DADMI, MANJUNATHA P. MUDAGAL, UDAY RAJ SHARMA, SURENDRA VADA, THIRIVEEDI HARIBABU

Department of Pharmacology, Acharya and BM Reddy College of Pharmacy, Acharya Dr. Sarvepalli Radhakrishna Road, Achit Nagar (Post), Soladevanahalli, Bengaluru, India
*Corresponding author: Suresh Janadri; *Email: sureshjanadri@gmail.com

Received: 25 Oct 2024, Revised and Accepted: 09 Dec 2024

ABSTRACT

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder primarily affecting individuals over 60. It is a multifactorial disease driven by both modifiable factors, such as lifestyle, diet, and prior health conditions, as well as non-modifiable factors, like age, genetics, and family history. The key pathological features of AD include the buildup of amyloid β plaques and neurofibrillary tangles resulting from hyperphosphorylated tau proteins in the brain. Biomarkers like amyloid β and tau protein levels in cerebrospinal fluid (CSF) and blood are essential for diagnosing and tracking AD progression. Current research focuses on developing drugs targeting multiple aspects of AD pathology, including inflammation, oxidative stress, synaptic dysfunction, and protein accumulation. These treatments aim to slow cognitive decline and neuronal damage. Given the complexity of AD, multi-targeted therapeutic approaches are being explored to enhance treatment efficacy. This review provides an overview of AD risk factors, key biomarkers used for diagnosis, and the latest advances in clinical drug development.

Keywords: Alzheimer’s disease, Diabetes, Amyloid beta, Tau therapy, Anti-amyloid therapy, Apolipoprotein E

© 2025 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijcpr.2025v17i1.6039 Journal homepage: https://innovareacademics.in/journals/index.php/ijcpr

INTRODUCTION

Neurodegenerative disorders such as Alzheimer's disease (AD) an irreversible conditions and cause atrophies in the cerebral cortex of the brain [1]. Alzheimer's disease is a complex disorder characterized by central nervous system neurodegeneration with significant involvement of the cholinergic system, resulting in gradual cognitive decline and dementia [2]. Recent discoveries, such as the detection of amyloid-beta (Aβ), tumor necrosis factors (TNFs), and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein are potential causes of Alzheimer's disease development. Multi-targeted compounds that inhibit cholinesterases while also interfering with Aβ-aggregation and/or tau protein neuroinflammation may be useful in the treatment of Alzheimer's disease [3, 4]. Alzheimer's disease (AD) is marked by intracellular neurofibrillary tangles containing tau and extracellular plaques containing amyloid β (Aβ) [5], which results in a gradual decline in mental behavioral, functional, as well as cognitive capabilities [6, 7].

According to the World Alzheimer Report 2022, more than 55 million people worldwide have AD or associated disorders, with that fig. expected to rise to 82 million by 2030 and 138 million by 2050 [8]. AD ranks as the fourth most common cause of death for older adults [9]. The number of Alzheimer's deaths in the US increased by 54.5% in 2014 to 25.4 deaths per 100,000 people, up from 16.5 in 1999. The percentage of Alzheimer's victims who passed away in hospitals dropped from 14.7% to 6.6%, whereas the percentage of victims who passed away at home rose from 13.9% to 24.9% [10]. According to recent studies conducted in 2022, the incidence cases of AD has increased to 7.24 million globally [11].

Various modifiable and non-modifiable factors are responsible for causing sporadic forms of AD [12]. Modifiable factors like Environmental influences, which can include lifestyle, diet, education, and exposure to various health factors, are also thought to play a role in the development of Alzheimer's disease. Non-modifiable factors like genetic influences i. e., mutations in specific genes (e. g., APP, PSEN1, PSEN2), gender, entity, and family histories may impact the risk of developing AD [13].

Biomarkers are measurable indicators of a biological state or condition. They can be molecules, genes, proteins, or other substances that are present in the body and can be detected and measured. Since there are no distinct symptoms or indicators for AD, biomarkers may help with early diagnosis, which is especially challenging. More importantly, they may help to identify people with preclinical Alzheimer's disease (those with AD neuropathology but no clinical symptoms) [14]. In addition to helping with disease diagnosis, biomarkers may also be useful for tracking the course of a disease and its reaction to therapy. Biomarkers for Alzheimer’s disease also can be evaluated from cerebrospinal fluid and blood serum [15].

