1,3Mata Gujri College of Pharmacy, Kishanganj, Bihar-855107
2Girijanandha Chowdhury University
Recent breakthroughs in the treatment of AD have focused on early identification and the creation of biomarkers to help in diagnosis and monitoring. Neuroimaging methods, such as PET, and CSF testing have offered significant tools for viewing and identifying AD disease. Additionally, research on serum uric acid levels and the identification of atypical forms of AD have helped to our knowledge of the illness. The merging of bioinformatics research, artificial intelligence technologies, and molecular imaging techniques has greatly increased our knowledge of AD processes and etiologies. Different biomarkers are discussed in this review such as blood based lipids, Plasma neurofilament light, Neuroimaging measurements, Magnetic resonance imaging, Positron emission tomography, Cerebrospinal Fluid, Retinal Imaging techniques, Optical coherence tomography. These discoveries offer promise for the discovery of viable medicines and improved management of AD.
Alzheimer's disease is a chronic neurological illness marked by a deterioration in memory, cognitive abilities, and the capacity to execute daily tasks. It is the most prevalent cause of dementia in later life. [1] The condition is linked with various neuropathologies and is defined by the accumulation of amyloid in the brain parenchyma and cerebrovasculature. Although the exact pathophysiology of Alzheimer's disease is unknown, it consists of the amyloid ?-peptide (A?) polymerizing into amyloid fibrils. [2] An important stage in the development of the illness is the deposition of amyloid in the brain. Apart from the amyloid accumulation, Alzheimer's disease is linked to malfunction in several sensory cortices, including the somatosensory areas. Studies have demonstrated that people with Alzheimer's disease display higher somatosensory responses compared to those with HIV-associated neurocognitive dysfunction. [3] Studies have not, however, compared somatosensory processing in individuals with Alzheimer's disease and HIV-associated neurocognitive dysfunction. This result implies that the two disorders may have different neuropathologies. [4] Also linked to the pathogenesis of Alzheimer's disease has been the cholinergic system. Glutamate release and concentration in the synaptic cleft may be modelled by the activity of muscarinic and presynaptic nicotinic receptors. Although variations in neurotransmitter other than acetylcholine have been noted in Alzheimer's disease, no medication specifically targeting these neurotransmitter systems has been licensed for treatment of the condition. [5] Driving abilities steadily worsen with a diagnosis of Alzheimer's disease or cognitive impairment. However, a diagnosis of Alzheimer's disease should not immediately prevent driving. Standardized tests like the occupational therapy-driver off-road assessment battery (OT-DORA Battery) can assist ascertain a client's fit for driving or not. Age and scores on certain subtests of the OT-DORA Battery can predict the result of the evaluation. [6] Olfactory impairment is frequent in older persons and can be an early indicator of neurodegenerative disorders such as Alzheimer's disease. Multiple factors contribute to age-related olfactory loss, including changes in the olfactory system's architecture, physiology, and pathophysiology. Decreased olfactory function can severely influence physical well-being, quality of life, nutrition, and everyday safety. [7] These pathological alterations lead to serious cognitive deficits, including memory loss and difficulty with language and reasoning abilities. [8]
Methodology
The most relevant literature was retrieved through a meticulous search on the electronic databases, PubMed, Google Scholar, Scopus, Web of Science. The keywords and phrases used during the search were Alzheimer’s Disease, Biomarker, Amyloid Beta plagues, neurotransmitters, tangles, Acetylcholine. The number of relevant articles finalized after extraction and analysis through the combination of the above keywords and phrases.
