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Blood level of β-amyloid, Tau, and p-Tau in mild cognitive impairment and Alzheimer disease: A follow up study
For correspondence: Dr Sharmistha Dey, Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110 029, India e-mail: sharmistha_d@hotmail.com
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Received: ,
Accepted: ,
How to cite this article: Pradhan R, Kumari S, Singh AK, Rao AR, Yadav Y, Upadhyay AD, et al: Blood level of β-amyloid, Tau, and p-Tau in mild cognitive impairment and Alzheimer disease: A follow up study. Indian J Med Res. 2026;163:166-73. doi: 10.25259/IJMR_2164_2025.
Abstract
Background and objectives
Deposition of β-amyloid and phosphorylated-tau proteins are major neuropathological abnormality in brain of patients with Alzheimer disease. This study aimed to study the role of various serum protein biomarkers to aid in the diagnosis and progression of Alzheimer disease.
Methods
Blood samples were collected from 96 patients with Alzheimer disease, 75 patients with mild cognitive impairment, and 70 geriatric controls at baseline. The number of patients (Alzheimer disease and mild cognitive impairment) who progressed after 1 year was 12, while the number of non-progressors was 24. Serum levels of β-amyloid1-42 (Aβ1-42), Tau, and phosphorylated-Tau181 (pTau) were quantified using surface plasmon resonance and further validated by Western blot.
Results
Comparison of proteins between the three groups revealed significantly lower Aβ1-42, higher Tau and pTau protein expression in serum of patients with Alzheimer disease as compared to patients with mild cognitive impairment and controls. In patients who progressed after one year, the baseline concentration of Aβ1-42 protein was significantly higher than their follow-up levels. Tau and pTau levels also increased significantly over the years. In non-progressors, no significant difference was observed in Aβ1-42, Tau, and pTau concentration between the baseline and follow up.
Interpretation and conclusions
Aβ1-42, Tau, and pTau proteins can serve as potential blood-based biomarkers for the diagnosis and monitoring the progression of Alzheimer disease.
Keywords
Alzheimer disease
Biomarker
Mild cognitive impairment
Non- progressor
Progressor
Surface plasmon resonance
Alzheimer disease is a leading cause of dementia. The neuropathological signatures of the disease include extracellular aggregation of β-amyloid (Aβ) plaques and the cytoplasmic clustering of mis-folded phosphorylated-Tau181 (pTau) resulting in the intraneuronal accumulation of neurofibrillary tangles.1
The proteolytic cleavage of amyloid precursor protein (APP) by the consecutive fractionation of α-secretase and γ-secretase results in the formation of Aβ in brain and peripheral circulation, throughout the life of an individual2 for controlling synaptic plasticity and regulating neurogenesis.3,4 At disease condition, APP is cleaved by β-secretase (BACE1) and γ-secretase to release pathogenic Aβ plaques and released into the peripheral blood by disrupting the blood-brain barrier (BBB) and receptor-mediated mechanisms.5 Being the upstream molecule, Aβ trigger the hyper-phosphorylation of Tau proteins,6 by the activation of glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase 5 (CDK5).7-11 GSK-3β is a key contributor to tauopathy and Aβ-induced toxicity of Tau protein.12,13 These together lead to the neuronal loss, synaptic damage and finally cognitive deterioration.
Active research is underway to establish Tau, p-Tau and Aβ as reliable blood-based biomarkers for Alzheimer disease.14-16 This includes a recent study published on an Indian cohort.17 Some metabolites and other compounds are also under research, so as to develop them as early blood-based biomarkers for the disease.18 Despite ongoing research, the search for Alzheimer disease diagnostic biomarkers has always been challenging, and the only invasive modalities for the diagnosis of Alzheimer disease are neuroimaging and CSF analysis. To detect and track the disease progression, there is an urgent need for the development of low-cost, less invasive, and convenient blood based biomarkers.
We conducted this study to assess the concentration of Aβ1-42, Tau and pTau181 proteins in serum samples of patients with (a) Alzheimer disease and (b) mild cognitive impairment at baseline and tracking disease progression via real-time, label-free surface plasmon resonance (SPR) technology to predict the potential of each protein as a diagnostic and prognostic marker.
Methods
This cross sectional and prospective follow up study (March 2021 - August 2024) was undertaken by the department of Biophysics, All India Institute of Medical Sciences (AIIMS), New Delhi. The study participants were recruited from the Memory Clinic and OPD of the Geriatric Medicine department, AIIMS, New Delhi. The Institute Ethics Committee approved the study protocol.
