Over seven million Americans are living with Alzheimer’s disease (ALD) 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 ALD, offering a simpler, non-invasive diagnostic tool that could reshape decades of conventional thinking about how this debilitating disease is understood and treated.
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, however, PET imaging for amyloid or tau PET emerged.
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. Instead of looking at the brain’s amyloid plaques, the team 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. Scientists 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.
Fifteen years ago, Dr. Marmarelis made a serendipitous observation: Alzheimer’s patients show impaired vasomotor reactivity. 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. 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. This could pave the way for new treatment and prevention strategies focused on improving the regulation of brain blood flow.
Dr Marmarelis said this could involve several promising avenues that are still being evaluated for their potential efficacy. Lifestyle changes are among these: 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. A recent study by the Alzheimer’s Association strongly corroborates this 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 is another possible intervention: 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. The last possible safe, non-invasive technique is the Transcutaneous Auricular Vagal Neurostimulation (TAVANS): 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.
- Edited by Dr.Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Marmarelis V, BIllinger S et al. Alzheim Dement. 2025; 17(3):e70134.
Marmarelis VZ et al. J Cereb Blood Flow Metab. 2024; 44(11):1288.
Rizko JM, Beishon LC et al. Front Physiol. 2024 Sep 9; 15:1350832.
Marmarelis VZ et al. J Appl Physiol (1985). 2020 Feb; 128(2):397-409.
