Biomarkers - Part 1

Abstract

Background: The CSF amyloid to tau ratio can isolate cognitively healthy participants into normal Aβ₄₂/tau (CH-NAT) or a pathological Aβ₄₂/tau (CH-PAT) with a low or high risk of cognitive decline, respectively. We aim to determine if plasma Aβ₄₂/tau ratios can differentiate CH-NAT from CH-PAT participants.

Method: Study participants (> 65 years of age) were recruited, and demographic, neurological, and neuropsychological data were obtained in an ongoing HMRI Brain Aging study. Overnight fasting plasma and CSF were collected within a month of examination, and the levels of Aβ₃₈, Aβ₄₀, Aβ₄₂ (MSD 6E10 kit), and total tau were quantified using the MSD electrochemiluminescence platform. Differences in fluid biomarker levels and the plasma ratios (n = 55) and CSF ratios (Aβ₄₂/Aβ₄₀, n = 41, Aβ₄₂/tau, n = 55) were determined using nonparametric student t-test and correlations using a Spearman test.

Result: Aβ₄₀ and Aβ₄₂ levels were higher (15-18-fold, and 10-14-fold, respectively), while tau levels are 8-13-fold higher in CSF than in plasma. Plasma and CSF Aβ₄₀ were not distinct in CH-NAT compared with CH-PAT. In contrast, Aβ₄₂ levels were 30.9% lower in CH-PAT (16.3 ± 18.3 pg/ml) compared with CH-NAT plasma (23.6 ± 26.4 pg/mL) (p < 0.05). CSF Aβ₄₂ levels in CH-PAT (171.6 ± 124.6 pg/mL) were lower by 47.6% compared with CH-NAT (327.6 ± 182.6 pg/ml) (p < 0.0001). The Aβ₄₂/Aβ₄₀ ratio was significantly lower in both plasma and CSF (Table 1A). Similarly, the Aβ₄₂/tau ratio was significantly lower in plasma and CSF (Table 1B). Individually, plasma levels of Aβ₄₂ and tau did not correlate with CSF levels. However, the ratio of Aβ₄₂ to total tau in plasma significantly correlated with the CSF ratios (Spearman r = 0.36, p = 0.0071). Finally, CSF Aβ₄₂/Aβ₄₀ ratio correlated with Aβ₄₂/tau ratio for all samples, CH (n = 100) and MCI (n = 35) (Fig. 1).

Conclusion: While not as robust as CSF ratios, plasma Aβ₄₂/Aβ₄₀ and Aβ₄₂/tau ratios can isolate cognitively healthy participants with lower risk from participants with a higher risk of cognitive decline. Thus, plasma represents a less invasive medium for the biomarker classification of aging participants.