RESULT AND DISCUSSION
Pathogenesis
Alzheimer's disease is a chronic neurological condition that is the major cause of dementia globally. [9] The pathogenesis of Alzheimer's disease involves various factors, including the upregulation of angiotensin-converting enzyme 2 (ACE2) protein expression in the brain found that the protein expression level of ACE2 is increased in the brains of patients with Alzheimer's disease, suggesting a direct relationship between Alzheimer's disease and ACE2 expression. This increase of ACE2 may be connected to oxidative stress, which is implicated in the etiology of Alzheimer's disease. The study also identified greater quantities of carbonylated proteins and an elevated thiol oxidation state of peroxiredoxin 6 (Prx6) in the brains with Alzheimer's disease, indicating increased oxidative stress. [10] A? oligomers, which are implicated in Alzheimer's disease, have been identified to cause synaptic degeneration by acting on dendritic spines and altering synaptic plasticity pathways. This mismatch of synaptic plasticity pathways contributes to synaptic degradation in Alzheimer's disease. [11] Furthermore, there is evidence of a relationship between Alzheimer's disease and inflammation. Microglia, a kind of immune cell in the brain, generate inflammatory cytokines that promote brain inflammation, which may be connected with Alzheimer's disease. Inflammatory mechanisms in the brain have been linked in the etiology of both Alzheimer's disease and significant depression. [12] The etiology of Alzheimer's disease involves several components, including the elevation of ACE2 protein expression, oxidative stress, synaptic degradation, inflammation, and probable linkages to other illnesses including as cancer and diabetes. Understanding these pathways is critical for the development of viable therapeutics for Alzheimer's disease. [Figure 1]
Figure 1: Pathogenesis
Recent therapies of Alzhiemer disease
Alzheimer's disease is a neurological ailment marked by increasing cognitive deterioration and memory loss. [13] Over the years, there have been considerable improvements in the treatment of Alzheimer's disease, with researchers concentrating on various techniques to slow down the course of the illness and enhance cognitive function. One possible therapy option is the use of neuroprotective drugs. Antagonists of Ca2+ channels and NMDA receptors have showed promise as neuroprotective medicines in the treatment of Alzheimer's disease. Dimebon, an antihistamine medication, has been studied as a possible neuroprotective and cognition-enhancing treatment for Alzheimer's disease. It operates as an antagonist of Ca2+ channels and NMDA receptors, which are implicated in neuronal excitotoxicity and cell death. [14] The use of Dimebon as a neuroprotective drug offers possibilities for the therapy of Alzheimer's disease. Another method to the treatment of Alzheimer's disease is the use of hormone therapy. Estrogen replacement treatment in postmenopausal women has been demonstrated to lessen the chance of acquiring Alzheimer's disease and slow down its course. Estrogen works as a cognitive enhancer and a neuroprotective agent. [15] The Alzheimer's Disease Composite Score (ADCOMS) has been established as a cognitive outcome measure in clinical studies. ADCOMS combines scores from multiple cognitive evaluation methods to evaluate the efficacy of prospective therapies for Alzheimer's disease. This technique tries to discover medications that can demonstrate a substantial difference from placebo in individuals with early-stage illness and mild cognitive impairments. [16] Improvements in nanotherapeutic treatments have opened up new prospects for the treatment of Alzheimer's disease. Nanomedicines have been designed to circumvent biological barriers, such as the blood-brain barrier, and enhance the transport of pharmaceuticals to the central nervous system. [17] These nanomedicines have the potential to boost the effectiveness of standard Alzheimer's treatments and improve patient outcomes. [Figure 2]
Figure 2: Recent treatment of Alzheimer’s Disease
Biomarker used in Alzheimer’s Disease
Biomarkers play a significant role in the early identification and diagnosis of Alzheimer's disease (AD). [18] AD is a progressive neurological disease that affects millions of individuals in the United States. Pathological processes in the brain begin long before clinical dementia, underscoring the relevance of biomarkers in diagnosing the illness at an early stage. [19] Various types of biomarkers have been explored for their potential in identifying AD.
Blood based lipids
Alzheimer's disease (AD) is a progressive neurological ailment that affects millions of persons worldwide. [20] Currently, the diagnosis of AD relies on invasive or costly procedures such as cerebrospinal fluid (CSF) or imaging biomarkers. [21] However, there is an increasing interest in developing blood-based biomarkers for AD that are less intrusive and more accessible for study, medication development, and clinical practice. [22] One putative blood-based biomarker for AD is plasma neurofilament light (NFL), which has been postulated as a biomarker for neurodegeneration in dementias.