The increasing prevalence of these diseases suggests that current treatment strategies are insufficient to effectively manage and prevent them [16]. As a result, novel treatment strategies are being investigated to cure these diseases by targeting the underlying mechanisms at the molecular level [17]. Novel therapies like gene therapy, stem cell therapy and targeting various mechanisms like inflammation, cell death, oxidative stress, amyloid beta (Aβ) peptide, tau protein, apolipoprotein E 4 (APOE4) effects, lipids and lipoprotein receptors, neurotransmitter receptors, neurogenesis, proteostasis, bioenergetics and metabolism, vascular factors and/or treating the diseases induce the Alzheimer’s disease [18].

Causative factors

Age

Alzheimer’s disease (AD) is the most common cause of dementia, affecting up to 20% of individuals>80 years of age [19]. A major meta-analysis discovered that brain amyloidosis is substantially linked with age; aging causes alterations in the transcriptome, resulting in two kinds of activated microglia (ARMs and IRMs) as well as AB deposition and that the curve showing the increase in amyloid with age corresponds to the increase in dementia prevalence with age [20, 21]. Both the entorhinal cortex (EC) and the hippocampus are sensitive to both normal aging and early Alzheimer's disease pathology. There is evidence that the anterolateral entorhinal cortex (AlEC) malfunctions in both healthy aging and preclinical Alzheimer's disease Tauopathy is associated with cognitive impairment in AD [22]. As a result, tauopathy affects the entire EC and spreads to the medial temporal lobe, including the hippocampus. The development of tauopathy across the EC, including the pmEC, could compromise grid-cell activity and contribute to pure path integration (PPI) impairments in the early stages of Alzheimer's disease [23].

Fig. 1: Classification of risk factors related to alzheimer’s diseases

Alzheimer's disease risk is influenced by both non-modifiable and modifiable factors. Non-modifiable factors include age, family history, specific genetic variations such as those in the APOE gene, and gender, with women being more susceptible. Modifiable factors that can be managed to reduce the risk include hypertension, obesity, poor dietary habits, and diabetes mellitus. Lifestyle choices, such as physical inactivity, smoking, and excessive alcohol consumption, also play a significant role. Additionally, exposure to heavy metals like lead and mercury has been linked to an increased risk of Alzheimer's disease.

Social isolation

Loneliness affects 12% to 40% of persons with age 65 and more, making them especially vulnerable to social isolation. Seniors who express feelings of loneliness are more likely to experience cognitive decline, memory impairment, and/or dementia [24]. Social Isolation and living alone may develop the possibility of getting Alzheimer's disease and dementia twice the risk [25]. Loneliness was one of the psychopathological aspects attributed to MCI [26]. Different cognitive domains are affected by social engagement at different times. Increased social interaction enhances speed, perceptual organization, and episodic memory but not working memory. While a larger social network may not always result in better mental efficiency, it may decrease specific cognitive domains, such as perceptual speed [27]. The categorization of risk factors associated with Alzheimer’s disease as depicted in fig. 1.

Disease factors

Diabetes

According to a recent meta-analysis, the risk of developing AD is 50% higher in T2D (Type 2 diabetes) patients over age-matched non-diabetic individuals [28]. T2D and Alzheimer's disease are metabolic diseases having similar characteristics in mitochondrial dysfunction and oxidative stress, impaired brain glucose metabolism, inflammation, insulin resistance (IR), advanced glycation end products formation, overproduction and aggregation of amyloid beta (Aβ), and tau protein hyper phosphorylation and deposition. This has led to the concept of "Type 3 diabetes" or "diabetes of the brain" [29, 30]. Glucose concentration will be higher in the brain tissue of Alzheimer’s patients in comparison to the age-matched non-diabetic patients [31]. This complication can lead to the condition called Diabetic encephalopathy [32].

Hypertension

A person who had hypertension in midlife had a higher risk of Alzheimer's disease than a person who was normotensive in midlife. Stroke is thought to act as a mediator in the relationship between high blood pressure (BP), cognitive decline and vascular dementia [33]. Angiotensin II directly causes brain oxidative stress and BBB disruption in hypertensive patient [34]. Hypertension is linked with Alzheimer's disease from mainly intracranial and extracranial mechanisms. Intracranial mechanisms-cerebral ischemia (41.3%), cerebral hemorrhage (19-63%), brain atrophy. Extracranial mechanisms-chronic kidney disease (40%), Extra-large vessels, cardiac disease (28%).