A total of 241 subjects aged 60 years and above were recruited of which 96 had Alzheimer disease, 75 had mild cognitive impairment, and 70 were normal controls. Patients with any other neurodegenerative disease, serious illness, or chronic disease were excluded.
Clinical assessment and management:
Assessment and diagnosis: Patient’s detailed history was obtained, including socioeconomic status, years of education, occupation, living status, comorbidities, disease duration, family history of Alzheimer disease, disease onset, progression, domains involved, mood, behavioral complaints, activities of daily living, and motor function. Neuropsychological assessment was conducted using the Hindi Mental State Examination (HMSE) and Addenbrooke’s cognitive assessment III (ACE-III) for individual patients and controls. HMSE scores categorized for these study groups were as follows-geriatric control: >26, mild cognitive impairment: 17-25 and Alzheimer disease:<17. According to ACE-III scores, these three groups were categorised as geriatric control: >71, mild cognitive impairment: 62-71, and Alzheimer disease: <62. The National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders (NINCDS-ADRDA) criteria and ACE III scores were used to diagnose Alzheimer disease. Geriatric control were aged 60 years and above and free from neurodegenerative disease, cancer, or any other chronic disease. Functionality was assessed using the Instrumental Activities of daily living scale (IADL-EDR), and depression was evaluated using the geriatric depression scale (GDS).
Common reversible causes of dementia were ruled out on the basis of thyroid function, serum Vitamin B12 levels, brain magnetic resonance imaging (MRI) and nuclear imaging (FDG and Tau-PET).
Management and follow up
All patients underwent integrated and individualized multimodal therapy, including physiotherapy, dietary interventions, and cognitive therapy. Patients with mild cognitive impairment continued non-pharmacological therapy, except for selected patients with amnestic-mild cognitive impairment who received anticholinesterase inhibitors (donepezil/rivastigmine). Anticholinesterase inhibitors, memantine, or a combination of both were initiated in patients with Alzheimer disease. Antidepressants and atypical antipsychotics were used when indicated for mood and behavioral complaints.
The patients were followed up every 6 months for 1 year, and a neuropsychological assessment was repeated to evaluate disease progression and response to therapy. The functional status of the patients and their caregiver’s stress levels were also assessed. The management plan was revised based on repeated evaluations.
Blood sample collection and serum separation
Three mL of blood sample was collected twice from study participants, at baseline and after completion of one year follow up. The blood was withdrawn into a plain sterile blood vial and serum separation was carried out by centrifuging the blood samples for 10 min at 3000 rpm. Serum was further aliquoted into the cryo-vials and was stored at -80°C for the experimental use. Serum levels of Aβ1-42 Tau and pTau protein were assessed at two time points, at baseline and follow-up in progressor and non-progressor patients using SPR and further validated by Western blot.
Quantification of serum proteins by SPR technique
Serum Aβ1–42 Tau and pTau protein levels were quantified by the SPR technique using BIAcore-3000 (Wipro GE Healthcare, Sweden), which was used for real-time monitoring of bimolecular interactions. Primary antibodies i.e., mouse anti-human Aβ1-42 monoclonal IgG (Santa Cruz Biotechnology), mouse anti-human Tau Monoclonal IgG (Santa Cruz Biotechnology), rabbit anti-human pTau 181 monoclonal IgG (Cell Signaling Technology) were used for immobilization on CM5 sensor chip using the amine coupling kit (Wipro GE Healthcare, Sweden).
Different concentrations of Aβ1-42 peptide (purchased from AnaSpec, USA) was passed over the immobilized Aβ1-42 antibody. Purified human Tau (recombinant protein) and synthesized phospho-peptide of Tau at threonine 181 (isoform1) were passed over the immobilized Tau and pTau181 antibodies.
Serum samples were diluted (1:80) with HBS-EP buffer and were passed over the immobilized antibodies on the CM5 sensor chip. The RU of each sample was extrapolated on the respective standard curves, the concentration of serum Aβ1-42, Tau and pTau181 proteins of all subjects were determined.
Western blot validation of serum proteins
The expression level of serum proteins at baseline and follow up in Alzheimer disease and mild cognitive impairment was analysed by western blot with few samples to further validate the SPR result done with monoclonal antibody to capture the proteins in serum. Albumin was separated from serum using the albumin out kit (G-Biosciences) and serum protein concentration was measured using BCA (Pierce™ BCA Protein Assay Kit). Two samples from each group of progressors and non-progressors at baseline and follow up were taken and loaded equally (30 µg) on 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS–PAGE) and further transferred to PVDF membrane.19The same primary antibodies mentioned above in the SPR study and HRP-conjugated secondary antibodies, were used for the western blot experiments.
