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

Background: 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. 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.

Methods: We 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.

Results: Elevated 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.

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.