A meta-analysis of population-based studies reported that prevalence of 41.3% (95%CI 29.6–53.1%) in hospital-based studies of stroke-induced dementia [35]. the higher blood pressure in the brain causes acute ischemic stroke and transient ischemic attack, which is characterized by the blockage of the blood vessels in the brain, thereby the insufficient blood supply to the brain cells that further leads to vascular dementia i. e. Post-stroke cognitive impairment (PSCI) [36]. Hypertension is a preventable risk factor for brain atrophy, which is one of the leading causes of neurodegenerative diseases. And elevated levels of neurofibrillary tangles and neuritic plaques in the hippocampus and neocortex [37, 33]. Oxidative stress-induced inflammation leads to the damage of the blood-brain barrier along with the microglia activation. Thereby impairment of glymphatic clearance pathway for amyloid clearance [38]. There is a 19-63% risk of having cognitive impairment in patients with intracerebral hemorrhage [39]. Patients with chronic kidney disease (CKD) are more likely to develop neurological decline or dementia. The angiotensin AT1 receptor contributes to the higher exposure of AD mice to CKD-induced cognitive impairment by blood-brain barrier (BBB) disruption or oxidative stress [40]. RAS-activated M1 microglia release proinflammatory signals that exacerbate cognitive dysfunction in the cortex, hippocampus, basal ganglia, and neuronal death [41]. There is a correlation between large vessel atherosclerosis and a higher risk of both ischemic stroke and Alzheimer's [42]. There is 28% relative odds increase in dementia risk in those with heart failure. Hypertension is a major risk factor for atrial fibrillation, which is linked to an increased risk of cognitive impairment. Atrial fibrillation was linked to a 50% increase in the relative odds of dementia or cognitive impairment in a meta-analysis of 43 cohort studies [43].

Obesity

Numerous factors, including oxidative stress, inflammation, dyslipidemia, insulin resistance, and metabolic syndrome, have been linked between neurodegenerative diseases and obesity [44]. Having a high-fat diet AD [45], and disruption in the mitogen-activated protein (p38 MAPK) leads to Aβ aggregation and tau phosphorylation [46] Higher BMI at middle age and late ages 70, 75, and 79 years have a higher risk of occurrence of dementia [47]. Cognitive function impairment in obesity-induced AD rats was triggered by disruptions in the antioxidant defense system, specifically high malondialdehyde (MDA) and low total antioxidant capacity (TAC) levels in the brain [48]. Improper adipokine regulation and long-chain fatty acid (C16, C18) deposition in brain tissue alters the vascular functions in the brain, making insulin resistance and also triggering astrocyte pro-inflammatory cascade that makes Aβ accumulation and tau phosphorylation [49, 50].

AIDS

The human immunodeficiency virus (HIV) can pass through the blood-brain barrier, causing neuronal dysfunction and cognitive decline. HIV patients may develop Aβ plaques or neurofibrillary tangles, suggesting a link between the two diseases. The virus may modulate Aβ and tau pathways, leading to neuroinflammation in both conditions [51]. The steps involved in causing Alzheimer’s disease by various disease conditions have been mentioned in fig. 2.

Fig. 2: Steps involved in causing Alzheimer’s diseases by various disease conditions

The fig. illustrates how various factors contribute to Alzheimer's disease. Cardiovascular disease and lead to hypoxia and neuroinflammation, increasing amyloid-beta (Aβ) levels and tau hyperphosphorylation, resulting in plaque formation and neurofibrillary tangles. Hypertension causes cerebrovascular damage and brain hypo perfusion, while obesity and type 2 diabetes impair brain metabolism, increasing Aβ and oxidative stress. Chronic kidney disease and atherosclerosis exacerbate hypoxia and vascular issues. These interconnected factors collectively contribute to the pathological features of Alzheimer's disease, including plaque formation, neuroinflammation, and neuronal damage.

Heavy metals

Aluminum exposure is believed to cause neurotoxicity in the central nervous system by damaging mitochondria, leading to excessive production of reactive oxygen species (ROS), DNA damage, and ultimately apoptotic cell death. This process is associated with a decrease in enzymatic activities, increased misfolded proteins, and oxidative stress [52]. Aluminum has been shown to bind negatively charged brain phospholipids with great affinity. These phospholipids contain polyunsaturated fatty acids that are readily attacked by reactive oxygen species (ROS) [53].

Lead acts as a neurotoxicant, causing non-specific brain disruption through oxidative stress and subsequent mitochondrial damage. In addition, it interferes with the essential metals' homeostatic levels and the metal signaling pathways that lead to neuroinflammation. It has been demonstrated that lead treatment causes deficits in learning and memory in addition to increasing levels of tau protein, amyloid β protein precursor, and amyloid β in the brain [54].

