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Blood–brain barrier impairment in Alzheimer disease

Stability and functional significance

From the Department of Neurology (G.L.B., J.A.K., J.F.Q.), Layton Aging and Alzheimer's Disease Center (J.A.K., M.M., D.W., N.E.C., J.F.Q.), Oregon Center for Complementary and Alternative Medicine in Neurological Disorders (G.L.B.), and Division of Biostatistics (N.E.C.), Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland.

Address correspondence and reprint requests to Dr Bowman, 3181 Southwest Sam Jackson Park Rd., CR-131, Portland, OR 97239 bowmang{at}ohsu.edu

Objective: To determine the stability and functional significance of blood–brain barrier (BBB) integrity in patients with mild to moderate Alzheimer disease (AD).

Methods: Thirty-six patients (mean age 71 ± 7 years) with mild to moderate AD (Mini-Mental State Examination [MMSE] 19 ± 5) participated in a biomarker study involving clinical assessments, brain imaging, and CSF and plasma collection over 1 year. BBB integrity was assessed with the CSF–albumin index (CSF-AI).

Results: BBB disruption was present in an important subgroup of patients (n = 8/36, 22%) at all time points measured. CSF-AI was highly reproducible over 1 year with an intraclass correlation of 0.96. Age, sex, and APOE status did not correlate with CSF-AI. Vascular factors (blood pressure, Hachinski ischemia score, MR-derived white matter hyperintensity, body mass index) were not strongly associated with CSF-AI levels (p = 0.066). CSF/plasma IgG ratio correlated with CSF-AI in a manner indicating that peripheral IgG has greater access to the CNS in patients with an impaired BBB. Further evidence for the physiologic significance of the CSF-AI was noted in the form of correlations with rates of disease progression, including annual change on MMSE (r² = 0.11, p = 0.023), annual Clinical Dementia Rating sum-of-boxes change (r² = 0.29, p = 0.001), and annual ventricular volume change (r² = 0.17, p = 0.007).

Conclusions: Blood–brain barrier (BBB) impairment is a stable characteristic over 1 year and present in an important subgroup of patients with Alzheimer disease. Age, gender, APOE status, vascular risk factors, and baseline Mini-Mental State Examination score did not explain the variability in BBB integrity. A role for BBB impairment as a modifier of disease progression is suggested by correlations between CSF–albumin index and measures of disease progression over 1 year.

Received November 21, 2006. Accepted in final form January 22, 2007.

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