Statistical analysis
Graph Pad prism8 and STATA 14 software (StataCorp, College Station, TX, USA) were used for statistical analysis. Variables were calculated as mean (SD) and frequency percentage. One-way ANOVA followed by Bonferroni post hoc test was used for continuous variables and chi-square test was used for categorical variables. Covariance analysis was performed to see the difference in the protein levels between Alzheimer disease, mild cognitive impairment, and geriatric control after adjusting age, duration of disease, family history of Alzheimer disease, joint disease and diabetes mellitus. ROC analysis was conducted to determine the cut-off concentration of Aβ1-42, Tau and pTau 181 proteins. The Mann-Whitney U test was performed to compare protein levels between baseline and follow up patients. Correlation between two continuous variables was determined by using Pearson’s correlation coefficient. Statistical significant was defined as P<0.05.
Results
Enrolment of participants is depicted in Figure 1.
- Schematic representations of recruited study group.
Demographic and clinical attributes of study subjects
Baseline characteristics of 241 study participants are presented in Table I. The mean age of study subjects in Alzheimer disease was higher than mild cognitive impairment and geriatric control [72.6 (6.9), 70.3 (5.4), and 68.5 (5.96)], respectively. Education, place of residence (urban/rural), and employment status did not differ between the 3 groups.
| Parameters | Alzheimer disease (n= 96) | Mild cognitive impairment (n=75) | Geriatric control (n=70) | P value |
|---|---|---|---|---|
| Sex (male:female) | 62:34 | 49:26 | 46:24 | 0.988 |
| Family history of Alzheimer disease, n (%) | 20 (20.9) | 13 (17.8) | 0 | 0.050 |
| Disease duration > 2yr, n (%) | 47 (63.5) | 18 (32.1) | NA | 0.001 |
| CDI (mean±SD) | 41.96±33.71 | 18.15±22.14 | 5.22±17.93 | <0.001 |
| HMSE (mean±SD) | 12.86±5.62 | 21.37±4.53 | 28.11±1.38 | <0.001 |
| ACE III (mean±SD) | 39.10±17.35 | 65.36±10.02 | 91.07±4.42 | <0.001 |
| GDS (mean±SD) | 3.76±3.15 | 4±3.32 | 2.61±2.87 | 0.478 |
| History of hypertension | 49 (51.0) | 33 (44.0) | 32 (45.7) | 0.626 |
| History of diabetes | 28 (29.2) | 22 (29.3) | 10 (14.3) | 0.051 |
| History of Joint disease, n(%) | 7 (7.3) | 1 (1.3) | 33 (47.1) | <0.001 |
CDI, cognitive disability index; HMSE Hindi Mental State Examination scores below 26; and ACE III Addenbrooke’s Cognitive Examination scores, below 72 indicates cognitive impairment; GDS, Geriatric Depression Scale scores above 9 reflects depression; NA, not applicable
Estimation of Aβ1-42, Tau and pTau protein levels by SPR
The baseline response unit (RU) obtained after immobilization for Aβ1-42, Tau and pTau was 22068.6, 22070.8 and 21986.3, respectively. Supplementary Figure 1. The standard curve was generated by plotting response units (RU) against their respective concentration and association of the above mentioned proteins with antibody are represented in Supplementary Figure 2.
The Aβ1-42 protein level was found to be significantly lower in Alzheimer disease as compared to mild cognitive impairment and geriatric control. Tau and pTau proteins were significantly increased in Alzheimer disease and mild cognitive impairment as compared to geriatric control ( Table II).