Cadmium, a redox-inactive metal, causes oxidative stress, which triggers neurodegeneration signaling pathways like mitogen-activated protein kinase (MAPK), protein kinase B (Akt), mammalian target of rapamycin (mTOR) and FasL-mediated mitochondrial apoptosis, ultimately leading to neuronal degeneration. Extracellular calcium influx increases due to disruptions in intracellular calcium homeostasis, and neuronal apoptosis is triggered by activating the MAPK and mTOR signaling pathways. Furthermore, affecting brain ion balance and nutrient uptake, cadmium damages the cerebral microvascular endothelium and raises BBB permeability [54].

Manganese is trace metal is essential for bone growth, blood clotting, immunity, carbohydrate metabolism, and brain function. High manganese exposure can accumulate in the brain and be neurotoxic. High manganese levels can impair cognitive function and contribute to Alzheimer's disease (AD). Oxidative stress, mitochondrial dysfunction, dysregulation of autophagy, build-up of intracellular toxic metabolites, and apoptosis are some of the underlying processes [54].

Elevated brain iron in AD has been linked to an accelerated clinical decline. High brain iron content produces ROS, which ultimately causes cell death. Iron chelation is thought to have neuroprotective effects by lowering brain iron levels, blocking the development of tau and Aβ pathology, and reducing harmful ROS [55].

Diet

The Western diet (WD) consists of ultra-processed, refined foods high in simple carbohydrates, salt, saturated fat, and cholesterol, which will increase the amyloid β and tau protein levels in the brain. Inadequate intake of vegetables, fruits which makes low intake of nicotinic acid (B3), folic acid flavonoids, vitamin B9, and betulinic acid following brain atrophy, age-related cognition decline, affects BBB permeability and, thereby the risk of Alzheimer’s disease more [56, 57].

Genetic polymorphism

TREM2, or trigger-expressing receptor expressed on myeloid cells 2, is a transmembrane receptor that is highly expressed in microglia cells and is involved in phagocytosis, inflammation, and glial cell activation. A genetic mutation in TREM2 enhances the risk of late-onset al. zheimer's disease [58].

β-site APP Cleaving Enzyme 1 (BACE1) is a β-secretase enzyme essential for the generation of Amyloid β monomeric forms like Aβ42. It is widely expressed in brain neurons. Mutations in the BACE1 gene can affect Beta-Secretase 1, resulting in increased production of amyloid-beta peptides, particularly longer, toxic forms. This leads to the build-up of amyloid plaques in the brain, which is a characteristic feature of Alzheimer's disease. These plaques disrupt neuronal communication, cause neuroinflammation, and eventually result in neuronal death and cognitive decline, exacerbating Alzheimer's disease progression [59].

Alzheimer's disease is associated with the gamma-secretase complex gene Presenilin 1 (PS1). The dysregulation of gamma-secretase activity resulting from mutations in the PS1 gene can lead to an increase in the production of amyloid-beta peptides, especially the plaque-forming amyloid-beta 42 peptides. These plaques cause inflammation, impair neuronal function and ultimately result in neuronal death, all of which contribute to the neurodegenerative process. These mutations are associated with early-onset familial Alzheimer's disease, which makes up a tiny portion of cases and usually appears before the age of 65. The precise processes by which PS1 mutations contribute to the pathology of Alzheimer's disease, however, are still being studied [60].

Biomarkers

Oxidative biomarkers

Anti-Oxidants like Superoxide Dismutase (SOD), Catalase (CAT), And Glutathione Peroxidase antioxidants will neutralize the reactive oxygen species (ROS) produced excessively in the body due to various causes. Antioxidant enzymes like superoxide dismutase (SOD), Catalase (CAT), and glutathione peroxidase activity towards breaking down of superoxide and hydrogen peroxide will be compromised in the Alzheimer's CSF and Plasma [61]. Oxidative Stress Markers like F2-Isops are prostaglandin-like compounds. The esterified F2-Isops increases the free F2-Isops in the tissue undergone oxidative stress, 3-Nitrotyrosine, Nitric Oxide, and Malondialdehyde are the compounds synthesized by lipid peroxidation in the brain upon accumulation of the Aβ [62, 63].

CSF biomarkers

APoD (Apolipoprotein D) is highly expressed in the brain, particularly in areas affected by AD, and its levels are often elevated in response to oxidative stress and inflammation, both of which are central to Alzheimer's pathology. APoD is thought to have neuroprotective functions by mitigating oxidative damage and promoting the clearance of harmful lipids. In AD, increased APoD expression has been observed in regions with amyloid-beta plaques and tau tangles, suggesting it may be part of the brain's response to ongoing neurodegeneration [64].

