Association of Rapidly Elevated Plasma Tau Protein With Cognitive Decline in Patients With Amnestic Mild Cognitive Impairment and Alzheimer's Disease

Abstract

Objective: Whether elevation in plasma levels of amyloid and tau protein biomarkers are better indicators of cognitive decline than higher baseline levels in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) remains understudied.

Methods: We included 67 participants with twice testing for AD-related plasma biomarkers via immunomagnetic reduction (IMR) assays (amyloid beta [Aβ]1-40, Aβ1-42, total tau [t-Tau], phosphorylated tau [p-Tau] 181, and alpha-synuclein [α-Syn]) and the Mini-Mental State Examination (MMSE) over a 1-year interval. We examined the correlation between biomarker levels (baseline vs. longitudinal change) and annual changes in the MMSE scores. Receiver operating characteristic curve analysis was conducted to compare the biomarkers.

Results: After adjustment, faster cognitive decline was correlated with lower baseline levels of t-Tau (β=0.332, p=0.030) and p-Tau 181 (β=0.369, p=0.015) and rapid elevation of t-Tau (β=-0.330, p=0.030) and p-Tau 181 levels (β=-0.431, p=0.004). However, the levels (baseline and longitudinal changes) of Aβ1-40, Aβ1-42, and α-Syn were not correlated with cognitive decline. aMCI converters had lower baseline levels of p-Tau 181 (p=0.002) but larger annual changes (p=0.001) than aMCI non-converters. The change in p-Tau 181 levels showed better discriminatory capacity than the change in t-Tau levels in terms of identifying AD conversion in patients with aMCI, with an area under curve of 86.7% versus 72.2%.

Conclusion: We found changes in p-Tau 181 levels may be a suitable biomarker for identifying AD conversion.

Keywords: Alzheimer’s disease; Amyloid; Biomarker; Mild cognitive impairment; Tau protein.

Figure 1.

Network analysis of intercorrelation between cognitive decline and protein biomarkers. Partial correlation with adjustment of age, gender, education levels, and follow-up duration was performed, and only statistically significant associations were shown. The asterisk indicates the four variables that were significantly correlated with the change of MMSE scores. The green line indicates positive association, whereas the red line indicates negative association. The thicker and thinner width of lines indicates higher and smaller association, respectively. The positive and negative number inside the lines indicates positive and negative association with variables, respectively. For example, the 0.33 between tTau_B and MMSE_C indicates faster cognitive decline defined by change of MMSE during 1-year follow-up period was correlated with lower baseline levels of tTau (β=0.332, p=0.030). Furthermore, -0.43 between pTau_C and MMSE_C indicates faster cognitive decline defined by change of MMSE during 1-year follow-up period was correlated with rapid elevation of p-Tau 181 levels. p-value<0.05 indicates statistically significant. α-Syn, alpha-synuclein; Aβ, amyloid beta; B, baseline; C, change; F, follow-up; MMSE, Mini-Mental State Examination; pTau, phosphorylated tau (pTau indicates p-Tau 181); tTau, total tau.

Figure 2.

Group differences in baseline levels, change levels, and follow-up levels of p-Tau 181. A: Baseline p-Tau 181 levels (pg/mL). B: Annual change in p-Tau 181 levels (pg/mL). C: Follow-up change in p-Tau 181 levels (pg/mL). p-Tau, phosphorylated tau; HC, healthy control; aMCI, amnestic mild cognitive impairment; AD, Alzheimer’s disease; ns, not significant.

Figure 3.

Baseline dementia-related proteins of aMCI converters vs. non-converters. aMCIs converters were defined as individuals with aMCI who eventually progress to AD after 1-year follow-up period. aMCIs non-converters were individuals with aMCI, who did not progress to AD after 1-year follow-up period. Bold type indicates statistical significance. A: aMCI non-converter. B: aMCI converter. p-Tau, phosphorylated tau; Aβ, amyloid beta; α-Syn, alpha-synuclein; aMCI, amnestic mild cognitive impairment; AD, Alzheimer’s disease.

Figure 4.

Discriminatory capacity of change levels of pTau 181 vs. Tau in predicting Alzheimer’s disease conversion. p-Tau, phosphorylated tau; ROC, receiver operating characteristic; AUC, area under the ROC curve.