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.
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.
| Original language | English |
|---|---|
| Article number | e70957 |
| Pages (from-to) | e70957 |
| Number of pages | 15 |
| Journal | Alzheimer's & Dementia |
| Volume | 21 |
| Issue number | 12 |
| Early online date | 30 Nov 2025 |
| DOIs | |
| Publication status | Published - 1 Dec 2025 |
Bibliographical note
Publisher Copyright:© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Keywords
- placental growth factor
- mild cognitive impairment
- soluble platelet‐derived growth factor receptor beta (sPDGFRβ)
- angiopoietin‐2
- blood–brain barrier
- endothelial
- angiotensin‐converting enzyme‐1 (ACE‐1)
- Alzheimer's disease
- cerebrospinal fluid
- pericyte