Aβ42 is considered to be at a higher level in the plasma in patients with AD. Usually, the Aβ42 binds with low-density lipoprotein receptor-related protein-1 (LRP1) in the brain but in the AD patient, the binding of Aβ42 with low-density lipoprotein receptor-related protein-1 (LRP1) is compromised, the biomarker efflux from the brain through the blood-brain barrier (BBB) and reaches plasma. A deposition can activate astrocytes and microglia through ROS generation, resulting in activation of the brain inflammatory pathway [64].

Tau proteins in neuronal axons help stabilize microtubules in the central nervous system (CNS). They consist of six soluble isoforms and numerous phosphorylation sites [65]. In neurons, hyperphosphorylated tau proteins detach from microtubules and form insoluble aggregates known as neurofibrillary tangles. There are two tau markers namely, total tau (t-tau) and phosphorylated tau (p-tau). The t-tau level in CSF represents the neuronal injury and p-tau represents the hyperphosphorylation of tau and formed neurofibrillary tangles [66, 67].

GFAP (Glial fibrillary acidic protein) is an astrocytic marker that mainly measures astrocytosis. CSF GFAP and plasma GFAP both are positively related to both age and gender. Plasma GFAP is associated with the accumulation of amyloid-β-PET in the neocortical regions and also its higher concentration is associated with Tau-PET. The accurate status of Amyloid – β deposition can be measured through the plasma GFAP marker [68].

YKL-40 is a secreted glycoprotein and it has a part in the activation of the innate immune system. Its elevated level in reactive astrocytes and microglial cells are directly associated with the neuroinflammatory processes. Dementia patients will have higher levels of YKL-40 in the CSF [69]. YKL-40 levels are elevated in autosomal dominant Alzheimer's disease mutation carriers 15 to 19 years before symptom onset, shortly after the start of brain amyloid accumulation. So, this biomarker can be used for the early detection of Alzheimer’s disease [70].

Aquaporin 4 (AQP4) is the primary water channel found in the central nervous system (CNS), specifically in astrocytes. AQP4 plays a role in neurological diseases by regulating brain fluid and ion homeostasis, potassium uptake and release by astrocytes, migration and glial scarring, neural signal transduction, proinflammatory factor secretion, astrocyte-to-astrocyte cell communication, and synaptic plasticity. Reducing AQP4 will impair learning and memory, it also affects synaptic plasticity. Maintaining the level of AQP4 in astrocytes is one of the molecular-level therapies for AD [71, 72].

α-Synuclein is the precursor protein of a non-amyloid β component of senile plaques (NACP) and positive aggregates are found in limbic regions in Alzheimer's disease. It plays a part in synaptic adaptations, such as synaptic plasticity during development, learning, and the regulation of synaptic vesicle mobilization at nerve terminals. Polymorphism of the α-syn gene and higher levels in CFS will be diagnosed as Alzheimer’s Disease [73].

Apolipoprotein E (APOE) is a protein involved in lipid metabolism and transporting lipids, in the central nervous system. It plays a crucial role in the clearance of the Aβ and is associated with the Tau protein aggregation. It also maintains the BBB integrity and the synaptic plasticity. Damage in the BBB integrity leads to neuroinflammation [74].

Elevated levels of YWHAG in cerebrospinal fluid (CSF) may indicate ongoing neurodegenerative processes. This protein is released into the CSF when neurons are stressed or damaged, making its concentration a reflection of the extent of neurodegeneration. Increased YWHAG levels have been observed in AD patients and correlate with the severity of cognitive impairment and brain damage. Consequently, measuring YWHAG in CSF can help monitor disease progression and evaluate the effectiveness of therapeutic interventions, providing valuable insights into the state of neurodegeneration in Alzheimer's disease [75].

The degradation of MBP (Myelin Basic Protein) contributes to demyelination, leading to impaired neuronal communication and cognitive decline. Elevated levels of MBP in cerebrospinal fluid (CSF) are often observed in AD, indicating ongoing neurodegeneration and white matter damage. MBP also interacts with amyloid-beta (Aβ) peptides, promoting plaque formation, a key feature of AD pathology [76].

Clusterin involves the clearance of amyloid-beta (Aβ) plaques. Clusterin binds to Aβ peptides, facilitating their transport and clearance from the brain, which may help mitigate plaque formation. However, elevated levels of clusterin have also been associated with increased amyloid burden and cognitive decline, suggesting a complex role in AD [77].

MMPs (Matrix Metalloproteinases) are enzymes that degrade extracellular matrix components and are involved in Alzheimer's disease (AD) through their effects on amyloid-beta (Aβ) plaques. While MMPs can aid in clearing Aβ, excessive activity may disrupt the blood-brain barrier and exacerbate neuroinflammation. Elevated levels of certain MMPs, like MMP-9, are linked to AD progression, highlighting their potential as both therapeutic targets and biomarkers [78].

