New non-invasive blood flow test outperforms standard Alzheimer’s diagnostic markers
A groundbreaking diagnostic test measuring brain blood flow dynamics has demonstrated superior accuracy in detecting Alzheimer’s disease compared to traditional markers, achieving a 96% diagnostic performance rate. The non-invasive cerebrovascular test offers hope for earlier, more accessible dementia screening whilst challenging conventional amyloid-focused diagnostic approaches.
Researchers at the University of Southern California have developed a novel diagnostic approach for Alzheimer’s disease that focuses on the brain’s blood flow regulation rather than traditional protein markers, achieving unprecedented accuracy in clinical trials.
The Cerebrovascular Dynamics Index (CDI), described in research published in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring on 18 July 2025, demonstrated an area under the curve (AUC) of 0.96 when differentiating patients with mild cognitive impairment (MCI) or Alzheimer’s from cognitively normal controls. This substantially outperformed the commonly used amyloid PET scan biomarker, which achieved only 0.78 AUC.
The multi-centre National Institutes of Health-funded study, led by Professor Vasilis Marmarelis from USC’s Alfred E. Mann Department of Biomedical Engineering, followed 200 participants over five years and represents a significant departure from the prevailing amyloid cascade hypothesis that has dominated Alzheimer’s research for decades.
Challenging conventional diagnostic wisdom
“Physicians take the emissions from that PET radioactive tracer as an approximate measure of how much amyloid or tau the person has in their brain,” Marmarelis explained. “Speaking from experience, after having seen data in my own study, I tell you that it’s very inadequate. But it’s the gold standard, although most physicians don’t do it because it’s very expensive.”
The research challenges the conventional focus on amyloid plaques and tau tangles, instead examining what Marmarelis describes as the brain’s “plumbing system” – how effectively blood vessels regulate flow to deliver oxygen and nutrients to brain tissue.
The authors propose that “dysregulation of cerebral perfusion dynamics may cause hypoxia due to hypoperfusion, which in turn boosts Aβ production via an increase of beta-secretase, further aggravating hypoperfusion due to cerebral amyloidosis and forming a vicious cycle of reciprocally reinforced detrimental effects that may lead gradually to neuronal degeneration.”
Diagnostic precision across multiple disease stages
The CDI test measures three key aspects of brain blood flow regulation using non-invasive Doppler ultrasound and near-infrared spectroscopy. The study found the CDI could differentiate MCI patients from mild Alzheimer’s patients with 0.98 AUC, whilst the amyloid PET scan showed no significant diagnostic capability for disease staging (p > 0.05).
Comparing sensitivity and specificity at maximum accuracy thresholds, the CDI achieved 87% sensitivity and 93% specificity for diagnosing MCI/Alzheimer’s patients, compared to amyloid PET’s 67% sensitivity and 92% specificity. Even cognitive screening tests like MoCA (0.92 AUC) and MMSE (0.91 AUC) demonstrated superior performance to the amyloid biomarker.
The research team calculated positive predictive values of 93% for CDI versus 73% for amyloid PET-SUVR, and negative predictive values of 87% for CDI versus 72% for amyloid PET-SUVR, indicating the blood flow test’s superior prognostic capability.
Therapeutic pathways and clinical accessibility
The vascular hypothesis underlying the CDI opens new therapeutic avenues focused on improving brain blood flow regulation. Marmarelis highlighted several promising interventions, including regular aerobic exercise, dietary modifications following the MIND diet, and novel techniques such as controlled intermittent hypoxia therapy and transcutaneous vagal nerve stimulation.
“What we have that others didn’t have before is a methodology to quantify these dynamic relations that’s extremely robust and accurate,” Marmarelis noted. The research team suggests this indicates “the particular aspect of dysregulation of cerebral perfusion regulation may be the critical aspect in the pathogenesis of this disease, probably in conjunction with other factors, including amyloid accumulation.”
Unlike expensive amyloid PET scans, which can cost thousands of pounds and require radioactive tracers, the CDI test uses readily available equipment and can be completed in clinical settings within minutes. The authors describe their findings as offering “the promise of a high-performance diagnostic physio-marker for MCI and AD, which can be obtained in a comfortable, rapid, and automated manner in clinical settings.”
Clinical validation and future challenges
The study involved 167 participants with adequate blood flow data, including 77 cognitively normal controls, 56 MCI patients, and 34 mild Alzheimer’s patients across three clinical centres. However, the research team acknowledges important limitations, particularly regarding cross-validation results.
Initial testing with smaller cohorts showed the CDI’s performance dropped to 0.83 AUC in cross-validation, though still exceeding amyloid PET performance. The authors emphasise that “such reduction in performance must be examined further with larger cohorts in the future, since the current cohort is rather limited.”
Future work will need to address diagnostic specificity for other dementia types, potential confounding effects of cardiovascular comorbidities, and explore relationships with tau pathology and neuroinflammation. The researchers note that combining CDI with cognitive screening tests could yield even higher diagnostic accuracy, potentially reaching 0.99 AUC.
The study represents a fundamental shift from protein-focused diagnostics towards understanding the complex association between vascular dysfunction and neurodegeneration in Alzheimer’s disease progression, offering new hope for earlier detection and targeted interventions.
Reference
Marmarelis, V., Billinger, S., Joe, E., et. al. (2025). Dysregulation of cerebral perfusion dynamics is associated with Alzheimer’s disease. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, 17, e70134. https://doi.org/10.1002/dad2.70134
