Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease

Abstract

Objective: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD.

Methods: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aβ42/Aβ40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD.

Results: CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T±N±; n = 558) or those with amyloid and tau pathologies (A+T+N±; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Aβ42/Aβ40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD.

Interpretation: Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages.

Figure 1

Correlations of CSF VEC with CSF and imaging biomarkers in preclinical AD. CSF VEC levels significantly correlated with (A) CSF p‐tau181 (r = 0.34, p = 0.0002), (B) CSF tau (r = 0.31, p = 0.0009), (C) CSF NFL (r = 0.50, p < 0.0001), and (D) global amyloid burden measured as mean cortical amyloid SUVR (r = 0.27, p = 0.0037) in individuals with significant amyloid deposition on amyloid PET scan (i.e., amyloid‐PET positive individuals; n = 112). CSF biomarker levels are shown as standardized z scores. VEC, VE‐cadherin; p‐tau181, tau phosphorylated at threonine 181; NFL, neurofilament light‐chain; SUVR, standardized uptake value ratio.

Figure 2

Correlations of CSF VEC with cognitive measures in preclinical AD. CSF VEC levels demonstrated significant negative correlations with (A) global cognition measured by PACC scores (r = −0.31, p = 0.0007; n = 112), (B) episodic memory measured by FCSRT‐Free (r = −0.26, p = 0.0053; n = 110), (C) executive function measured by the Digit‐Symbol Substitution test (r = −0.29, p = 0.0049; n = 95), and (D) language functions measured by Animal Fluency (r = −0.18, p = 0.05; n = 111) in the subset of individuals with significant amyloid deposition on amyloid PET scan (i.e., amyloid‐PET‐positive individuals; n = 112). Pearson correlation coefficient (r) values represent unadjusted correlations. CSF VEC levels and cognitive measures are shown as standardized z scores. VEC, VE‐cadherin; PACC, Preclinical Alzheimer's Cognitive Composite; FCSRT‐Free, free recall score from the Free and Cued Selective Reminding Test.

Figure 3

Functional pathway analyses of VEC in AD using STRING. Our functional pathway analyses suggest significant interactions of CDH5 with APOE and the NRP1‐PLXNA4‐SEMA3A complex. The evidence score for CDH5–APOE interaction is 0.41 and that for the CDH5–NRP‐1 interaction is 0.51. Data‐mining results suggest that CDH5 functional interactions are predominantly with the E4 allele of APOE (i.e., APOE4). Average node degree is 3.33 and average local clustering coefficient is 0.806. Network nodes represent proteins; splice isoforms or post‐translational modifications are collapsed so that each node represents all the proteins produced by a single protein‐coding gene locus. Edges represent protein–protein associations that are meant to be specific and meaningful. Color coding for the interactions are as follows: known interactions from curated databases (teal); known experimentally determined interactions (purple); predicted interactions from gene neighborhood (green), gene fusions (red), or gene co‐occurrence (blue); predicted interactions from text‐mining (yellow), co‐expression (black), and protein homology (lavender). APOE, apolipoprotein E; CDH5, cadherin‐5, aka VEC, vascular endothelial‐cadherin; NRP‐1, neuropilin‐1; PLXNA4, Plexin A4; SEMA3A, semaphorin‐3A; KDR, kinase insert domain receptor, aka vascular endothelial growth factor receptor 2, VEGFR2.