A Comprehensive Investigation of the Associations Between Cerebral Blood Flow and Cerebrospinal Fluid Biomarkers Across the Alzheimer's Disease Continuum Publisher



F Khosravi FARBOD ; H Nasiri HAMIDE ; F Alvandi FARZANEH ; M Kavian MELIKA ; M Janbazi MARYAM ; Mm Gheissari Mohammad MEHDI ; M Noroozi MASOUD ; G Atashi GHAZAAL ; Z Asghari ZAHRA ; Ng Majd Nazanin GHASEMI
Source: Clinical Neurology and Neurosurgery Published:2025

Abstract

Background: Alzheimer's disease (AD) is characterized by a complex interplay between amyloid-β (Aβ) and tau pathologies, with increasing evidence implicating cerebral blood flow (CBF) alterations as a critical, yet underexplored, contributor to disease progression. This study aimed to investigate the associations between regional CBF and cerebrospinal fluid (CSF) biomarkers— Aβ1–42, total tau (T-Tau), and phosphorylated tau (P-Tau181)—across the AD continuum. Methods: We conducted a cross-sectional analysis using data from 416 participants enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal individuals, patients with mild cognitive impairment (MCI), and those with AD. CSF biomarker concentrations were measured using the INNO-BIA AlzBio3 immunoassay on the Luminex xMAP platform. Regional CBF was quantified using arterial spin labeling (ASL) MRI. Associations between CSF biomarkers and CBF were assessed using partial correlation and general linear models, adjusting for age and gender. Multiple comparisons were corrected using the false discovery rate (FDR) approach. Results: In CN participants, CBF in the right inferior temporal cortex showed a positive association with Aβ1–42 levels (r = 0.348, p = 0.04). In the MCI group, elevated T-Tau and P-Tau181 levels were inversely associated with CBF in the left temporal pole (T-Tau: r = –0.296, p = 0.016; P-Tau₁₈₁: r = –0.311, p = 0.011). In participants with AD, widespread and robust positive correlations emerged between tau biomarkers and CBF, particularly in the posterior cingulate cortex, corpus callosum, and multiple frontal and parietal regions (e.g., P-Tau181 and posterior cingulate: β = 0.850, p = 0.004). Conclusion: Our findings reveal stage-dependent and region-specific associations between cerebral perfusion and CSF biomarkers. In early stages, tau pathology is linked to hypoperfusion, whereas in established AD, elevated tau levels are paradoxically associated with increased CBF—potentially reflecting compensatory or neuroinflammatory mechanisms. These results underscore the complex neurovascular dynamics in AD and support the vascular hypothesis, suggesting that targeting CBF alterations may offer a viable therapeutic avenue, particularly in preclinical and prodromal stages. © 2025 Elsevier B.V., All rights reserved.