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Vascular contributions to cognitive impairment are increasingly recognized.sup.1-5 as shown by neuropathological.sup.6,7, neuroimaging.sup.4,8-11, and cerebrospinal fluid biomarker.sup.4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD).sup.3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-[beta] (A[beta]).sup.3,11,14, and more recently tau.sup.15. Animal studies suggest that A[beta] and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown.sup.14-16. Although neurovascular dysfunction.sup.3,11 and BBB breakdown develop early in AD.sup.1,4,5,8-10,12,13, how they relate to changes in the AD classical biomarkers A[beta] and tau, which also develop before dementia.sup.17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-[beta].sup.8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging.sup.8-10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer's A[beta] and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of A[beta] and tau. Neuroimaging and cerebrospinal fluid analyses in humans reveal that loss of blood-brain barrier integrity and brain capillary pericyte damage are early biomarkers of cognitive impairment that occur independently of changes in amyloid-[beta] and tau., Author(s): Daniel A. Nation [sup.1] [sup.2] [sup.3] , Melanie D. Sweeney [sup.1] , Axel Montagne [sup.1] , Abhay P. Sagare [sup.1] , Lina M. D'Orazio [sup.2] [sup.4] , Maricarmen Pachicano [...]

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized.sup.1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction.sup.7, including the early clinical stages of Alzheimer's disease.sup.5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease.sup.11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes.sup.15-19, which maintain BBB integrity.sup.20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the [epsilon]3/[epsilon]4 or [epsilon]4/[epsilon]4 alleles) are distinguished from those without APOE4 ([epsilon]3/[epsilon]3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-[beta] or tau pathology measured in cerebrospinal fluid or by positron emission tomography.sup.23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFR[beta].sup.7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-[beta] and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway.sup.19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers. Breakdown of the blood-brain barrier in individuals carrying the [epsilon]4 allele of the APOE gene, but not the [epsilon]3 allele, increases with and predicts cognitive impairment and is independent of amyloid [beta] or tau pathology., Author(s): Axel Montagne [sup.1] , Daniel A. Nation [sup.1] [sup.2] [sup.3] [sup.4] , Abhay P. Sagare [sup.1] , Giuseppe Barisano [sup.1] , Melanie D. Sweeney [sup.1] , Ararat Chakhoyan [sup.1] [...]