CSF markers of vascular injury correlate with tau and cognitive decline in early Alzheimer's disease

Abstract INTRODUCTION Cerebrovascular injury is common in Alzheimer's disease (AD), but its timing in relation to Aβ and tau pathology and cognitive decline remains unclear. METHODS We measured baseline vascular marker levels in cerebrospinal fluid (CSF) and serum from 75 Alzheimer's Disease Neuroimaging Initiative (ADNI) study participants, stratified into cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD groups ( n = 25/group) and investigated associations with disease pathology (CSF and positron emission tomography PET amyloid beta Aβ and tau) and cognition (Clinical Dementia Rating scale CDR, Montreal Cognitive Assessment, Mini‐Mental State Examination, and Alzheimer's Disease Assessment Scale). RESULTS CSF markers of endothelial (placental growth factor, angiopoietin 2, angiotensin‐converting enzyme‐1 ACE‐1) and pericyte (soluble platelet‐derived growth factor receptor beta sPDGFRβ) injury were elevated in AD. Most were also higher in CDR 0.5 than CDR 0 and correlated with CSF tau and cognitive impairment in CU and MCI groups, particularly in PET Aβ‐positive (Aβ+) participants. Serum sPDGFRβ, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains‐2 (TIE‐2), and ACE‐1 correlated with CSF measurements. DISCUSSION Cerebrovascular injury precedes the development of dementia and, particularly in PET Aβ+ individuals, progresses in close association with CSF tau and cognitive decline. Highlights We measured the levels of multiple markers of neurovascular injury in serum and CSF taken at baseline from CU, MCI, and AD participants in the ADNI study and investigated associations with CSF and PET markers of disease pathology and with cognitive decline. CSF markers of neurovascular injury, particularly PlGF, are elevated in very early stages of AD, including in MCI and in PET Aβ+ CU individuals. The levels are closely related to CSF t‐tau and p‐tau and to cognitive decline Levels of only a few neurovascular markers in serum correlate with those in CSF: sPDGFRβ, TIE‐2, and ACE‐1.