Plasma Tau levels in cognitively normal middle-aged and older adults
Plasma Tau levels in cognitively normal middle-aged and older adults
Key Findings
- Study Population: 126 cognitively normal middle-aged and older adults (45-95 years old)
- Plasma Tau Levels: Older group (65-95 years): 18.14 ± 7.33 pg/ml vs. Middle-aged group (45-64 years): 14.35 ± 6.49 pg/ml (P = 0.029)
- Age Association: Plasma tau levels positively associated with age (r = 0.359, P < 0.001)
- Variance Explained: Age explained approximately 13% of the variance in plasma tau levels (R² change 0.129, P < 0.001)
- ApoEε4 Effect: Carriers had higher plasma tau levels than non-carriers (F = 6.149, P = 0.001)
- Gender Effect: Men had higher plasma tau levels than women (F = 6.149, P = 0.001)
Abstract
Using an ultra-sensitive technique, an immunomagnetic reduction assay, the plasma tau level can be measured to a limit of quantification of pg/ml. In total 126 cognitively normal middle-aged and older adults (45–95 years old) were recruited. The plasma tau levels were significantly higher in the older group (aged 65–95 years) 18.14 ± 7.33 pg/ml than those in the middle-aged group (aged 45–64 years) 14.35 ± 6.49 pg/ml when controlled gender and ApoEε4 carrier status (F = 3.102, P = 0.029).
The ApoEε4 carriers had higher plasma tau levels than the non-carriers when controlled age and gender (F = 6.149, P = 0.001). Men had higher plasma tau levels than their women counterparts when controlled ApoEε4 carrier status and gender (F = 6.149, P = 0.001). The plasma tau levels were found to be positively associated with their ages (r = 0.359, P < 0.001).
Study Design and Methods
Participants
The study recruited 126 cognitively normal adults aged 45–95 years (mean: 66.7 ± 9.6 years), of whom 61.1% were women. The subjects included:
- Middle-aged group: 56 participants (45-64 years old)
- Older group: 70 participants (65-95 years old)
| Characteristics | All (126) | Middle-aged (56) | Older (70) |
|---|---|---|---|
| Years of age (range) | 66.7 ± 9.6 (45–95) | 58.1 ± 4.9 (45–64) | 73.6 ± 6.3 (65–95) |
| Gender women % | 61.6 | 70.9 | 54.3 |
| Years of education | 13.2 ± 3.7 | 13.5 ± 3.5 | 13.0 ± 3.9 |
| TMSE score | 28.5 ± 1.6 | 29.0 ± 1.3 | 28.2 ± 1.8 |
| ApoEε4 (%) | 18.3 | 14.3 | 21.4 |
| Plasma tau (pg/ml) | 16.46 ± 7.2 | 14.35 ± 6.49 | 18.14 ± 7.33* |
*Significant group difference when controlled for gender and ApoEε4 carrier status by ANCOVA, F = 3.102, P = 0.029
Immunomagnetic Reduction (IMR) Assay
The plasma tau protein levels were measured using an ultra-sensitive immunomagnetic reduction assay:
- Reagent: Dextran-coated Fe₃O₄ nanoparticles functionalized with anti-tau antibodies
- Antibody: Mouse monoclonal clone tau46 (Sigma, T9450) recognizing phosphorylation-independent epitope in amino acids 404-441
- Mean Diameter: 53 nm nanoparticles
- Detection Method: SQUID-based AC magnetosusceptometer (XacPro-S, MagQu)
- Sample Preparation: 60 µl plasma mixed with 60 µl reagent at room temperature
- Limit of Quantification: pg/ml level
Structural MRI Analysis
High-resolution brain MRI scans were acquired using a 1.5 T MRI scanner (n = 123 subjects):
- T1-weighted 3D SPGR sequence (TE = 9.3 ms, TR = 3.9 ms, TI = 600 ms, flip angle = 12°)
- Matrix size = 192 × 192, FOV = 25 cm
- 170 contiguous sagittal slices at 1.3 mm thickness
- Analysis using FreeSurfer software package (version 5)
Results
Age and Plasma Tau Relationship
Correlation analyses demonstrated significant relationships:
