APOE2 gene shields the brain’s blood vessels
Not all APOE genes are equal. People carrying the APOE2 variant appear to have a lower risk of Alzheimer’s disease than those with APOE3 or APOE4. A new study offers a clue as to why: the cells that wrap around small brain vessels function considerably better with APOE2.
The brain is protected by a biological filter known as the blood-brain barrier (BBB). This barrier prevents unwanted substances from entering the brain. Specialised support cells called pericytes are key to keeping it intact. The study shows that pericytes in mice carrying the human APOE2 gene are more abundant and better functioning than those in APOE3 or APOE4 mice.
The researchers also found that APOE2 pericytes are more resistant to cellular ageing (senescence) and accumulate less amyloid-beta, the protein that clumps into plaques in Alzheimer’s disease. Additional analyses revealed that APOE2 pericytes process fats more efficiently, with greater activity of proteins involved in lipid breakdown and transport.
A crack in the wall
As we age, the blood-brain barrier typically becomes leakier. This leakage triggers inflammation and damage in brain tissue, and is considered an early sign of neurodegenerative conditions. APOE4 has long been known as a risk factor for Alzheimer’s. This research adds a new mechanism: APOE4 pericytes maintain the barrier less effectively than APOE2 pericytes.
Notably, treatment with recombinant APOE2 protein was able to partially restore pericyte function in APOE3 and APOE4 cell lines in the laboratory. This has so far only been shown in cell culture models, not in living humans. But it raises the possibility that the APOE2 protein itself could be a therapeutic target.
Implications for healthy ageing
This research, published in the journal Brain, helps explain why APOE2 carriers tend to live longer and develop less Alzheimer’s disease. The mechanism runs not only through cholesterol metabolism or immune cells, as previously thought, but also through the structural integrity of brain blood vessels. For longevity science, this is a meaningful addition: vascular health in the brain appears to be strongly genetically influenced, via a gene that many people already know from genetic testing.
Search terms to explore further: pericytes blood-brain barrier ageing | APOE2 neuroprotection | amyloid-beta vascular senescence