CSF p‐Tau/Aβ40 ratio predicts longitudinal hypometabolism and cognitive decline in amyloid‐negative elderly adults

Abstract

AbstractBackgroundTauopathy can be measured with PET imaging and CSF phosphorylated tau (p‐Tau), and recent studies have suggested that CSF p‐Tau may be superior to tau PET for detecting early tau increase. We recently found the use of a CSF p‐Tau/Aβ40 ratio improved the associations with Alzheimer’s disease (AD) biomarkers over CSF p‐Tau. However, the significance of elevated CSF p‐Tau in the absence of abnormal Aβ is unclear, as is how it relates to neurodegeneration, cognitive decline, and other factors.MethodWe analyzed 201 non‐demented ADNI participants who were Aβ‐ on both CSF Aβ42/Aβ40 and PET, and who had concurrent Aβ PET, CSF (Aβ40, Aβ42 and p‐Tau181), white matter hyperintensities (WMH), and vascular risk factors measured within one year. Of these, 81 individuals had 18F‐fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV). We also examined available longitudinal CSF, aHCV, FDG PET and Preclinical Alzheimer’s Cognitive Composite (PACC) measurements in 20‐40% of participants.ResultIn Aβ‐ individuals, older age, male sex, greater WMH burden and hypertension (Fig. 1) were related to elevated CSF p‐Tau/Aβ40, which was associated with temporoparietal (metaROI) hypometabolism and hippocampal atrophy (Fig. 2). Longitudinally, lower CSF Aβ42/Aβ40, higher WMH, and hypertension predicted faster CSF p‐Tau/Aβ40 increase over around 5 years (Fig. 1), and higher CSF p‐Tau/Aβ40 predicted faster FDG SUVR decrease (Fig. 2) over around 3 years. Furthermore, baseline CSF p‐Tau/Aβ40 was associated with subsequent PACC decline over around 5 years, and this was partially mediated by glucose metabolism and fully mediated by hippocampal atrophy (Fig. 3).ConclusionOur results suggest that both cerebrovascular disease and subthreshold levels of Aβ, as well as age, are related to CSF p‐Tau/Aβ40 accumulation. Crucially, evidence of this CSF tau pathology shares features with AD including an AD‐like pattern of hypometabolism and hippocampal atrophy. Thus, this phenotype of Aβ‐ CSF tau elevation is similar to AD, which implies that it may represent an Aβ‐independent pathway to AD, a clinical syndrome that mimics AD, or very early interaction between Aβ and vascular disease that underlies neurodegeneration and cognitive decline.