SNAP-25 (Synaptosomal-Associated Protein 25) is a critical protein involved in the regulation of neurotransmitter release by facilitating the fusion of synaptic vesicles with the presynaptic membrane. In Alzheimer's disease (AD), SNAP-25 levels and function are often disrupted, leading to impaired synaptic transmission and communication between neurons. This disruption is particularly significant as synaptic dysfunction is one of the earliest pathological features of AD and closely correlates with cognitive decline [79].

Plasma metabolites

Leptin is a 16 kDa adipokine that is mainly secreted by adipocytes and plays a crucial role in controlling body weight and fat reserves. Leptin influences hippocampal neuron excitability through both synaptic and nonsynaptic pathways, mainly acting on arcuate nuclei in the hypothalamus. It also affects hippocampal-dependent learning and memory [79]. Leptin activates AMPK signaling pathways, which reduces Aβ deposition in neuronal cultures. A negative correlation was observed between plasma leptin and presenilin 1 protein expression, indicating that leptin controls γ-secretase activity in vivo. The Aβ-cleaving enzyme aspartyl protease β-site is decreased by leptin, reducing Aβ deposition [80-82].

BGLAP (Bone Gamma-Carboxyglutamate Protein), also known as osteocalcin, is a protein primarily involved in bone metabolism; osteocalcin can cross the blood-brain barrier and influence brain regions involved in memory and cognition. In the context of Alzheimer's disease (AD), lower levels of osteocalcin have been associated with an increased risk of cognitive decline. This protein is believed to enhance the production of neurotransmitters and support neurogenesis, potentially offering protective effects against neurodegenerative processes [83].

Flotillin is connected to amyloid-beta plaques due to its role in organizing lipid rafts and processing amyloid precursor protein (APP). It may also affect tau protein pathology through its influence on cellular signaling and membrane dynamics. Variations in flotillin levels or function could, therefore impact both the formation of amyloid-beta plaques and tau protein abnormalities in Alzheimer's disease. Elevated or reduced flotillin in cerebrospinal fluid or blood could reflect disease presence or progression [84].

Inflammatory biomarkers

α1-anti-chymotrypsin (a1-ACT), which are produced by astrocytes. The compounds released from the astrocytes, microglia and neurons act as the inflammatory mediators; cytokines such as TNF-α, IL-1b and IL-6; and chemokines such as macrophage colony-stimulating factor and macrophage inflammatory proteins [85].

APoD (Apolipoprotein D): APoD is widely expressed in the brain, especially in AD-affected regions, and its levels are frequently raised in response to oxidative stress and inflammation, two factors that are essential to the pathophysiology of Alzheimer's disease. APoD is hypothesized to have neuroprotective properties via reducing oxidative damage and increasing the clearance of toxic lipids. Greater expression of APoD has been seen in areas of AD where tau tangles and amyloid-beta plaques are present, indicating that this may be the brain's response to the ongoing neurodegeneration [86].

Since neuroinflammation plays a major role in AD pathophysiology, CRISPLD2's (Cysteine-Rich Secretory Protein LCCL Domain Containing 2) involvement in controlling inflammation and its anti-inflammatory capabilities are especially pertinent. Chronic inflammation contributes to the advancement of neurodegeneration in Alzheimer's disease, and proteins such as CRISPLD2 may assist to mitigate these effects. Recent research suggests that CRISPLD2 may be activated in the brain in response to inflammatory signals, possibly serving as a defence mechanism against the deleterious consequences of protracted inflammation [87].

Advancements in treatment

Alzheimer’s is a multifactorial disease, though we need multi-therapeutic approaches to cure the Alzheimer’s disease. Memory, thinking, behavioral, and learning impairments are the main characteristics of AD [88]. Reducing extracellular deposition of Amyloid β and intracellular deposition of tau proteins are the major objectives of the therapies for Alzheimer’s disease [89]. As AD is an irreversible chronic condition, we can control the disease but cannot cure it completely [90].

