Study identifies Alzheimer's biomarkers linked to blood vessel changes in the brain

• In Alzheimer’s disease, the most common form of dementia, the blood-brain barrier is disrupted.
• A new study has uncovered unique molecular signatures linked to the disruption of this blood-brain barrier in Alzheimer’s disease.
• These findings could lead to new ways of using biomarkers in the diagnosis and treatment of this increasingly common disease.

Dementia currently affects more than 57 million people worldwide, and is projected to affect some 150 million by 2050. And up to 80% of people diagnosed with dementia have Alzheimer’s disease.

People with Alzheimer’s disease experience a range of symptoms , which usually start with memory issues, confusion, coordination problems, personality changes, and difficulty completing familiar tasks.

Changes in the brain that lead to these symptoms include the buildup of amyloid beta (Aβ) and tau proteins, as well as inflammation. Studies suggest that these may, in part, result from changes in the blood-brain barrier (BBB) — a semi-permeable membrane in the small blood vessels that shields the brain from toxic substances and supplies the brain with nutrients.

Now, a study led by researchers at the Mayo Clinic in Florida has found unique molecular changes in the blood-brain barrier of people with Alzheimer’s disease, markers of which can be detected in the blood.

The study, which is published in Nature Communications , suggests that these molecular signatures could lead to new methods for diagnosing and treating Alzheimer’s disease.

“Although disruption of the BBB is well-known in AD, the mechanisms by which this disruption occurs [are] not well known. In our study, we characterized human brains from the Mayo Clinic Brain Bank at a single cell level and discovered a pair of molecules that are important in the maintenance of the BBB and the expression levels of which are perturbed in AD. This finding is important, because it provides a new mechanism of BBB disruption in AD.”

— Nilüfer Ertekin-Taner, M.D., Ph.D. , senior author, chair of the Department of Neuroscience at Mayo Clinic, and leader of the Genetics of Alzheimer’s Disease and Endophenotypes Laboratory at Mayo Clinic in Florida.

Blood-brain barrier changes in Alzheimer’s

The blood-brain barrier lines capillaries (the smallest blood vessels) in the brain and is made up of three cell types — endothelial cells , pericytes , and astrocytes — plus capillary basement membrane.

In healthy people, these structures work together to control the passage of molecules between the blood and the nervous system, ensuring that harmful molecules do not reach the brain. However, in Alzheimer’s disease, this system can break down.

In this study, the researchers used postmortem brains donated by 12 people with Alzheimer’s disease and 12 without to investigate the changes in the blood-brain barrier. Using these samples and external data sets, they analyzed thousands of cells from many regions of the brains.

They examined molecular changes associated with Alzheimer’s disease, primarily in the vascular tissue, focusing on pericytes, that maintain the integrity of the blood-brain barrier, and astrocytes, the support cells.

Molecules change communication between cells

Communication between the two cell types was different in the samples from Alzheimer’s patients than in samples from people without Alzheimer’s.

The researchers identified 2 molecules that were changing the way the cells communicated:

• VEGFA , or vascular endothelial growth factor A, a molecule that is important in blood vessel development
• SMAD3 , a protein that regulates gene activity and cell proliferation.

They then performed further experiments in vitro using the two molecules.

In vitro, the researchers found there was an inverse relationship between VEGFA and SMAD3. Activation of the VEGFA pathway decreased SMAD3 in pericytes, whereas inhibition of the VEGFA pathway increased it.

To validate their findings, they performed experiments in zebrafish. In these experiments, when VEGFA signaling was blocked, SMAD3 was upregulated, and the blood-brain barrier began to break down.

“The discovery of unique molecular signatures related to blood-brain barrier dysfunction in Alzheimer’s disease (AD) could revolutionize diagnosis and treatment.”
— Emer MacSweeney, MD , consultant neuroradiologist and CEO at Re:Cognition Health, speaking to Medical News Today .

Effect of SMAD3 in people

To further investigate the effect of SMAD3, the researchers took blood samples from living older volunteers. Those whose blood contained higher levels of SMAD3 showed lower levels of Alzheimer’s pathology, such as amyloid deposits and brain shrinkage.

The authors caution that their findings cannot determine whether elevated SMAD3 levels and signaling damage the blood-brain barrier, or are a protective response to Alzheimer’s pathologies.

Erketin-Taner explained:

“Blood SMAD3 level associations per se do not prove causality, they indicate a potential role of this molecule for Alzheimer’s in both brain and periphery. Taken together, our findings support a model wherein VEGFA reduction and signaling in the presence of Aβ (and possibly other Alzheimer’s neuropathologies) lead to increased SMAD3 levels, signaling, and BBB disintegrity.”

“We need studies to measure SMAD3 in the same individuals where blood samples were collected while the donors were alive and where brain samples are also available. We are leading a major NIH-supported study called CLEAR-AD, where such work is underway,” she told MNT .

Meanwhile, MacSweeney said that this study opens “new avenues for understanding Alzheimer’s pathology and developing innovative interventions.”

“These signatures, particularly involving VEGFA and SMAD3, may serve as novel biomarkers for early detection and provide targets for therapies aimed at stabilizing the blood-brain barrier. Such advances could lead to personalized treatment strategies, potentially slowing disease progression and improving patient outcomes,” she said.

A new potential diagnostic or therapy for Alzheimer’s?

In living patients, the researchers found that blood levels of SMAD3 were associated with imaging findings of Alzheimer’s, providing evidence that Alzheimer’s brain changes can be detected in the blood of living patients. Ertekin-Taner suggested that these brain-linked signatures could be potential biomarkers of Alzheimer’s.

Ertekin-Taner commented:

“Vascular and BBB dysfunction are critical aspects and earlier events of Alzheimer’s disease. Identified genes and molecules in our study have the potential to become both biomarkers and potential therapeutic targets of BBB dysfunction in Alzheimer’s disease.”

“These molecules (SMAD3 in brain vascular cells called pericytes and VEGFA in the brain support cells called astrocytes) can be targeted in therapeutic efforts to maintain BBB in Alzheimer’s,” she added.