Blood-Based Biomarkers and Risk of Onset of Mild Cognitive Impairment Over the Short and Long Term.

Abstract

BACKGROUND AND OBJECTIVES Blood-based biomarkers of amyloid and tau have been shown to predict Alzheimer disease (AD) dementia. Much less is known about their ability to predict risk of mild cognitive impairment (MCI), an earlier disease stage. This study examined whether levels of blood biomarkers of amyloid (Aβ42/Aβ40 ratio), tau (p-tau181), neurodegeneration (NfL), and glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], YKL40, soluble triggering receptor expressed on myeloid cells 2 [sTREM2]) collected when participants were cognitively normal are associated with the time to onset of MCI. METHODS Cognitively unimpaired participants from the longitudinal observational BIOCARD study provided blood plasma at their baseline evaluation ("baseline 1"). A second "baseline" specimen (collected using slightly different procedures) was evaluated for participants who were still cognitively normal approximately 7 years later. The plasma assays were based on the NeuroToolKit (cobas Elecsys assays, Roche Diagnostics). Cox regression models tested the association of biomarker levels with time to MCI symptom onset, separately for both baselines. RESULTS Participants included 271 individuals at "baseline 1" (mean age = 57.5 years, 60.5% female, including 82 who progressed to MCI/dementia) and 202 individuals at "baseline 2" (mean age = 64.5 years, 62.4% female, including 31 progressors). The mean clinical follow-up was 15.5 years for "baseline 1" and 9.9 years for "baseline 2." For both baselines, lower plasma Aβ42/Aβ40 ratio (both hazard ratios, HRs ≤ 0.69, 95% CIs ≤ 0.55-0.87, p ≤ 0.034), higher GFAP (HRs ≥ 1.83, CIs ≥ 1.28-2.60, p < 0.002), and a higher ratio of p-tau181/(Aβ42/Aβ40) (HRs ≥ 1.64, CIs ≥ 1.25-2.13, p ≤ 0.001) were each associated with an earlier time to MCI symptom onset. For baseline 2, higher p-tau181 (HR = 2.07, CI = 1.12-3.83, p = 0.021) and higher NfL (HR = 1.75, CI = 0.99-3.10, p = 0.05) were also associated with earlier MCI symptom onset for progression within 7 years. When combining biomarkers, neither GFAP nor NFL was associated with MCI symptom onset after accounting for AD biomarker levels (e.g., p-tau181/(Aβ42/Aβ40)), which remained significant. YKL40 and sTREM2 were not associated with MCI onset. DISCUSSION Results indicate that during preclinical AD, more abnormal blood biomarker levels of amyloid (Aβ42/Aβ40), p-tau181, neurodegeneration (NfL), and neuroinflammation (GFAP) individually are associated with progression from normal cognition to MCI, but the AD-nonspecific neurodegeneration and inflammation markers were not associated with symptom onset after accounting for amyloid and p-tau levels.