Table 1: Ongoing therapeutic agents targeting tau pathology in alzheimer's disease

Name Type Phase Site of action Mechanism of action Reference
ABBV-181 Monoclonal Antibody Phase 2/3 Tau protein Targets specific epitopes of tau protein to inhibit aggregation and reduce neurofibrillary tangles. [91]
TauVID (Flortaucipir) PET Imaging Agent Phase 2 Tau protein aggregates Binds to tau aggregates for imaging purposes to assess tau pathology and treatment efficacy. [92]
LMTX (TRx0237) Tau Aggregation Inhibitor Phase 3 Tau protein Inhibits tau aggregation, preventing the formation of neurofibrillary tangles. [93]
AADvac1 Vaccine Phase 2 Tau protein Stimulates an immune response against tau protein to reduce tangles and neurodegeneration. [95]
PTI-125 Small Molecule Phase 2 Tau protein Binds to tau protein to inhibit its aggregation and mitigate tau-related neurodegeneration. [91]
TPI-287 Small Molecule Phase 2 Tau protein and microtubules Stabilizes microtubules and inhibits tau aggregation. [94]

GV-971

(Oligomannate)

 Marine-derived Polysaccharide Phase 3 Tau protein and amyloid-beta Modulates neuroinflammation and targets both tau and amyloid-beta to reduce associated pathology. [96]

Tau therapy

Tau therapies for Alzheimer's disease mentioned in table 1 focus on targeting the tau protein, which forms harmful tangles in the brain. ABBV-181 is a monoclonal antibody that inhibits tau aggregation by targeting specific tau epitopes [91], while TauVID (Flortaucipir) is used as a PET imaging agent to visualize tau pathology [92]. LMTX (TRx0237) and PTI-125 are designed to prevent the formation of neurofibrillary tangles by inhibiting tau aggregation [93]. TPI-287 not only inhibits tau aggregation but also stabilizes microtubules [94]. AADvac1 is a vaccine that stimulates an immune response against tau [95] and GV-971 (Oligomannate) targets both tau and amyloid-beta to reduce neuroinflammation and associated pathology [96].

Anti-amyloid therapy

Anti-amyloid drugs for Alzheimer's target amyloid-beta plaques to reduce their buildup and associated damage mentioned in table 2. Lecanemab (Leqembi) [97], an approved drug, and other monoclonal antibodies like Donanemab and Gantenerumab promote plaque clearance. Crenezumab targets both plaques and soluble forms [98], while ALZ-801 prevents oligomer aggregation [99]. Vaccines like ACC-001 [100] and UB-311 stimulate the immune system to clear amyloid-beta, aiming to halt plaque formation and progression [101-103].

Table 2: Ongoing therapeutic agents targeting amyloid-beta in alzheimer's disease

Name Type Phase Site of action Mechanism of action Reference
Lecanemab (Leqembi) Monoclonal Antibody Approved Amyloid-beta plaques and soluble amyloid-beta Binds to amyloid-beta plaques and soluble forms, promoting clearance through microglial phagocytosis. 97
Donanemab Monoclonal Antibody Phase 3 N3pE-modified amyloid-beta plaques Targets N3pE-modified amyloid-beta, promoting plaque removal by the immune system. 98
Gantenerumab Monoclonal Antibody Phase 3 Amyloid-beta plaques Binds to amyloid-beta plaques, inducing microglial activation to enhance plaque clearance. 98
Crenezumab Monoclonal Antibody Phase 3 Amyloid-beta plaques and soluble amyloid-beta Binds to amyloid-beta plaques and soluble forms, promoting removal and reducing plaque formation. 98
ALZ-801 Modified Drug Phase 3 Amyloid-beta oligomers and plaques Binds to amyloid-beta oligomers, preventing aggregation and promoting plaque clearance. 99
IV Immunoglobulin (IVIG) Immunotherapy Phase 3 Amyloid-beta plaques and neuroinflammation Contains diverse antibodies that modulate immune response, reduce inflammation, and aid in plaque clearance. 102
ACC-001 Vaccine Phase 1/2 Amyloid-beta peptides and plaques Induces immune response against amyloid-beta, promoting plaque removal via antibody binding. 100
Eli Lilly's Amyloid-beta Vaccine (LY3303560) Vaccine Phase 1 Amyloid-beta plaques Stimulates immune system to produce antibodies against amyloid-beta plaques, facilitating their clearance. 103
Protofibril Vaccine Vaccine Phase 1/2 Protofibril forms of amyloid-beta Targets protofibrils to induce immune response and prevent their aggregation into plaques. 103
UB-311 Vaccine Phase 2 Amyloid-beta plaques and soluble amyloid-beta Stimulates immune response to produce antibodies against amyloid-beta, aiding in plaque removal. 101

Gene and cell therapies

Gene and cell therapies are innovative approaches being explored for Alzheimer's disease, targeting the root causes of neurodegeneration. AAV2-CRISPR uses viral vectors to deliver gene-editing tools [104], while Cerebrolysin and NeuroStem-1 focus on neuroprotection and repair using peptides and stem cells, respectively [105, 106]. Stem Cell-Derived Neurons aim to replace damaged neurons [106], and GDNF Therapy delivers neurotrophic factors to support neuron survival [108]. In preclinical stages, Ad5-CMV-PSEN1 and AAV-GFAP are designed to modify gene expression and enhance astrocyte function, offering hope for slowing disease progression [109, 106, 110].

