Ostaszewski, Beth L.

Abstract INTRODUCTION Tau species lacking truncation of the N‐terminal region, including plasma N‐terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late‐onset sporadic Alzheimer's disease (AD). METHODS Here, we examined cross‐sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD). RESULTS NT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non‐carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross‐sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p‐tau217 and other phospho‐tau species. DISCUSSION Together, our results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related clinical, cognitive, and biomarker outcomes. Highlights Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non‐carrier family members, our results suggest that plasma N‐terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β‐amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related tau pathology and neurodegeneration across a wide spectrum of disease.

AbstractBackgroundBlood based biomarkers that predict cognitive decline and Alzheimer’s disease (AD) pathology have the potential to accelerate AD therapeutic development and improve clinical care. Prior work suggests that plasma biomarkers of tau pathology (particularly post‐translational modifications of tau) may be highly useful in diagnosis and risk stratification for AD‐related neurodegeneration and cognitive decline. Levels of tau species lacking truncation of the N‐terminal region, particularly plasma and cerebrospinal fluid (CSF) levels of N‐terminal tau fragment 1 (NT1), have previously been shown to predict cognitive decline, neurodegeneration, and tau pathology in preclinical and symptomatic late‐onset AD. Here we examined plasma NT1 as a possible predictor of cognitive, clinical, pathologic, and neurodegenerative trajectories in autosomal dominant AD (ADAD) using data from the Dominantly Inherited Alzheimer Network Observational Study (DIAN‐Obs).MethodsAssociations between plasma NT1 levels and Mini‐Mental State Exam (MMSE), Clinical Dementia Rating SumBox® (CDR‐SB), hippocampal volume (HV), estimated years to symptom onset (EYO), Pittsburgh‐Compound‐B PET, and CSF Aβ42, and p‐tau181 were assessed using linear regression (150 pathogenic variant carriers, 81 non‐carriers; mean[SD] carrier age = 40.1 [10.4] years and EYO = ‐5.4 [10.4]). Plasma NT1 was measured using the Quanterix HD‐X platform. PET, MRI, clinical, and biofluid measures were derived using previously described procedures in DIAN‐Obs.ResultsCross‐sectional plasma NT1 levels in ADAD carriers were significantly associated with MMSE, CDR‐SB, HV, and p‐tau181 even after adjusting for EYO (Table 1; Figure 1). NT1 levels statistically diverged between carriers and non‐carriers 6.8 years before estimated symptom onset (Figure 2). In contrast, plasma NT1 levels were not significantly correlated with measures of β‐amyloid pathology after adjusting for EYO.ConclusionPlasma NT1 levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with CSF measures of tau pathology, but NT1 levels were not strongly associated with CSF or PET measures of β‐amyloid pathology, unlike some previously‐studied plasma tau measures. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1 may be a useful biomarker of AD‐related tau pathology and neurodegeneration across a broad spectrum of disease.