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Document Type : Review Article


Department of Biotechnology, School of Life Sciences, Swami Ramanand Teerth Marathwada University, Nanded 431606, India


Alzheimer’s disease (AD) is the widely known neuro-degenerative disease, responsible for cognitive decline and progressive memory loss, results from the brain shrinkage (called atrophy) and degradation of neurons of brain, globally almost 60-70% people are suffering from it and most prevalent amongst older peoples of above 40 years. The major or marker symptoms symptom of this disease is dementia, impairment of thinking, and changes in behavioral pattern. The disease progression commences with short memory loss to severe memory impairment. To cope with this, prior disease diagnosis helps in the prevention and treatment of diseases, as there is no complete treatment and cure available to this disease. Once the patients have been diagnosed with this disease, there are several pharmacological or non-pharmacological treatments can be given. Up to now, the technique available for the AD detection is CSF and PET scan which are painful and expensive. Several blood or plasma biomarkers can be used to detect the progression or prevalence of the diseases, based on non-invasive blood-based biomarker and it is cost-effective technique and with similar efficiency in comparison to classical one.In this investigation, we focus on potential biological markers for the investigation and AD detection. The blood biomarkers can be useful are Plasma GFAP has been found to be the most potential blood biomarker. There is no any standard procedure/test been accepted to be used for the AD diagnosis as a blood biomarker. The other biomarkers can be used along with Plasma GFAP are level of TGF-β1 in plasma and Activity NO synthase in Leukocytes, plasma gelsolin (GSN) and matrix metalloproteinase 3 (MMP3), plasma Cystatin C, and High-Density Lipoprotein.

Graphical Abstract

Potential Plasma Biomarkers for Diagnosis of Alzheimer’s Disease: An Overview


Main Subjects


The neurodegenerative disease Alzheimer’s disease (AD) was first encountered in D. Auguste, one of patient of Alois Alzheimer, which was further named as Alzheimer’s disease by Kraepelin [1]. The typical clinical symptoms of AD include memory disturbances, with neuro-pathological detection of Amyloid β (Aβ) plaques and neurofibrillary tangles; are known to be as the hallmark of Alzheimer’s disease (AD). The principle detectable symptom of AD is dementia, observed in 50-60% cases, prevalence of dementia is observed to be around 1% in age ranges from 60-64 years and it becomes intense around 24-33% with increase in age around 85 or older [2]. The people aged with 65, 80 and 90 having chances of disease prevalence around 5, 20, and 33% [3]. Loss of memory and inability tocarry normal behavior, results from cerebral atrophy which targets hippocampus and entorhinal cortex [4]. The disease evolves silently and reported that the detection and cognitive impairment observed in the patients after the 10-12 years of onset of disease [5]. The disease prevalence increasing with increasing population and it is to be estimated that up to 2050, the individuals suffering from AD will be 115 million [6].

The conventional diagnosis having around 15% chances to diagnose AD wrongly. Differential diagnosis of dementia can be because of poisoning of carbon monoxide, drug interactions, deficiency of vitamins, and subdural hematoma. The more common cause of dementia is depression, Parkinsonian vascular and fronto-temporal dementia. Hence, differential diagnosis of dementia related to AD is very necessary towards accurate therapeutic treatments [7]. The dementia caused in older life ecause of vascular or neuro-degeneration is called as Geriatric syndrome [8,9]. The hallmark symptoms of neuropathologic AD are neuron degeneration, synaptic loss, tau protein, and amyloid β rich plaques. The plaques of amyloid β and neurofibrillary tangles formed by phosphorylated tau protein are major sign of AD while cognitive decline is because of synaptic loss or synaptic dysfunction [10].

The risk factor involved in AD can be genetic and epigenetic. Other than increasing older age, the major risk factors involved in intellectual decline is also it may include educational attainment and brain size. Illiteracy and less awareness have been one of the risk factor for prevalence and incidence dementia. Severe cognitive deficit and prevalence of AD symptoms in childhood results in smaller brain size [11]. The environmental factors related to AD are principally aging and other factors involved are head trauma, systemic arterial hypertensions, diabetes, and obesity. The factors which aids in the disease symptoms are depression, social isolation, and smoking and hearing loss [12,13].From the symptoms we can assumed that by changing the lifestyle it can be mitigated.