Table 3: Current and emerging gene and cell therapies for Alzheimer's disease

Name Type Phase Site of action Mechanism of action Reference
AAV2-CRISPR Gene therapy Early clinical trials Target genes associated with Alzheimer's Uses adeno-associated virus (AAV) vectors to deliver CRISPR/Cas9 gene-editing tools to modify genes related to Alzheimer's pathology. [104]
Cerebrolysin Cell therapy Phase 3 Brain neuroprotection A peptide mixture derived from pig brain tissue that is believed to enhance neuroprotection and support neuronal survival. [105]
NeuroStem-1 Stem cell therapy Phase 1 Brain regions affected by Alzheimer's Uses human neural stem cells to replace damaged neurons and promote repair in the brain. [106]
Stem Cell-Derived Neurons Cell therapy Preclinical to phase 1 Brain regions affected by Alzheimer's Transplants neurons derived from human stem cells into the brain to replace damaged neurons and restore function. [107]
GDNF (Glial cell line-derived neurotrophic factor) therapy Gene therapy Preclinical Neurons in the brain Delivers GDNF to support neuron survival and function, aiming to slow the progression of neurodegeneration. [108]
Ad5-CMV-PSEN1 Gene therapy Preclinical Neurons in the brain Uses adenoviral vectors to deliver PSEN1 (Presenilin 1) to modify gene expression and influence Alzheimer's disease progression. [109]
AAV-GFAP Gene therapy Preclinical Astrocytes in the brain Delivers genes that encode for growth factors to support astrocyte function and protect against neurodegeneration [107]

CONCLUSION

Alzheimer's disease (AD) is a multifaceted neurodegenerative condition primarily affecting older individuals, characterized by the accumulation of amyloid-beta plaques and tau protein tangles in the brain. Age-related changes in the transcriptome, social isolation, and various health factors, including diabetes, hypertension, and obesity, contribute to its development. Genetic predispositions also play a significant role, with polymorphisms in genes like TREM2 and BACE1 influencing susceptibility. Biomarkers such as oxidative stress indicators, CNS metabolites, plasma metabolites, and inflammatory markers provide insights into AD pathology and serve as potential targets for therapeutic interventions. Oxidative stress, reflected in compromised antioxidant enzymes and increased oxidative stress markers, contributes to neuronal damage and Aβ accumulation. CNS metabolites like APP, Aβ42, tau proteins, and inflammatory markers like α1-anti-chymotrypsin exacerbate neuroinflammation, furthering disease progression. In therapeutic endeavors, targeting amyloid β deposition and tau protein accumulation remains pivotal. Novel compounds like salicylic acid–donepezil–rivastigmine hybrids offer multifunctional effects including inflammation inhibition and neuroprotection. Therapeutic strategies encompass diverse approaches such as anti-amyloid and tau therapies, inflammation modulation, neurogenesis promotion, and metabolic optimization. However, AD remains irreversible, necessitating a shift towards disease management rather than a complete cure. While there is ongoing research and innovation in therapeutic developments, the complexity of AD demands a comprehensive approach involving early detection, lifestyle interventions, and personalized treatment plans to improve the quality of life for affected individuals and their caregivers.

In the future, Alzheimer's disease research and treatment will focus on early detection methods, personalized medicine, and disease-modifying therapies. Non-pharmacological interventions, digital health technologies, and combination therapies will also play important roles. Immunotherapy and brain stimulation techniques show promise, while multidisciplinary care models will cater to the complex needs of patients and caregivers. Global collaboration and advocacy efforts will be crucial in advancing Alzheimer's care and reducing its impact worldwide.

ACKNOWLEDGMENT

All authors contributed to the conceptualization, design, research, writing, and review of the manuscript. They all approved the final version for publication. The authors express gratitude to the chairman, management, principal, teaching, and non-teaching staff of Acharya and BM Reddy College of Pharmacy, Bengaluru, for their support during the review submission process.

FUNDING

No funding was provided for this study.

AUTHORS CONTRIBUTIONS

Suresh Janadri: Conceptualization, Supervision, Shreelaxmi Dadmi: Writing Original draft preparation and Visualization, Manjunatha P Mudagal: Conceptualization and Supervision, Uday Raj Sharma: Reviewing and Editing, Surendra Vada: Reviewing and Editing, Thiriveedi Haribabu: Visualization.

CONFLICTS OF INTERESTS

The authors have no conflicts of interest to declare.

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