Elevated CSF angiopoietin-2 correlates with blood-brain barrier leakiness and markers of neuronal injury in early Alzheimer’s disease

Breakdown of the neurovascular unit in early Alzheimer’s disease (AD) leads to leakiness of the blood-brain barrier (BBB), contributing to cognitive decline and disease pathology. Vascular stability depends on angiopoietin-1 (ANGPT1) signalling, antagonised by angiopoietin-2 (ANGPT2) upon endothelial injury. We have examined the relationship between CSF ANGPT2 and CSF markers of BBB leakiness and disease pathology, across three independent cohorts: (i) 31 AD patients and 33 healthy controls grouped according to their biomarker profile (i.e., AD cases t-tau > 400 pg/mL, p-tau > 60 pg/mL and Aβ42 < 550 pg/mL); (ii) 121 participants in the Wisconsin Registry for Alzheimer’s Prevention or Wisconsin Alzheimer’s Disease Research study (84 participants cognitively unimpaired (CU) enriched for a parental history of AD, 19 participants with mild cognitive impairment (MCI), and 21 with AD); (iii) a neurologically normal cohort aged 23–78 years with paired CSF and serum samples. CSF ANGPT2 level was measured by sandwich ELISA. In cohort (i), CSF ANGPT2 was elevated in AD, correlating with CSF t-tau and p-tau181 but not Aβ42. ANGPT2 also correlated positively with CSF sPDGFRβ and fibrinogen – markers of pericyte injury and BBB leakiness. In cohort (ii), CSF ANGPT2 was highest in MCI. CSF ANGT2 correlated with CSF albumin in the CU and MCI cohorts but not in AD. ANGPT2 also correlated with t-tau and p-tau and with markers of neuronal injury (neurogranin and α-synuclein) and neuroinflammation (GFAP and YKL-40). In cohort (iii), CSF ANGPT2 correlated strongly with the CSF:serum albumin ratio. Increased CSF ANGPT2 and the CSF:serum albumin ratio showed non-significant associations with elevated serum ANGPT2 in this small cohort. Together, these data indicate that CSF ANGPT2 is associated with BBB leakiness in early AD and is closely related to tau pathology and neuronal injury. The utility of serum ANGPT2 as a biomarker of BBB damage in AD requires further study.