Plasma neurofilament light
Plasma neurofilament light (NfL) has emerged as a possible biomarker for Alzheimer's disease (AD) due to its relationship with neurodegeneration and neuronal damage. [23] NfL is a protein that is released into the bloodstream when axonal damage occurs, making it a good option for monitoring disease progression and measuring cognitive loss in AD. A study done by explored the longitudinal correlations of plasma phosphorylated tau at threonine 181 (p-tau181) and NfL with neurodegeneration in AD. The study indicated that both plasma p-tau181 and NfL levels were linked with neurodegeneration and cognitive loss in AD patients. However, the link between plasma p-tau181 and neurodegeneration was higher than that of NfL. This implies that plasma p-tau181 may be a more sensitive biomarker for tracking disease development in AD. [24] Another research by evaluated plasma NfL levels in different phases of AD, including cognitively normal persons, amnestic mild cognitive impairment (aMCI), and AD patients. The study demonstrated significantly elevated plasma NfL levels in both aMCI and AD groups compared to cognitively normal persons. However, there was large overlap across the groups, indicating that plasma NfL levels may not be a viable biomarker for the detection of prodromal and senile phases of AD. [25] With AD, plasma NfL has also been examined in relation to other neurodegenerative illnesses. Plasma NfL levels are raised in many neurodegenerative illnesses, including AD, frontotemporal dementia, multiple sclerosis, and traumatic brain injury. [26] This shows that plasma NfL may function as a generic marker of neurodegeneration rather than a specialized diagnostic for AD.
Neuro imaging measurements
Neuroimaging methods have played a vital role in evaluating pathological brain alterations linked with Alzheimer's disease (AD). These approaches have been utilized to detect substantial structural changes in brain areas such as the hippocampus and entorhinal cortex between healthy brains and brains with AD. [27] Neuroimaging results in AD have been demonstrated to occur in diverse brain areas across different investigations but localize to the same functionally linked brain network. This shows that seemingly varied neuroimaging findings in AD can be attributable to the participation of multiple brain areas within the same network. [28] Various neuroimaging modalities have been applied in AD research. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are extensively employed procedures. [29]
Magnetic resonance imaging
Magnetic resonance imaging (MRI) has been widely utilized as a non-invasive tool to identify and assess structural changes in the brain associated with AD. Several MRI-based biomarkers have been examined in AD research, offering useful insights into the pathophysiology and course of the disease. One MRI biomarker that has showed potential in AD research is the evaluation of synapse density. Synaptic loss is a significant aspect of AD, and measuring synaptic density can offer vital information regarding the development of the illness. In addition to structural and functional MRI, several MRI-based biomarkers have been examined in AD research. For example, volumetric analysis of brain areas has been utilized to detect shrinkage and changes in brain structure associated with AD. [30] Studies have indicated that particular brain areas, such as the hippocampus and entorhinal cortex, demonstrate considerable shrinkage in AD. [31] These volumetric alterations may be evaluated using automated segmentation methods and employed as biomarkers for early identification and monitoring of AD. [30] In recent years, machine learning technologies have been used to MRI data to construct prediction models for AD diagnosis and progression. These models leverage several MRI indicators, including as cortical thickness, hippocampus volume, and white matter integrity, to categorize individuals as AD patients or healthy controls. [32]
PET
Positron emission tomography (PET) is a powerful imaging method used in the diagnosis and management of Alzheimer's disease (AD) and associated neurodegenerative illnesses. PET scans can give useful information on the existence and distribution of pathological characteristics such as amyloid plaques and tau tangles in the brain. [33] Amyloid PET, which identifies amyloid plaques, is particularly effective in the diagnosis of AD, as amyloid plaques represent a key neuropathological characteristic of the illness. [34] Tau PET, on the other hand, allows for the evaluation of tau proteins in the brain, which are linked with neurofibrillary tangles and are diagnostic of AD and other tauopathies. Several studies have studied the use of PET imaging in AD research and clinical treatment. For example, performed the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) research, which investigated the connection between amyloid PET and subsequent changes in clinical treatment for Medicare beneficiaries with moderate cognitive impairment (MCI) or dementia. The study indicated that amyloid PET was related with changes in clinical management, suggesting that it has the potential to alter patient care and treatment decisions. [33] PET imaging can also give insights into the pathogenesis of AD. Individuals with AD have unusually low PET measures of the cerebral metabolic rate for glucose (CMRgl) in certain brain areas. This discovery implies that PET imaging can be utilized to detect regional hypometabolism, which is a typical hallmark of AD. [35] PET imaging has also been used to examine the course of AD and to assess the efficacy of prospective therapies. provided a case study of a patient with AD who underwent PET imaging with the amyloid tracer Pittsburgh Compound B (PiB). The work connected the clinical progression, amyloid PET imaging, and molecular neuropathological abnormalities at autopsy to obtain insights into the interaction between ?-amyloid buildup, inflammatory processes, and the cholinergic neurotransmitter system in AD. [36]