The second risk factor related to AD is genetic; autosomal dominant mutations results in early onset of AD in 70% of individuals, more often occurrence of disease observed before age 65 years. The autosomal dominant mutations are on the three genes such as presenilin 1, presenilin 2, and amyloid precursor protein (APP) which can be inherited [14]. At molecular level, the expression of disease symptoms of AD is due to these three genes such as amyloid precursor protein (APP) present on chromosome 21, Presenilin 1 (PS 1) present on chromosome 14 and Presenilin 2 (PS 2) present on chromosome 1. Expression of autosomal dominant disease just in the third decades of life is to be observed in the some of the families because of expression of PS 1[15]. More than 50% chances of AD are because of genetic factor APOEε4. The analysis and evaluations of APOEε4 through the autopsy was proved to be responsible for AD dementia [16]. Based on other investigations of autopsy, specific presence of O4 allele indicates 100% confirmation of AD [17-19].

Other factors involved in the expression disease conditions are; lifestyle factors like High diet fat, lack of exercise, etc. and changes in hormonal levels (See Fig 1).

Alzheimer disease variants

Along with the typical AD, its variants have also been detected such as frontal variant, logopenic variant, and posterior cortical atrophy. The logopenic variant of AD is progressive aphasia. The change in behavioral pattern with memory loss for shorter span is linked to frontal variant, these individuals are highly impatient and irritable [20].

The other variant of AD is posterior cortical atrophy which has similar symptoms like Balint-Holmes syndrome and Gerstmann syndrome. Posterior cortical atrophy related to visuospatial dysfunction and apperceptive visual agnosia. The patients with posterior cortical atrophy variants have preserved memory insight, but have develop constructional, dressing and ideomotor apraxia. The patients with logopenic aphasia variants are having problems with repetitions of anonymous words and poor naming [21].

AD diagnosis and detection

The patients suspected for the AD are classified into three groups’ preclinical, mild cognitive impairment (MCI) [22], and dementia [23]. For the AD diagnosis, several methods have been adopted among them most often used is detection amyloid-β deposition responsible for the dementia. AD diagnosis also can be achieved from some clinical parameters like biomarkers present in body fluids such as plasma and cerebrospinal fluid (CBF) or with the direct imaging method (PET) [5]. The AD is diagnosed very lately, it has two sorts of states symptomatic and asymptomatic [24].

The dementia, keymarker symptoms of AD is initiated with cognitive decline and takes long time to reach dementia, the hallmark symptom of AD which indicates greater brain impairment [25].The known method for the detection and diagnosis of AD is done by collecting CSF (Cerebra-Spinal Fluid) sample by lumbar puncture and Positron Emission Tomography (PET) which are expensive and invasive techniques and out of reach of common people. Therefore, it requires thorough study and investigations to find cheaper and non-invasive diagnosis technique for AD which can be affordable to even common people. In this article, we focus on the Plasma Biomarkers for AD diagnosis in a non-invasive technique.

Positron emission tomography (PET)

Diagnosis of clinical symptoms is very essential for the treatment and management of the disease. Other than the clinical symptoms, the AD neuropathology can be detected with positron emission tomography of deposited amyloid [21]. The genetic risk factors are responsible for early onset of AD [26]. In the asymptomatic stages of early onset of AD, the neurodegeneration can be detected with the 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) by monitoring glucose [27]. The patients detected with the AD while monitoring neuronal activity through the CMRglc shown reduction in parietotemporal, frontal, and posterior cingulated cortices [27]. Detection of common symptoms for the all sorts of dementia including AD is hypometabolic regions hence further it can be firmed by applying amyloid PET scan which helps to figure out surface area of amyloid plaques [28].

The major characteristic which makes AD from other diseases and dementia is Amyloid-β (Aβ) plaques and neurofibrillary tangles of tau protein. PET scan of Cerebrospinal fluid using Pittsburgh B (PiB) radiotracer (PiB-PET scan) shows uncontrolled production and clearance of amyloid-β proteins in human brain [29]. Other than amyloid β, pathologic symptoms involved in AD are loss of functions of tau protein by neurofibrillary tangles and phosphorylation, neuroinflammations, uncontrolled glucose metabolism, and oxidative stress [30].

