APOE*ε4 is linked to BBB breakdown

The ε4 allele of the apolipoprotein E gene (APOE*ε4) is a well-established genetic risk factor for Alzheimer disease (AD), but the mechanisms through which this variant influences AD risk remain unclear. As reported in Nature, a new study by Berislav Zlokovic and colleagues demonstrates an association between APOE*ε4 carrier status and blood–brain barrier (BBB) breakdown, which could contribute to cognitive decline.

The investigators recruited 435 participants aged ≥45 years, 245 of whom underwent dynamic contrast-enhanced MRI of the brain to measure BBB integrity. APOE*ε4 carriers — that is, people with the APOE*ε3/ε4 or the APOE*ε4/ε4 genotype — showed increased BBB breakdown in the hippocampus and parahippocampal gyrus compared with APOE*ε3/ε3 individuals, even in the absence of cognitive impairment. BBB damage was not linked to amyloid-β or tau accumulation in the brain, suggesting that it occurred independently of AD pathology.

To examine whether the APOE genotype and/or BBB dysfunction could predict future cognitive decline, the researchers used soluble platelet-derived growth factor receptor-β (sPDGFRβ) in the cerebrospinal fluid (CSF) as a marker of BBB damage. Among 146 participants who underwent longitudinal assessments, the combination of APOE*ε4 carrier status and high levels of sPDGFRβ in the CSF at baseline was associated with accelerated cognitive decline, and with evidence of increased activity of the cyclophilin A–matrix metalloproteinase 9 (CypA–MMP9) pathway.

“This study sheds light on a new way of looking at this disease and possibly treatment in people with the APOE*ε4 gene, looking at blood vessels and improving their function to potentially slow down or arrest cognitive decline,” concludes Zlokovic. The authors point out that the CypA–MMP9 pathway has previously been implicated in BBB breakdown and could represent a target for therapeutic intervention in APOE*ε4 carriers.