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Background  We recently reported that CSF phosphorylated tau (p-Tau 181 ) relative to Aβ 40  (CSF p-Tau/Aβ 40  ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau 181  alone. While elevations of CSF p-Tau/Aβ 40  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.    Methods  We examined relationships between CSF p-Tau/Aβ 40 , and CSF Aβ 42 /Aβ 40 , 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  18 F-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/Aβ 40  associations with these measures as well.    Results  Elevated CSF p-Tau/Aβ 40  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 Aβ 42 /Aβ 40 , 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/Aβ 40  increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ 40  and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements.    Conclusions  These 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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13195-021-00913-5.

Age, vascular disease, and Alzheimer’s disease pathologies in amyloid negative elderly adults