Could early signs of Alzheimer’s disease be found in the brain’s vascular defenses? New research published in Alzheimer’s & Dementia has found that blood-brain barrier function may differ in individuals with the APOE4 gene, a known genetic risk factor for Alzheimer’s disease. The study found increased permeability in the blood-brain barrier of APOE4 carriers, including those without cognitive symptoms or amyloid beta buildup.
The blood-brain barrier is a critical protective shield that separates the brain from the bloodstream. It regulates the exchange of substances between the brain and the rest of the body, ensuring that harmful toxins, pathogens, and immune cells stay out while essential nutrients and oxygen pass through.
The blood-brain barrier plays a vital role in preserving the brain’s delicate environment, allowing it to function optimally. However, when this barrier becomes more permeable or “leaky,” harmful substances can infiltrate the brain, potentially leading to inflammation, neuronal damage, and the development of neurological diseases.
Alzheimer’s disease is a progressive neurodegenerative disorder that affects memory, cognition, and behavior, eventually leading to severe disability. It is characterized by the accumulation of toxic proteins, such as amyloid beta plaques and tau tangles, which disrupt normal brain function. The blood-brain barrier’s dysfunction has been implicated in the disease’s progression, as it may exacerbate the buildup of these proteins and impair the brain’s ability to clear them.
APOE4 is a genetic variant strongly associated with an increased risk of developing sporadic Alzheimer’s disease. It affects multiple processes in the brain, including lipid metabolism, inflammation, and vascular health. APOE4 has been linked to structural and functional changes in the blood-brain barrier, suggesting that individuals carrying this gene may be particularly vulnerable to barrier dysfunction. However, how APOE4 contributes to blood-brain barrier breakdown and its subsequent effects on Alzheimer’s-related changes has not been fully clarified.
“We now appreciate that there are likely many converging avenues leading towards Alzheimer’s disease,” said study author Emilie Reas, an assistant professor of neuroscience at the University of California, San Diego.
“Disruption of the blood-brain barrier is a potential pathway by which factors such as inflammation, environmental toxins, vascular disease, or metabolic dysfunction could all promote neurodegeneration and cognitive decline. This made us interested in understanding what happens to the blood-brain barrier in the very earliest stages of Alzheimer’s disease – before symptoms appear – and how its breakdown might affect brain health.”
The research included 55 participants aged 61 to 90, drawn from the San Diego community and an Alzheimer’s research center. Participants were categorized as cognitively normal or mildly impaired based on cognitive tests.
To evaluate blood-brain barrier function, the team used dynamic contrast-enhanced magnetic resonance imaging, a technique that tracks how a contrast agent moves from blood vessels into surrounding brain tissue. This allowed them to measure blood-brain barrier permeability across different brain regions, including the hippocampus, entorhinal cortex, and broader cortical gray matter. They also assessed brain microstructure using diffusion imaging and measured amyloid beta levels using positron emission tomography or cerebrospinal fluid analysis.
Participants underwent genetic testing to determine APOE4 status. The researchers then analyzed how blood-brain barrier permeability varied by APOE4 presence and amyloid status, and how it related to structural brain changes and cognitive performance.
The researchers found that APOE4 carriers had higher blood-brain barrier permeability across the brain’s gray matter compared to non-carriers. Notably, this difference was observed even in cognitively normal individuals who tested negative for amyloid beta, suggesting that blood-brain barrier dysfunction occurs early, before other Alzheimer’s markers are detectable. Among amyloid-positive individuals, the relationship between blood-brain barrier dysfunction and structural changes in the entorhinal cortex was especially pronounced, with evidence of neuronal loss and increased fluid accumulation in brain tissue.
Blood-brain barrier permeability did not correlate with cognitive test performance, suggesting that dysfunction may precede noticeable cognitive decline. Additionally, no significant association was found between age and blood-brain barrier permeability, supporting the idea that changes observed in APOE4 carriers reflect pathological processes rather than normal aging.
“Other studies have found blood-brain barrier breakdown in adults with Alzheimer’s dementia or memory impairment, but to our surprise, we observed no difference between those with or without memory impairment,” Reas told PsyPost. “The main difference is that our study was enriched with cognitively normal older adults who are at higher risk for Alzheimer’s disease. So we believe these individuals were already showing blood-brain barrier dysfunction because they are already on the trajectory to Alzheimer’s disease.”
Interestingly, the breakdown of the blood-brain barrier in APOE4 carriers was not limited to regions traditionally associated with early Alzheimer’s, such as the hippocampus. Instead, it appeared diffusely across the cortical gray matter. This widespread dysfunction could reflect the APOE4 gene’s influence on vascular health, including its effects on inflammation, tight junctions between cells in the blood-brain barrier, and the brain’s waste-clearing mechanisms.
“Our findings suggest that the blood-brain barrier becomes ‘leaky’ in the very early stages of Alzheimer’s disease,” Reas explained. “We believe it’s an early change because it appears in people at higher genetic risk for Alzheimer’s disease, even before any memory problems or abnormal proteins are detectable. We also found that it is also associated with subtle, or ‘microstructural,’ damage to important memory regions, suggesting that it may be involved in early neurodegenerative changes.”
The study offers valuable insights but also has limitations. Its cross-sectional design means it cannot establish a timeline for when blood-brain barrier dysfunction begins relative to other Alzheimer’s-related changes, such as amyloid beta buildup or tau tangles. The small sample size, especially among participants with cognitive impairment, may have limited the ability to detect certain effects.
“Important limitations of our study are the small number of participants who were mostly non-Hispanic White, and that we were only able to conduct MRI at one time-point,” Reas noted. “We are currently expanding our dataset with a more diverse sample, and hope to conduct longitudinal follow-up imaging in the future.”
“In the future, we hope to monitor changes in blood-brain barrier function across the time-course of Alzheimer’s disease, and to understand how it relates to other key pathological changes during the disease. We also aim to understand how protective or risk factors – including health, lifestyle, or genetics – modify blood-brain barrier function over the final decades of life.”
The study, “APOE 𝜀4-related blood–brain barrier breakdown is associated with microstructural abnormalities,” was authored by Emilie T. Reas, Seraphina K. Solders, Amaryllis Tsiknia, Curtis Triebswetter, Qian Shen, Charlotte S. Rivera, Murray J. Andrews, Austin Alderson-Myers, and James B. Brewer.
