Editors' ChoiceAlzheimer's Disease

Looking into the Crystal Ball for Alzheimer’s Disease

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Science Translational Medicine  16 Oct 2013:
Vol. 5, Issue 207, pp. 207ec169
DOI: 10.1126/scitranslmed.3007756

As our population ages, the incidence of Alzheimer’s disease (AD) continues to increase at a rapid rate. An estimated 5 to 10% of individuals over 65, and 40% of individuals over 85, will be affected. The problem is that we cannot accurately predict which of us will be the unlucky ones. Halliday and colleagues examined subtle changes in the cerebrospinal fluid of cognitively healthy individuals that may help identify early, preclinical indicators of disease.

Although apolipoprotein E4 (APOE4) is a known genetic risk factor for AD, the mechanisms underlying neurodegeneration remain unclear. The authors studied blood-brain barrier (BBB) breakdown and biomarkers of the cyclophilin A matrix metalloproteinase 9 pathway in cognitively normal individuals with differing APOE genotypes. They sought to determine whether patients with the APOE4 allele are susceptible to age-dependent BBB breakdown before the onset of clinical dementia.

Individuals with three different APOE genotypes were studied: APOE2/E3, APOE3/E3, and APOE3/E4. Group stratification (ages 40 through 65 and ages 66 through 85) controlled for age-dependent allele effects. Older, cognitively normal individuals carrying one APOE4 allele had increased BBB breakdown [cerebrospinal fluid (CSF)/plasma albumin quotients]. Further, these individuals harbored significantly elevated CSF cyclophilin A and active matrix metalloproteinase 9 levels when compared with younger, cognitively normal APOE4 carriers or age-matched APOE4 noncarriers. No age-dependent changes in cyclophilin A or active matrix metalloproteinase 9 CSF levels were associated with APOE2 or APOE3 alleles.

Targeted AD therapies are unlikely to prove effective if patients are treated in the advanced stages of disease. This study indicates that CSF biomarker analysis can contribute to early detection of vascular dysfunction in patients at risk for cognitive decline and AD. The information can help recognize susceptible individuals in the preclinical period and identify potential molecular targets for new therapies.

M. R. Halliday et al., Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown. JAMA Neurol. 70, 1198–200 (2013). [Full Text]

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