Age, vascular disease, and Alzheimer\u2019s disease pathologies in amyloid negative elderly adults

Tengfei Guo,Susan M Landau,William J Jagust

doi:10.1186/s13195-021-00913-5

Abstract

BackgroundWe recently reported that CSF phosphorylated tau (p-Tau181) relative to Aβ40 (CSF p-Tau/Aβ40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau181 alone. While elevations of CSF p-Tau/Aβ40 can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity.MethodsWe examined relationships between CSF p-Tau/Aβ40, and CSF Aβ42/Aβ40, Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer’s disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had 18F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ40 associations with these measures as well.ResultsElevated CSF p-Tau/Aβ40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ42/Aβ40, higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements.ConclusionsThese data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.

Highlights

We recently reported that Cerebrospinal fluid (CSF) phosphorylated tau (p-Tau181) relative to Aβ40 (CSF p-Tau/Aβ40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau181 alone
Previous studies [4,5,6,7,8] suggest that medial temporal lobe (MTL) tau aggregation may occur in the absence of abnormal Aβ pathology while Aβ pathology may be involved in driving the spread of tau out of MTL regions, producing neocortical neurodegeneration, and global cognitive decline
We examined Alzheimer’s disease neuroimaging initiative (ADNI) participants who were unambiguously Aβ- based on both CSF Aβ42/Aβ40 and Aβ PET biomarkers in order to investigate how age, sex, apolipoprotein E (APOE)-ε4, and vascular risk factors associate with the earliest detectable CSF tau crosssectionally and longitudinally, and whether elevation of CSF p-Tau can predict longitudinal hippocampal atrophy, hypometabolism, and cognitive decline

Summary

Introduction

We recently reported that CSF phosphorylated tau (p-Tau181) relative to Aβ40 (CSF p-Tau/Aβ40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau181 alone. On the AD continuum, it is likely that elevated Aβ pathology alone may be insufficient to result in global brain atrophy, cortical hypometabolism, and generalized cognitive decline, requiring this spread of tau to induce these global and neocortical abnormalities [9,10,11,12,13]. This series of events raises the question of whether Aβ is necessary for these downstream events. Recent work has suggested that while elevated MTL tau may be related to local atrophy and cognitive decline regardless of Aβ status [14,15,16], evidence of cortical hypometabolism appears to require elevated Aβ [17, 18]

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