Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype

Abstract

Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF biomarkers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage.

Keywords: APOE ε4; Amyloid; Blood-brain barrier; Dementia; Diabetes; Vascular pathology.

Fig. 1

The cerebrospinal fluid/plasma albumin ratio (Qalb) in different diagnostic groups and APOE genotypes in cohort 1. (A) The Qalb in cognitively healthy controls and patients with stable mild cognitive impairment (sMCI), MCI that progressed to Alzheimer's disease (MCI-AD), AD, dementia with Lewy bodies or Parkinson's disease with dementia (DLB/PDD), vascular dementia (VaD), and frontotemporal dementia (FTD). (B) The Qalb in different diagnostic groups stratified according to APOE genotype (APOE ε4 carriers vs. noncarriers). Data are presented as mean ±95% confidence interval; p-values are from univariate general linear models controlling for age and gender: ^∗p < 0.05 and ^∗∗p < 0.01, compared with controls.

Fig. 2

Cerebrospinal fluid (CSF) biomarkers of angiogenesis or endothelial damage in cohort 1. CSF vascular endothelial growth factor (VEGF) (A), the VEGF/soluble VEGF receptor 1 (sVEGFR-1) ratio (B), intercellular adhesion molecule 1 (ICAM-1) (C), and vascular cell adhesion molecule 1 (VCAM-1) (D) were measured in cognitively healthy controls and patients with stable mild cognitive impairment (sMCI), MCI that progressed to Alzheimer's disease (MCI-AD), AD, dementia with Lewy bodies or Parkinson's disease with dementia (DLB/PDD), vascular dementia (VaD), and frontotemporal dementia (FTD). Data are presented as mean ±95% confidence interval; p values are from univariate general linear models controlling for age and gender: ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001 compared with controls.

Fig. 3

The CSF/plasma albumin ratio (Qalb) and cerebrospinal fluid (CSF) biomarkers of angiogenesis or endothelial damage in diabetes. The Qalb in patients with and without diabetes in cohort 1 (A) and cohort 2 (B). CSF levels of intercellular adhesion molecule 1 (ICAM-1) (C), vascular cell adhesion molecule 1 (VCAM-1) (D), and vascular endothelial growth factor (VEGF) (E) in patients with and without diabetes in cohort 1. Data are presented as mean ±95% confidence interval; p values are from univariate general linear models controlling for age, gender, and diagnosis: ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001.