It is acknowledged in the medical community that clumps of misfolded tau proteins and amyloid-β are markers of Alzheimer’s disease.
The evidence presented in recent article in Nature, shows that the degree of disruption to the blood brain-barrier (BBB) corresponds to a person’s cognitive dysfunction.
The article adds a third element to the well-known theory that the gene variant APOE4 simply “contributes” to Alzheimer’s when it in fact plays a much larger role in the disease.
It is possible, however, that APOE4 may slow tau and amyloid-β clearance thus increasing cognition decline.
A separate article in Nature by Montagne et al. presents new evidence. It points to apolipoprotein E4 (APOE4) as possibly being responsible for a breakdown in the BBB. The function of the BBB is to prevent neurotoxic plasma-derived cells and infectious agents (pathogens) from entering the brain.
Early dysfunction of the BBB has been evident in Alzheimer’s before neurodegeneration, brain atrophy, or dementia occur. Yet the exact role of the BBB in neurodegenerative diseases is still being explored.
About the Montagne et al. Study
One of the papers issued by the Montagne group noted that APOE4 may lead to BBB dysfunction and is predictive of cognitive decline.
An issue that Montagne et al. hoped to resolve is whether APOE4 causes early dysfunction in the BBB on its own or in tandem with tau and amyloid-β.
After investigating, the team determined that BBB leakage was not related to tau and amyloid-β accumulation. Their assessment resulted from studies of cerebrospinal fluid and through PET brain imaging.
To date, it has been established that a person who carries the gene APOE4 has an increased risk of Alzheimer’s. Researchers have discovered that APOE4 is associated with BBB defects and eventual cognitive decline.
The three types of APOE are AE2, 3 (the most common), and 4. People have two copies of the APOE variant. The two copies carried by a person may either be similar or dissimilar.
When comparing APOE3 variant to APOE4, researchers found that APOE4 increases the possibility of Alzheimer’s disease four-fold if a person has one copy of the variant. If a person has two copies of APOE4, their risk increases fifteen- fold.
Another observation by the researchers pertained to people carrying the variant APOE4 who developed Alzheimer’s. They found that this group had a tendency to experience symptoms earlier than people who did not carry APOE4.
Proteins that have possibly leaked from the BBB have been found in the liquid surrounding the spinal cord and brain (cerebrospinal fluid). Although at the time of discovery the person may be healthy, if that person is carrying APOE4, the individual will eventually develop Alzheimer’s.
Another issue is that the leakage is an indication of a loss of integrity of the BBB prior to a loss of cognitive brain function.
About the Study
The authors began their investigation by grouping people in accordance with their APOE status. The subjects were either healthy or had some degree of cognitive impairment.
The team studied the BBB breakdown using animal models. The mice used in the study were well suited for the analysis of the pathophysiology of Alzheimer’s.
There is some evidence that the breakdown of BBB may be caused by the degeneration of cells that are embedded in cerebral capillary walls (pericytes).
The team discovered that cognitively healthy people could be carriers of copies of APOE4 yet still have leaks in the BBB. The leaks occurred in the two regions of the brain that affected cognition and memory. They were more severe in people who were experiencing cognitive decline.
By observing various other factors, the researchers determined that disruption of BBB is an early indicator of neurodegeneration.
Studies of gene variants may bring about even more in-depth approaches to treating Alzheimer’s disease.