| Protein | Unadjusted/Adjusted* | Alzheimer disease (A) | Mild cognitive impairment (B) | Geriatric control (C) | P value |
Post-hoc comparisons (P value) |
|---|---|---|---|---|---|---|
| Aβ1-42 (µg/µL) | Unadjusted | 1.16±0.01 | 1.22±0.01 | 1.35±0.02 | <0.001 | A vs. C <0.001; B vs. C <0.001; A vs. B <0.003 |
| Adjusted | 1.16±0.01 | 1.19±0.01 | 1.35±0.02 | <0.001 | A vs. C <0.001; B vs. C <0.001; A vs. B 0.522 | |
| Tau(ng/µL) | Unadjusted | 64.50±1.19 | 60.46±1.01 | 54.13±1.24 | <0.001 | A vs. C <0.001; B vs. C <0.001; A vs. B 0.012 |
| Adjusted | 64.49±1.06 | 60.47±1.21 | 52.09±1.38 | <0.001 | A vs. C <0.001; B vs. C <0.001; A vs. B 0.007 | |
| pTau(ng/µL) | Unadjusted | 0.74±0.01 | 0.66±0.01 | 0.58±0.07 | <0.001 |
A vs. C <0.001; B vs.C <0.001; A vs. B <0.001 |
| Adjusted | 0.74±0.01 | 0.66±0.01 | 0.57±0.02 | <0.001 | A vs. C <0.001; B vs. C <0.001; A vs. B <0.001 |
*Adjusted for age, duration of disease, family history of Alzheimer disease, joint disease and diabetes mellitus
After the adjustment of age, duration of disease, family history of Alzheimer’s disease, joint disease, and diabetes mellitus, the serum protein levels of Aβ1-42, were significantly lower, while Tau and pTau were higher in Alzheimer disease as compared to mild cognitive impairment and geriatric controls ( Table II). The serum Tau level varied significantly with respect to education in the illiterate and literate subgroups of the Alzheimer’s disease category. Whereas, no significant differences were observed between protein concentrations with respect to sex, occupation, locality, and hypertension within the groups (Supplementary Table I).
ROC analysis
ROC analysis was performed to evaluate the diagnostic potential of Aβ1-42, Tau and pTau as biomarkers of disease. For differentiating Alzheimer disease vs. geriatric control, the area under curve (AUC) was found to be 0.829 for Aβ1-42, 0.770 for Tau and 0.846 for pTau. While, for differentiating mild cognitive impairment vs geriatric control, the area under curve (AUC) was found to be 0.762 for Aβ1-42, 0.681 for Tau and 0.680 for pTau. The sensitivity, specificity and cut off of the protein markers are illustrated in the Figure 2.
- ROC Curve analysis of (A), (B) Aβ1-42, (C), (D) Tau and (E), (F) p Tau proteins in Alzheimer disease vs. geriatric control and mild cognitive impairment vs. geriatric control at baseline.
Correlation analysis of protein concentration. with ACE III and HMSE score
Pearson correlation analysis revealed that decreased HMSE and ACE III scores were associated with lower Aβ1-42 protein levels, demonstrating a significant positive correlation. However, in the case of Tau and pTau, poor HMSE and ACE III scores correlated with higher protein levels exhibiting a significant negative correlation ( Fig. 3). Correlation among the protein markers, HMSE scores and ACE III scores were interpreted in a correlation matrix (Supplementary Figure 3).
- Correlation between (A), (B) Aβ1-42, (C), (D) Tau and (E), (F) pTau protein concentrations with HMSE and ACE III scores at baseline.
SPR data of follow up patients with demographic and clinical parameters
Progressors who exhibited severe deterioration in functionality showed a decrease in mean HMSE and ACE III scores from baseline. In contrast, non-progressors with stable cognitive status displayed minimal changes in these scores over the one-year follow-up period (Supplementary Table II).
In progressors, baseline Aβ1-42 protein concentration was significantly higher as compared to follow-up. While in non-progressors, no significant difference in protein levels at baseline and follow up was observed.
In progressors, follow up concentration of Tau and pTau increased significantly as compared to the baseline values. However, among non-progressors, no significant difference was observed in protein concentration at baseline and follow up ( Table III).
| Protein concentration |
Progressor baseline (n=12) |
Progressor follow up (n=12) |
P value | Non progressor baseline (n=24) | Non progressor follow up (n=24) | P value |
|---|---|---|---|---|---|---|
| Aβ1-42 (µg/µL) | 1.20±0.11 | 1.09±0.13 | 0.030 | 1.23±0.16 | 1.21±0.16 | 0.496 |
| Tau (ng/µL) | 65.20±10.25 | 77.32±13.39 | 0.030 | 66.32±9.71 | 67.37±9.65 | 0.797 |
| pTau (ng/µL) | 0.69±0.12 | 0.85±0.09 | 0.003 | 0.73±0.12 | 0.74±0.11 | 0.796 |
Western blot of patients on follow up
For Aβ1-42, in the case of progressors, there was a decrease in the band density in follow up compared to baseline. In non-progressors, there was a slight change in band density between follow up and baseline. For the Tau and pTau proteins, the band density increased in the follow-up cases relative to baseline in the progressors. In non-progressors, there was a slight change in band density between follow up and baseline (Supplementary Fig. 4).