Cerebrospinal fluid (CSF)

Detection of neuropathology have brought about by the scanning CSF biomarkers such as amyloid-β and tau proteins for diagnosis of AD (Fig 2). The biomarkers present in CSF are Aβ42 and Aβ40 and their ratio is decreased in AD positive individuals. Instead of individual Aβ42 and Aβ40, their ratio is more reliable marker for detection of AD [8,31]. The deposition of amyloid plaques results in loss in Aβ42. Other than the amyloid level in CSF, there is other nanodiagnostic approach to detect the AD by monitoring AbO level in CSF. Nanodiagnostic approaches uses nanoparticles as the DNA carrier to monitor the level of AbO in CSF. This technique used the nanoparticles such as magnetic nanoparticles and DNA conjugated with antibody AbO [32].

Biological markers [34]

There are several biomarkers present in the biological fluids that can be used for the diseases diagnosis. The major biological markers can be fluids present in human body which includes cerebrospinal fluid and blood or peripheral tissue. These biomarkers can be helpful in the diagnosis and confirmation of disease.

Some peculiarity ideal biomarkers are mentioned as:

  • Highly sensitive around 80%
  • High specificity around 80%
  • Probable positive confirmation around 90%
  • Help in neuropathological detection
  • Helps in disease diagnosis in childhood
  • Reliable, non-invasive, and cost effective
  • Easily distinguishes dementia of AD and others

Plasma blood biomarkers

Plasma glial fibrillary acidic protein (GFAP) [35]

Proliferation and abnormal activation of astrocytes can be marked by GFAP during astrogliosis results in neural damage [36]. The GFAP expression in brain tissue suffered with AD associated with Aβ plaque density [37].

In one of the case study of 134 volunteers, which were selected on the basis of inclusive and exclusive criteria regarding AD [38-40] and 105 cases observed through neuro-imaging, neuropsychometric evaluation, and blood collection, and also among them 00 had been found to have Normal Global Cognition on the basis of MMSE [41]. Around 95 cases were detected with Aβ 1 and Aβ 1-42 in their plasma, Plasma GFAP concentrations were detected in 96 and total set of GFAP and Aβ 1 and Aβ 1-42 were detected in of 94.

In this case study, it was observed that, biomarker GFAP elevation found in the high brain Aβ load which serves as blood biomarkers for early detection of diseases. Furthermore, their study also shown how it can be used to distinguish Aβ + and Aβ – individuals on the basis of disease’s risk factors such as age, sex, and APOEε4 carriage along with GFAP with 90 % sensitivity and 80% specificity. Individuals having compromised blood-brain barrier have been shown elevated Plasma GFAP levels along with astrogliosis. The study also indicates that the GFAP levels increases with age.

TGF-β1 level in plasma and activity NO synthase in leukocytes [42]

During monitoring of brain activity in AD diagnosis and it was observed that some of the activity can be used as the significant biomarkers which are present in plasma and leucocytes such as levels of TGF-β1 and activity of NO synthase, respectively. In the Central Nervous System (CNS) expression of TGF-β related to several abnormal events related to brain which directly related to events of AD, including brain injury, astrocytosis, regulation of α2M, etc. [43].

The free radical involved in the inflammations is Nitric Oxide (NO) and its excessive productions switch its effect from physiological neuro-modulator to a neuro-toxic effect [44]. In one of the investigations, it was reported that, in AD patients, activity of NO synthesis is enhanced in leucocyts [45]. In one of the investigations there were random 48 subjects with AD (60-89 years old) were chosen and also 23 healthy control subjects (60-92 years old) and in this cases AD subjects met the criteria recommended by National Institute of Neurological and Communicative disorders and stroke and AD Related Disorders Association (NINCDS-ADRDA). In this study they found, on an average of all control subjects taken into investigations, their functional TGF-β-1 should be lower. In all the 48 AD subjects, they found to have enhanced activity of NOS in Leukocytes. In result of this invesitigation TGF-β-1 and of NOS activity can be possibly used practically to identify all AD subjects and can be used as diagnostic marker in AD Subjects.

