APOE4 Variant Linked to Poorer Neurological Outcomes in Boys with Cerebral ALD, Study Finds

APOE4 Variant Linked to Poorer Neurological Outcomes in Boys with Cerebral ALD, Study Finds

Carrying the APOE4 gene variant is associated with greater disease severity, and poorer neurological function, in boys with cerebral adrenoleukodystrophy (cALD), a study found.

The study, “Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy,” was published in the journal Nature Scientific Reports.

Up to 40% of young males with ALD develop cerebral complications, which include inflammation and demyelination — the loss of the insulating layer of nerve fibers, called myelin.

APOE4 is one of the variants of the APOE gene, and is associated with disruptions on the blood-brain barrier (BBB), a thin membrane protecting the brain from large molecules and harmful microorganisms in circulation in the peripheral blood. The APOE4 variant also is recognized as a risk factor for the development of early Alzheimer’s disease.

Aiming to test whether carrying APOE4 could be a biomarker for earlier detection and treatment of cALD, a team from the University of Minnesota and Penn State evaluated 83 young males with newly diagnosed and symptomatic cALD.

Results showed that the proteins found at higher levels in 18 cALD patients, as compared with controls, were implicated in inflammatory response, and cellular movement and signaling, among other biological processes.

Next, the team focused on assessing ApoE4 protein. They found that 17.5% of cALD boys were carries of APOE4 variant. While this rate was slightly higher than the 12% reported in the general population, the difference was not significant. Only three cALD patients had APOE4 in both gene copies — one inherited from the mother and the other from the father. The mean age of the carriers at diagnosis — 8.8 years, range 3.8-14.2 years — also was not different than that of non-carriers.

As seen earlier in a study with mice, the presence of ApoE4 protein induced oxidative stress, and impaired the function of mitochondria — the cells’ power plants — in human endothelial cells, which are part of the BBB.

APOE4 carriers with cALD had similar total protein levels in the cerebrospinal fluid (CSF, the liquid surrounding the brain and spinal cord) as compared to non-carriers. CSF analysis also showed similar activity of chitotriosidase enzyme — a biomarker of activated macrophages, which are a type of immune cell – in both groups. In contrast, magnetic resonance imaging (MRI) scans indicated significantly more demyelination, and greater ongoing neuroinflammation, in the brains of APOE4 carriers than of non-carriers.

A 25-point scoring system further showed that APOE4 carriers had significantly worse neurologic function, with an average score of 2.4 versus 1.0 in non-carriers. Carriers also showed higher levels of a protein known as MMP2 in the CSF. The researchers noted that the role of APOE4 in activating this MMP2 protein, and leading to BBB disruption, had been suggested in previous mouse studies.

“These are the first data showing that APOE4 is associated with increased severity of cerebral disease in cALD and suggest it may be a modifier of disease,” the researchers said.

“Future studies should focus on longitudinal evaluation of young males with ALD who do not yet manifest cerebral disease to learn if APOE4 status truly modulates the onset of cerebral disease as well as learn if there is any change in the velocity of cerebral disease progression,” they added.

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