CSF
Cerebrospinal fluid (CSF) biomarkers play a significant role in the diagnosis and monitoring of Alzheimer's disease (AD). These biomarkers give useful insights into the underlying pathophysiological alterations associated with AD and can assist in the early identification of the illness. [37, 38] One of the most well-known CSF biomarkers for AD is amyloid-? 42 (A?42), which is a significant component of amyloid plaques in the brain. Reduced levels of A?42 in the CSF have been consistently found in people with AD compared to healthy persons. This reduction in CSF A?42 is considered to represent the buildup of amyloid plaques in the brain. In a research by, the authors observed that the quantity of A?42 in the CSF was negatively linked with the amyloid plaque burden as evaluated by positron emission tomography (PET) imaging. [39] This shows that CSF A?42 levels can serve as a biomarker for amyloid pathology in AD. Another relevant CSF biomarker for AD is tau protein. Tau is a microtubule-associated protein that creates neurofibrillary tangles in the brains of persons with AD. Increased levels of total tau (t-tau) and phosphorylated tau (p-tau) in the CSF have been detected in AD patients compared to healthy controls. These high levels of tau in the CSF are symptomatic of neurodegeneration and tau disease in the brain. [40] CSF biomarkers for AD, such as synaptotagmin and glial fibrillary acidic protein (GFAP). Synaptotagmin is a presynaptic vesicle protein that has been discovered to be diminished in the CSF of AD patients relative to healthy controls. [41] This drop in synaptotagmin levels may suggest synapse loss and dysfunction in AD. GFAP, on the other hand, is a sign of astrogliosis, which is a reactive process of astrocytes in response to neuronal damage or inflammation. Increased levels of GFAP in the CSF have been seen in numerous neurodegenerative illnesses, including AD. [42]
Retinal Imaging Techniques
In recent years, there has been rising interest in employing retinal imaging methods as possible indicators for Alzheimer's disease. The retina, which is an extension of the central nervous system, shares similar embryological origins and structural and physiological qualities with the brain. [42]This intimate link between the retina and the brain has motivated researchers to study whether retinal abnormalities might act as surrogate indicators for brain pathology in Alzheimer's disease. Several retinal imaging techniques have been utilized to explore retinal biomarkers in Alzheimer's disease, including optical coherence tomography (OCT) imaging and hyperspectral imaging. [42,43] Optical coherence tomography (OCT) is a non-invasive imaging technology that enables for high-resolution imaging of the retina. It offers precise information regarding retinal thickness and structure, including the retinal nerve fiber layer and ganglion cell-inner plexiform layer. [44] Studies have indicated that patients with Alzheimer's disease and moderate cognitive impairment demonstrate retinal neurodegenerative alterations, such as thinning of retinal layers, compared to control participants. [43,44] These alterations in retinal structure may reflect underlying neurodegenerative processes in the brain. Hyperspectral imaging is another retinal imaging technology that has been examined as a possible biomarker for Alzheimer's disease. This approach examines the reflectance spectra of the retina and can detect changes in retinal reflectance between persons with significant amyloid beta (A?) load on brain imaging and those with moderate cognitive impairment. The deposition of A?, a characteristic of Alzheimer's disease, has been discovered to have a wavelength-dependent influence on light scatter in the retina. [45] Therefore, hyperspectral imaging may give useful insights into the existence and course of A? disease in the brain. Despite structural abnormalities, retinal vascular alterations have also been explored as possible indicators for Alzheimer's disease. The retinal microvascular network may be directly examined and may give insights on parallel cerebral microvascular disease. [43] Retinal imaging factors, such as retinal layer thickness and microvascular measures, have been associated with gray matter and white matter data collected from magnetic resonance imaging (MRI) and diffusion tensor imaging. [46] Several findings indicate that retinal imaging techniques may give useful information regarding structural brain alterations in Alzheimer's disease. Retinal imaging methods, such as optical coherence tomography (OCT) imaging and hyperspectral imaging, have showed promise as prospective biomarkers for Alzheimer's disease. These approaches enable for the identification of retinal neurodegenerative changes and abnormalities in retinal vascular density, which may represent underlying brain pathology in Alzheimer's disease.
