Dr Seth Gale points out evidence of Alzheimer’s disease on PET scans at the Center for Alzheimer Research and Treatment (CART) at Brigham and Women’s Hospital in Boston, Massachusetts, US, Mar 30, 2023. REUTERS/Brian Snyder
A common genetic variant strongly associated with Alzheimer’s disease may raise the risk of dementia partly by triggering a scarring process in the brain’s blood vessels, The Guardian reports, citing new research published in the journal Cell.
The variant, known as APOE4, is found in roughly six out of every 10 Alzheimer’s patients.
Despite its strong link to the disease, many carriers never develop dementia, leaving scientists puzzled about its precise role.
The new study, led by neuroscientist Joel Blanchard of the Icahn School of Medicine at Mount Sinai in New York City, offers a possible explanation.
Using a gene expression atlas built from data covering 66,000 cells drawn from 220 people, the team found that APOE4 carriers had fewer pericytes -- cells that wrap around and stabilise blood vessels -- and more myofibroblasts, which are cells typically associated with injury response that produce a protein called fibronectin.
The researchers suspected the pericytes were transforming into myofibroblasts.
Tests on 3D brain tissue models grown from stem cells confirmed the shift.
Crucially, when fibronectin production was blocked in those models, the accumulation of amyloid-beta -- a protein whose buildup is considered one of the earliest markers of Alzheimer’s -- also dropped.
The team also identified a possible trigger: an immune signalling molecule called TGF-beta appeared to drive the cellular transformation.
Blocking it in cell models and aged mice restored normal pericyte levels around blood vessels.
According to The Guardian, scientists not involved in the study cautioned that TGF-beta performs many functions throughout the body, making it difficult to target safely with a drug.
Researchers noted that vascular damage is only one of several ways APOE4 has been linked to Alzheimer’s, with the variant also known to affect inflammation and interact with another disease-linked protein, tau.