Discussion
Our study investigated the prospective progression by SPR based detection of blood Aꞵ1-42, Tau and pTau proteins, hall-mark pathology correlating their levels with cognitive status over the time. The difference in serum levels of Aβ1-42, Tau and pTau181 protein at baseline data and progression were associated with prospective cognitive deterioration. The blood level of Aβ1-42 can differentiate Alzheimer disease and mild cognitive impairment from elderly controls with higher sensitivity and specificity, whilst Tau and pTau levels can only differentiate between Alzheimer disease and geriatric control. Our findings hypothesized that blood Aꞵ1-42 levels decrease, while Tau and pTau levels increase, with disease progression.
Our findings on association of educational status with serum Tau concentrations coincide with Tau-PET study, which associated the low concentration of tau protein with higher levels of education20. On Alzheimer disease continuum, in association with cognitive changes, mild cognitive impairment is a transitory state between aging and early Alzheimer’s disease.21 Amnestic mild cognitive impairment constitutes a group characterised by deficits in the primary memory component, affecting either a single or a multiple cognitive domains, but is not sufficient to determine the severity of dementia.22,15 Prevention of mild cognitive impairment to Alzheimer disease conversion may offer substantial clinical and social benefits. In our study, a significant difference in protein levels was observed between mild cognitive impairment and geriatric control, indicating that these proteins may help to identify amnestic mild cognitive impairment patients and can prevent cognitive decline. In many studies, it has been hypothesized that Aβ accumulation results from a disruption in the balance between its production and clearance. Extracellular deposition of Aβ is removed from the brain by various interacting clearance systems.23 LRP-1 (lipoprotein receptor-related protein-1) regulates the clearance of Aβ from the brain into the bloodstream, whereas RAGE (receptor for advanced glycation end products) controls the influx from the blood into the brain.24,25 In Alzheimer disease, expression LRP-1 at the blood brain barrier decreases and results in abnormal deposition of Aβ. Our study reciprocated this result, finding significantly lower levels of Aβ1-42 expression in Alzheimer disease patients than in mild cognitive impairment and geriatric controls. These levels decreased further with the progression of the disease. Several earlier studies have reported the levels of these proteins at a single time point across Alzheimer disease, mild cognitive impairment and geriatric control and observed that the decreased level of Aβ1–42/Aβ1–40 in Alzheimer disease patients correlated inversely with the neocortical amyloid burden.26 Another 18 months follow up study reported decreased plasma Aβ1–42 levels in patients who had started showing a decline in cognitive functions.27 Accumulated Aβ1-42 protein in the brain cannot be measured properly in the circulatory level. Transport mechanisms across the blood brain barrier specific for Tau remains unidentified and the specific mechanisms by which Tau is excreted from the brain are areas of ongoing research and debatable. It has been suggested that clearance of Tau mainly relies on degradation mechanism intracellularly by lysosomes and ubiquitin–proteasome mediated pathway.28 In our study, pairwise comparisons between the three study groups observed significant higher Tau and pTau protein expression in Alzheimer disease than in mild cognitive impairment and elderly controls. Our results showing increased levels of Tau and pTau in the serum of progressors with disease progression and decline in cognitive status are similar to an earlier report.15
The novelty and strength of the present study is SPR-based detection of serum levels Aβ1-42, Tau, and pTau protein markers in the prospective follow up of Indian cohort. The primary limitations of this study stem from the small sample size and short follow-up duration, which restrict the generalisability of our findings and limit our ability to establish robust, long-term correlations. Also the Western blot validation for the monoclonal antibody used in the SPR study was performed on a limited scale.
Our results provide evidence for the clinical utility of serum Tau and pTau181 as potential biomarkers for the diagnosis and monitoring progressive cognitive decline. Specifically, tracking the levels of these proteins can mark mild cognitive impairment progression, enabling earlier clinical intervention to potentially slow or prevent its deterioration into more severe stages of Alzheimer disease.
Author contributions
RP: Experiment, manuscript writing; AR: Provided the patients samples, manuscript writing; SK: Collected samples; AKS: Run some samples in Biacore; YY: prepared aggregated abeta; PK and ABD: Diagnosed the patients, provided blood samples; AKU: Statistical analysis; SD: Concept and design of work, manuscript writing. All authors have read and approve the final printed version of the manuscript.
Financial support & sponsorship
The study received funding support from the Indian Council of Medical Research (grant no (54/1/GER/2020- NCD-II) and Department of Health Research for providing the Women Scientist fellowship (R12013/27/2020-HR/E-Office:8045536) awarded to first author (RP).
Conflicts of Interest
None.
Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation
The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.
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