Over seven million Americans are living with Alzheimer's disease (AD) and the heartbreaking day-to-day battle with the effects of cognitive decline. According to the Alzheimer's Association , the brain changes that cause the disease actually begin 20 years or more before symptoms start, highlighting the critical need for early and accurate diagnosis. However, current diagnostic tools involve painful spinal taps, expensive scans and cognitive tests that can be limited in their accuracy.
New research led by biomedical engineers at USC Viterbi School of Engineering has uncovered the key role the brain's blood flow dynamics play in AD, offering a simpler, non-invasive diagnostic tool that could reshape decades of conventional thinking about how this debilitating disease is understood and treated. Led by Vasilis Marmarelis , Dean's Professor in the Alfred E. Mann Department of Biomedical Engineering , the work was published in the journal Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring .
For years, the prevailing consensus in Alzheimer's research and clinical care has been the "amyloid cascade hypothesis." This theory suggests that a protein fragment called amyloid beta is the main culprit in Alzheimer's. When too much amyloid beta builds up in the brain, it triggers the accumulation of another protein, Tau, that forms twisted clumps known as "tau tangles" within brain cells. These tangles are then thought to cause brain cells to malfunction and eventually die, leading to the cognitive decline seen in Alzheimer's.
Current diagnostic methods largely revolve around detecting these amyloid and tau pathologies. This often requires uncomfortable and risky spinal taps to draw cerebrospinal fluid for analysis. More recently, Positron Emission Tomography (PET) imaging, or "amyloid or tau PET," emerged, where a radioactive tracer is injected to visualize amyloid plaques or tau tangles in the brain, a test that is so costly it is usually confined to academic research settings. Most recently, blood biomarkers that serve the same purpose show promise for the future.
"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 said. "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."
Without these costly and invasive biological tests, many neurologists turn to cognitive assessment tests like the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), behavioral interview-based questionnaires aimed at testing cognitive function.
"The MoCA does give you an idea about the cognitive abilities of a person," Marmarelis said. "But these are not biological or physiological tests. These are just behavioral tests that are subject to all kinds of biases, imperfections and errors."
Flipping the Script: A New Focus on our Brain's "Plumbing"
Instead of looking at the brain's amyloid plaques, Marmarelis and his collaborators focused on the way blood flow through the brain is autoregulated in order to oxygenate the brain tissue, and whether possible dysregulation may cause cognitive impairment. Think of it like a meticulous inspection of how your home's plumbing system is functioning rather than just looking at the rust on the pipes.
The research team's National Institutes of Health (NIH)–funded study harnessed data from 200 participants over five years, investigating the intricate dynamic relationship between natural changes in arterial blood pressure, carbon dioxide (CO₂) levels in the blood, and the resulting fluctuations of cerebral blood flow and cortical tissue oxygenation.
"When we exert cognitive effort, we generate CO₂ from the metabolism in our cerebral cells, which obviously has to be taken away by our blood to avoid acidosis," Marmarelis said. "Our body is endowed with this regulatory mechanism called vasomotor reactivity, which dilates (widens) our cerebral vessels when CO₂ goes up in the blood, so that more blood can go through and the excess CO₂ be washed out."
Fifteen years ago, Marmarelis made a serendipitous observation: Alzheimer's patients show impaired vasomotor reactivity. "They cannot dilate the cerebral vessels to bring more blood in and provide adequate blood perfusion to the brain. This means they don't get the oxygen, nutrients and glucose that we need for cognition in a timely manner," he said.
In their new study, Marmarelis' team tested this observation, developing a novel "physio-marker" called the Cerebrovascular Dynamics Index (CDI). This non-invasive test uses non-invasive Doppler ultrasound to measure blood flow velocity in some main arteries of the brain, and near-infrared spectroscopy to measure oxygenation in the front part of the brain's cortex. This "input-output type of conceptualization" uses sophisticated "dynamic modeling" methods developed in our lab to quantify how quickly and effectively the brain's blood supply responds to subtle changes in pressure and CO₂.
Unprecedented Accuracy and New Hope for Treatment
The research team obtained some encouraging results — The CDI showed excellent diagnostic performance, differentiating individuals with mild cognitive impairment (MCI) or Alzheimer's from cognitively normal control subjects with an Area Under the Curve (AUC) of 0.96.
AUC is a common statistical measure of diagnostic performance; a value of 1.0 is perfect, and 0.5 is random chance. For context, the amyloid PET test achieved an AUC of only 0.78, while the MoCA and MMSE cognitive tests were 0.92 and 0.91, respectively.
Marmarelis stressed that the difference between 0.78 and 0.96 translated to a "very substantial improvement" in the test's ability to correctly identify those with and without the condition.
"What we have that others didn't have before is a methodology to quantify these dynamic relations that's extremely robust and accurate," Marmarelis said. "We can now differentiate patients with mild cognitive impairment and Alzheimer's from cognitively normal controls far better than the PET measurement and even better than the MoCA neurocognitive test. This indicates that 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."
This profound shift in the understanding of Alzheimer's could pave the way for new treatment and prevention strategies focused on improving the regulation of brain blood flow and oxygenation. Marmarelis said this could involve several promising avenues that are still being evaluated for their potential efficacy:
- Lifestyle Changes: Marmarelis said a good approach would involve regular aerobic exercise, as simple as a 20-30 minute daily walk to activate mechanisms that restore healthy blood flow regulation. This would also be backed up with a healthy diet, avoiding excessive blood fats and sugars, as well as reducing stress. Marmarelis noted that a recent study by the Alzheimer's Association strongly corroborates this therapeutic approach, with results showing marked cognitive benefits in participants who took part in a two year program of aerobic exercise and adherence to the MIND diet, which emphasizes leafy greens, berries, nuts, whole grains, olive oil and fish, and limits sugar and unhealthy fats.
- Induced Intermittent Hypoxia and Hypercapnia: This involves controlled inhalation of slightly reduced oxygen and increased CO2 using a mask. Similar to training methods athletes use to enhance performance, preliminary data show that it can improve cerebral blood flow regulation.
- Transcutaneous Auricular Vagal Neurostimulation (taVNS): This safe, non-invasive technique stimulates the auricular branch of the vagus nerve (the body's key nerve that helps regulate many body functions) through an earpiece. Preliminary results suggest this can also positively impact cerebral blood flow regulation.
Other beneficial interventions can be developed and tested in the future. Marmarelis said that in addition to Alzheimer's, these results hold broader implications for the treatment and diagnosis of other dementias.
The research was supported by NIH grants. Other co-authors on the paper included Helena C. Chui , director of the Alzheimer's Disease Research Center at the Keck School of Medicine of USC, and Sandy Billinger, professor of neurology at Kansas University Medical Center, as well as collaborators from the Department of Neurology at the University of Texas Southwestern Medical Center.