- Positive correlation: Age and plasma tau levels (r = 0.359, P < 0.001)
- Negative correlation: Age and TMSE scores (r = -0.543, P < 0.001)
- Age explained approximately 13% of the variance in plasma tau levels (R² change 0.129, F = 18.329, P < 0.001)
Brain Structure Associations
Stepwise regression analysis revealed age effects on brain structures:
| Brain Structure | Model | R² Change | F Value | P Value |
|---|---|---|---|---|
| Right Hippocampus Volume | Age | 0.167 | 23.607 | < 0.001 |
| Right Hippocampus Volume | ApoEε4 | 0.030 | 4.390 | 0.038 |
| Left Hippocampus Volume | Age | 0.131 | 17.836 | < 0.001 |
| Right Amygdala Volume | Age | 0.086 | 11.131 | 0.001 |
| Left Amygdala Volume | Age | 0.097 | 12.622 | 0.001 |
| Corpus Callosum Central Volume | Age | 0.085 | 10.949 | 0.001 |
| White Matter Hypodensity | Age | 0.123 | 16.561 | < 0.001 |
Important Finding: However, the plasma tau levels did not further explain any residual variance in the volume of brain structures beyond the age effect.
Discussion
Age Effect on Plasma Tau
The aging-related elevation of plasma tau protein levels found in cognitively normal adults might be a consequence of the normal aging process of the brain. The elevated plasma tau levels may imply increasing production of tau protein in the brain with increasing age. This hypothesis is compatible with the age-related increment in tau-related pathology, such as tangle formation and neuronal loss, even in non-demented aging individuals.
Clinical Implications
- Surrogate Biomarker: Plasma tau levels appear useful as a surrogate biomarker representing disease severity rather than only the effect of aging
- Disease Monitoring: Can be used to monitor disease progression or beneficial responses to disease-modifying therapies
- Contrast with MCI/AD: Plasma tau levels were negatively correlated with hippocampal and brain volumes in patients with MCI or mild AD, but not in cognitively normal controls
Advantages of IMR Assay
- Ultra-high Sensitivity: Detection limit at pg/ml level
- Resistance to Interference: More resistant to interference from blood components (albumin, bilirubin)
- Simplified Sample Preparation: Straightforward processing avoiding loss of target protein
- Total Tau Measurement: Antibody recognizes all six isoforms of tau
- Higher Measures: Approximately twofold higher than conventional ELISA or Simoa™ digital ELISA
Conclusions
The study demonstrated that age significantly affects plasma tau protein levels in cognitively normal adults. The effect of age on plasma tau levels should always be considered in clinical applications of this surrogate biomarker to middle-aged and elderly subjects. The findings provide important baseline data for using plasma tau as a biomarker in neurological diseases and highlight the need to account for age-related changes when interpreting plasma tau levels in clinical settings.
Citation
M. J. Chiu, L. Y. Fan, T. F. Chen, Y. F. Chen, J. J. Chieh, H. E. Horng, "Plasma Tau levels in cognitively normal middle-aged and older adults", Front. Aging Neurosci., (2017).
Article Links
https://doi.org/10.3389/fnagi.2017.00051 http://journal.frontiersin.org/article/10.3389/fnagi.2017.00051/fullAcknowledgements
This work is supported by grants in part from New Taipei City Government (103049 SBIR), National Health Research Institutes (05A1-PHSP03-028) and National Taiwan University (105R8954-2). Technical supports for IMR from Drs. Che-Chuan Yang, Bing-Hsien Liu, Shieh-Yueh Yang at MagQu Lab, New Taipei City, Taiwan.