OCT
Optical coherence tomography (OCT) is a non-invasive imaging technology that has been widely employed in the research of Alzheimer's disease (AD) and other neurodegenerative illnesses. OCT provides for high-resolution imaging of the retina, offering unique insights into retinal microvascular and neurodegenerative alterations associated with AD. [42, 47] Several research have studied the use of OCT in assessing retinal abnormalities in AD. undertook a cross-sectional investigation to investigate and compare retinal microvasculature in patients with AD, moderate cognitive impairment (MCI), and cognitively intact controls using OCT angiography (OCTA). The study indicated that patients with AD and MCI had a reduction in vessel density and increase of the foveal avascular zone compared to controls, suggesting retinal microvascular alterations in early stages of AD. [42] Thomson et al. conducted a systematic review and meta-analysis to study retinal nerve fiber layer (RNFL) abnormalities in dementia, including AD, using OCT. The meta-analysis comprised 17 studies comparing AD with healthy controls and found a substantial decline in mean RNFL thickness in AD patients. [48] This data shows that thinning of the RNFL may serve as a possible biomarker for AD. In addition to RNFL alterations, additional retinal layers have also been examined in the context of AD. Garcia-Martin et al. examined the thickness of 10 retinal layers in individuals with AD using a novel segmentation method of OCT. The study discovered that particular retinal layers were thinner in AD patients compared to controls, and the thickness of these layers corresponded with AD severity. [49] These findings imply that OCT can give useful information on neurodegeneration and disease progression in AD. OCT has been utilized to research retinal ganglion cell (RGC) destruction in numerous neurodegenerative illnesses, including AD. RGCs play a vital role in visual processing, and their degeneration has been identified in AD. Morgia et al. analyzed OCT studies and discovered that the pattern of RGC degradation in AD is distinct from other neurodegenerative illnesses, such as Parkinson's disease. [50]
CONCLUSION
This review paper has shed light on the latest improvements in the therapy and biomarkers utilized in Alzheimer's disease (AD). The area of AD research has experienced substantial advances in the past several years, bringing promise for better management and early identification of this severe neurodegenerative condition. Regarding therapy, various potential therapeutic techniques have developed. Targeting beta-amyloid plaques, the characteristic pathology of AD, has been a prominent focus. Immunotherapies and anti-amyloid medicines have showed potential in removing amyloid deposits, however their effectiveness in clinical studies is still being assessed. Other therapy methods, like as tau-targeted treatments and neuroprotective drugs, are also being researched and show promise evidence for the future. In terms of biomarkers, there has been a significant movement towards employing imaging and fluid-based biomarkers for early identification and accurate diagnosis of AD. Neuroimaging methods like positron emission tomography (PET) and magnetic resonance imaging (MRI) have offered vital insights into brain structure and function alterations linked with AD. Otherside cerebrospinal fluid (CSF) and blood-based biomarkers, including amyloid and tau proteins, have showed promise in predicting AD development and identifying persons at risk. However, despite these gains, difficulties persist. The intricacy of AD, with its multifaceted nature and heterogeneity, needs more study to uncover accurate and precise biomarkers and create effective therapeutics. Collaborative efforts between researchers, doctors, and pharmaceutical firms are vital to expanding our understanding of AD and implementing these discoveries into clinical practice.
ACKNOWLEDGEMENT: Huge thanks to the entire faculty of Mata Gujri College of Pharmacy, Kishanganj, Bihar who shared their valuable knowledge throughout this review.
CONFLICTS OF INTEREST: The authors declare no conflict of interest.
REFERENCES
Sabitri Pradhan, Rintu Saikia, Pranita Sunar, Recent Biomarker in Alzheimer’s Disease: A Systemic Review, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 1, 1735-1746. https://doi.org/10.5281/zenodo.14699731
10.5281/zenodo.14699731