Plasma gelsolin (GSN) and matrix metalloproteinase 3 (MMP3) [46]

Plasma gelsolin can be used for diagnosis of AD patients as its concentration significantly dropped in disease conditions [47]. GSN is a 93 kDa protein, involved in de-fibrilization of the Aβ protein and also defibrilize preformed fibrils [48] and it is correlated with disease progression rate estimation by MMSE decline per year [47]. One of the principal GSN-degrading enzyme is Matrix metalloproteinase 3 (MMP3), found in two active forms (45 kDa and 28 kDa) [49], reported to have enhanced concentration in patients suffering from AD [50].

In this study, they had randomly selected total 113 subjects each as Normal as control and AD, which had undergone many inclusive and exclusive parameters. The AD subjects met the criteria of NINCDS-ADRDA for probable AD symptoms. Blood sample were taken and those subjects detected with ε4 allele classified as APOEε4. APOEε4 should be with minimum one copy of ε4 allele. The decreased level of Aβ42/40 ratio detected in AD subjects and the plasma GSN levels are negatively co-related with MMP3 activity in AD subjects. The Plasma GSN levels directly related to MMSE scores while dropped concentration of level of GSN in plasma and higher activity of MMP3 activity gives probable of confirmation of AD diseases, hence GSN level and MMP3 activity can be used as the significant biomarker for AD detection with accuracy, sensitivity, and specificity of around in the range of 76.1%, 77%, and 75.2%, respectively.

Plasma cystatin C and high-density lipoprotein [51]

The cystatins (Cys) are the major group of protein in neurological disorder more often called as cysteine protease inhibitor. Predominantly Cys B and Cys C are detected for the Vascular Dementia (VaD) and AD. Cys B involved in the regulation of Aβ peptide and maintenance of auto-fluorescence associated with lipofuscin and giant lipid of autolysosomes involved in AD [52]. Lipoproteins can be helps in the restoration of cognitive functions [53], among them HDL (High Density Lipoprotein) present in systemic circulation. Lipoprotein helps in the lipid related molecules present all over the body can be effectively delivered and cleared [54].

In this study, the researchers have tried to check whether High Density Lipoprotein or Plasma Cystatin C can be used as a reliable biomarker to differentiate dementia of AD and others and these biomarkers investigated in VaD and AD. Therefore, they had recruited 88 subjects with dementia. 43 subjects with AD, whose diagnosis was confirmed using NINCDS-ADRDA and 45 subjects as normal control group were selected. Further Blood sample measurement of all subjects was carried out to measure level of Cys C along with the concentrations of HDL in the plasma and they found that elevated level of plasma CysC in AD subjects.

Drug treatments in alzheimer’s disease

Drug therapy was recommended for the treatment of AD was aducanumab, and it is setback because of its side effects. There is still hope to develop drug therapies for the treatment in future time for disease-modifying treatment (DMT) for AD [55]. BAN2401 was recommended drug for the cognitive decline after Phase II trial. The Recommended drugs for the treatment of AD should be used in initial period of AD and to prevent further progression and manifestation of disease and dementia. Such treatment needs to find patients with early stages of AD, hence for such therapies patient should be diagnosed, evaluated, and treated for prior disease condition [29]. Aducanumab was the initially approved drug for disease-modifying treatment (DMT) by Food and Drug Administration (FDA, USA) targeting to targeting amyloid beta (Aβ) plaques. However, this drug does not full access all over globe by European Medicines Agency as they recommended further clinical trial for the efficacy of the drug [33].

The drugs available now days are based on the prevention of symptoms and their control, the therapy are based on four targets such as acetylcholinesterase inhibitors and tau hyperphosphorylation, diabetes, and psychological help [5]. The drugs recommended for disease modifying treatments are based on their approach of disease modification such as neuroprotection or neurotrophic, which mainly consist of anti-amyloid therapy [56] (Table 1).

Anti-amyloid therapy

As the hallmark symptoms of AD is accumulation of amyloid, hence majority of treatment therapies target to the amyloid protein. The principal approach used to target amyloid is passive immunization by provision of exogenous monoclonal antibodies (mAbs) [57].

Cholinesterase inhibitors

The currently available drug therapy approved by FDA are based on cholinesterase inhibitions  consists of four drugs  for the treatment of AD viz., tacrine, donepezil, galantamine, and rivastigmine, all of which are cholinesterase inhibitors. These drugs are helps in improvement of neurotransmission by keeping intact acetylcholine. The cholinergic neurotransmitter have vital role in cognition and memory comes with several side effects such as nausea, diarrhea and vomiting [67]. Other than the targeted cholinesterase inhibition, other drugs recommended are N-methyl-D-aspartate (NMDA)-receptor antagonists [68].

