On 29 April, Dr Axel Montagne and co-investigators published an article in Nature, showing that APOE4 is linked to breakdown of the blood-brain barrier (BBB) contributing to the cognitive decline observed during the development of Alzheimer’s disease (AD).
APOE4 is the leading genetic risk factor for AD, increasing the risk of developing AD up to 4-fold in people who carry one copy of the gene, and 15-fold in those who carry two APOE4 copies. Recent studies indicate that APOE4 may accelerate breakdown of the blood-brain barrier, the vascular layer that separates the brain from the peripheral blood circulation, by activating an inflammatory pathway that injures BBB cells called pericytes. However, it was unclear whether there was a connection between the vascular damage caused by APOE4, and the cognitive impairment that characterizes AD.
To address this important question, Dr Montagne and colleagues investigated the permeability of the BBB in 245 people with or without mild cognitive impairment, using a sophisticated brain imaging technique called dynamic contrast-enhanced MRI. These analyses revealed an APOE4-dependent pattern of BBB breakdown in the hippocampus and medial temporal lobe, two areas of the brain that are particularly important for memory and cognition. Although BBB breakdown was worse in APOE4 carriers with cognitive impairment, evidence of BBB breakdown was still present in cognitively unimpaired APOE4 carriers. In addition, the BBB changes in the hippocampus and medial temporal lobe appeared to precede tissue loss in these areas – suggesting that BBB breakdown is an early event in the development of AD. Interestingly, these findings did not seem to be associated with amyloid or Tau pathology, as measured by PET scans or in cerebrospinal fluid samples. Finally, the researchers investigated whether the BBB changes were associated with inflammatory pathways that had previously been linked to pericyte damage. They found higher levels of two inflammatory proteins, MMP9 and CypA, in CSF samples from APOE4 carriers with cognitive impairment, pinpointing a mechanism that links inflammatory molecules, pericytes, BBB damage and APOE4 with cognitive decline in AD.
The original article was published in Nature and can be found here: https://go.nature.com/3d2W4s6
