Neurovascular Clues Offer New Path to Early Alzheimer’s

A study published in Brain Communications revealed new insights into early detection of Alzheimer’s disease. Researchers have used noninvasive techniques, including near-infrared spectroscopy and electroencephalography, to examine functioning of the neurovascular unit in this disease.

The study compared 19 patients with Alzheimer’s disease with 20 control individuals, revealing a significant decrease in cerebral oxygenation oscillations and reduced coordination between oxygenation and neuronal activity in the Alzheimer’s disease group. Patients with Alzheimer’s disease also had a higher average respiration rate than the control individuals. These findings suggested that neurovascular dysfunction may lead to reduced oxygen delivery to the brain, which could affect adenosine triphosphate production, and reduce beta-amyloid clearance.

These changes in cerebral oxygenation and neurovascular dynamics can serve as key markers for early diagnosis and disease progression. These may also be useful for evaluating the effect of therapeutic interventions in Alzheimer’s disease.

Biomarker Challenges

In Brazil, the diagnosis of Alzheimer’s disease in symptomatic cases still relies on structural imaging such as MRI, CT, and laboratory tests to rule out reversible causes. However, these methods do not identify typical pathologic changes such as beta-amyloid plaques and hyperphosphorylated tau (p-tau) tangles in Alzheimer’s disease.

“More accurate biomarkers have been developed over the past 20 years, but their use in Brazil remains limited due to availability,” said Wagner Brum, researcher at University of Gothenburg, Gothenburg, Sweden. “Studies show that cognitively healthy individuals with altered beta-amyloid and tau biomarkers have a higher risk of developing Alzheimer’s.”

However, the use of these markers in asymptomatic individuals remains controversial and is restricted to academic research.

Key Biomarkers

Alzheimer’s disease is defined by the amyloid (A), tau (T), and neurodegeneration (N) criteria, collectively known as the ATN framework. However, there is still debate over these criteria. The Alzheimer’s Association in the United States considers elevated amyloid protein alone sufficient to define the disease, while Alzheimer Europe classifies such individuals as only at risk.

Amyloid and tau can be measured in the cerebrospinal fluid via lumbar puncture or detected using a PET scan. “Brazil lags behind in adopting tests such as amyloid PET scan, which is not widely available in the Unified Health System,” said Márcia Regina Cominetti, professor and researcher in the Department of Gerontology, Federal University of São Carlos in Sao Paulo, Brazil, who supports the European diagnostic criteria.

Given the limitations of invasive and expensive tests, blood biomarkers are gaining attention. The p-tau217 protein has demonstrated high diagnostic accuracy (> 90%) for pathologic changes in Alzheimer’s disease, making it a promising clinical tool.

However, beta-amyloid biomarkers show limited reliability, with only an 8%-14% reduction in patients with Alzheimer’s disease, which is insufficient for broad clinical use, according to Wagner.

Neurofilament light chain, another biomarker, is useful for monitoring neuronal damage but can be altered in several neurologic conditions, not just Alzheimer’s disease.

Márcia’s research also focuses on ADAM-10, a metalloprotease that regulates amyloid precursor protein processing and beta-amyloid plaque formation. She advocated for the incorporation of ADAM-10 into the ATN criteria.

“In the future, we will need a panel of biomarkers, not just one isolate,” she stated.

Technical Hurdles

Plasma biomarkers hold promise for the early detection of Alzheimer’s disease; however, their widespread use faces challenges. Many current measurement techniques are ultrasensitive but impractical for routine clinical settings. Standardization is crucial for large-scale implementations.

“Once an immunoassay meets clinical needs, the next challenge is calibration with certified reference materials and quality control programs,” Wagner explained. “With standardized materials, a test performed in Brazil could be interpreted using the same scale as those in the United States or Europe, even if cutoff values differ.”

A recent study at the University of Gothenburg, in collaboration with pharmaceutical and biotech companies, compared 33 blood-based p-tau tests and evaluated both research-based and automated methods. This study also assessed potential reference materials.

“The p-tau217 protein consistently demonstrated the most accurate biomarker for detecting pathologic changes linked to Alzheimer’s disease,” Wagner stated. However, he noted that the reference materials evaluated underperformed, indicating the need for further refinement before widespread clinical use.

A study published in Alzheimer’s and Dementia raised concerns about p-tau217’s reliability as a universal Alzheimer’s biomarker. In a cohort of 221 participants, blood and cerebrospinal fluid p-tau217 levels correlated at 70%, but with marked racial differences. The sensitivity and specificity were 90.3% and 81.1% in White individuals, respectively, but lower in Black individuals (73.7% and 72.5%, respectively). The positive predictive value also differed (58% in White individuals vs 87% in Black individuals), highlighting potential diagnostic disparities.

“For Black patients, the impact is twofold,” William Hu, lead author of the paper, said in a press release. Hu is a director of the Center for Healthy Aging Research, Rutgers Institute for Health, and chief of Division of Cognitive Neurology and Alzheimer’s Disease Clinic, Robert Wood Johnson Medical School, both in New Brunswick, New Jersey. He noted that the accuracy of test is lower in these cases and further refinement is required before clinical implementation.

“In 5-10 years, these tests could reach a reliable level, but currently, they are comparable to some home COVID-19 tests, which have accuracy issues,” said Hu.

Future Outlook

Ongoing efforts aim to refine biomarker-based diagnostics for faster, more accurate, and accessible detection of Alzheimer’s disease. The ultimate goal is to identify biological changes before the appearance of cognitive symptoms, enabling earlier intervention.

“In the future, we will screen with biomarkers and initiate treatments, such as monoclonal antibodies, if needed,” Márcia explained.

Since 2021, monoclonal antibodies such as donanemab have received US Food and Drug Administration approval to target beta-amyloid. Although ineffective in advanced cases, they may slow down early-stage progression.

As diagnostic techniques advance, early detection of Alzheimer’s disease could become a clinical reality, transforming treatment strategies and improving patient outcomes.

This story was translated from Medscape’s Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.