Tacrine or tetra-hidro-aminoacridine (THA)

One of cholinesterase inhibitor recommended and approved by FDA is Tacrine, having reversible inhibitions of cholinesterase. The tacrine having half-life up to 4 hours and can be metabolized in liver through cytochrome. There are investigation have been conducted to detect the efficacy of this drug since 1981 and each study have shown its significant effectiveness [69] and also shown improvement [70].


The second recommended drug as the cholinesterase inhibitor is Donepezil, which is more potent than Tacrine. In one of the case study in which around 900 patients were treated with this drug and observed positive outcome in 15 to 30 weeks such as cognitive improvement and doses, were administered for this investigations were 5 to 10 mg [71].


Rivastigmine is another cholinesterase inhibitor drug involved in specific carbamates acetylcholinesterase activity in brain. The drug induces pseudoirreversible, helps in consistent prevention of acetylcholinesterase activity, even after the removal of the drug. The half-life of these drugs is up to 1 hour and efficacy of the drugs can be lasts for up to 10 hours [72].


Galantamine is one more cholinesterase inhibitor acts on nicotine receptors through the allosteric modulatory action. This drug has dual action like cholinesterase inhibitor and presynaptic activation for the secretion of acetylcholine, glutamate, monoamines, and GABA. The drug has shown significant recovery in case of cognitive decline and psychiatric symptoms [73-74].

Conclusion and future prospective

Blood biomarkers are the important source of non-invasive diagnosis of AD, but unfortunately the specificity and sensitivity of CSF biomarkers remain higher than that of Blood Biomarkers. Indeed, it is necessary to produce a biomarker to predict AD before symptoms arise. Genetic risk factors and neuro-imaging will definitely play a vital role in AD biomarker. Even after an extensive study research in this area, yet there is no potential standard blood biomarker available for AD diagnosis. On the basis of reports available from various study groups, GFAP can be considered one of the most potential biomarkers with a sensitivity of 90% and specificity of 80%, which also matches with the condition and parameters for an ideal biomarker. Based on the results, it can be concluded that Cystatin and high density lipoproteins can be used to detect AD subjects from normal subjects.

The progress and development therapeutics for the AD treatment with the help of antibody can be one of the beneficial approaches which have shown significant mitigation but yet failed to pheasible clinical translations [75-80] may be because of secondary effect of antibodies. Therefore, the application of antibody approach needs thorough investigation to increase the therapy efficacy [81]. The antibody approach used to diagnosis and treatment of AD have some other issue also like drug molecules involved can cross blood-brain barrier (BBB) and targets other molecules can cause other pathologies [82].

There is need of development modern therapy for the complete mitigation of AD as the dementia can be symptoms of AD and other diseases. Hence, there be wrong diagnosis more often has been done regarding this. To mitigate AD along with pharmacological treatment also requires special care to individuals suffering from it as bio-psychosocial aspects.

For future, there is urgent need to develop which can use biomarkers from peripheral blood or plasma which helps in the rapid diagnosis of AD. As the protein like amyloid, tau and neuro-filament protein involved in AD, hence we require accurate and sensitive technique to monitor the level of such molecules in body fluids for rapid diagnosis of AD with respect to amyloidogenesis and neurodegeneration [24,83-84].


Authors are thankful to the Department of Biotechnology, School of Life Sciences, Swami Ramanand Teerth Marathwada University, Nanded for laboratory and other necessary facilities.

Conflict of interest

The authors declare that they have no conflict of interest.

Declaration of ethical studies

No actual animal studies were performed in the present investigations.


Shaikh AbdulBasit MustakAhamad

Umesh Pravin Dhuldhaj


The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.


Conflict of interest: The authors have no relevant financial or non-financial interests to disclose.

Ethical approval: Not applicable.

Consent to participate: Not applicable.

Consent for publication: Not applicable



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Citation: Shaikh Abdul Basit Mustak Ahamad, Umesh Pravin Dhuldhaj. Potential Plasma Biomarkers for Diagnosis of Alzheimer’s disease: an Overview. Prog. Chem. Biochem. Res., 7(2) (2024) 114-128