New pathways for Alzheimer’s prevention

Too often, people learn they have Alzheimer’s disease (AD) when it’s too late. The changes in the brain that lead to AD manifesting with symptoms have already been occurring for decades.

A new interdisciplinary study at the University of Delaware seeks to study AD by examining changes in the arteries and brain tissue in midlife adults in their 50s and 60s. The findings could identify the earliest mechanisms linking vascular aging to the loss of brain tissue integrity, leading to new targets for interventions aimed at preventing age-related cognitive impairment. 

“People who develop high blood pressure or stiffening of the aorta and carotid arteries in midlife are at a much higher risk for developing cognitive impairment or dementia in late life,” said Christopher Martens, the principal investigator of the study. 

Martens, an associate professor of kinesiology and applied physiology in the College of Health Sciences and director of the Delaware Center for Cognitive Aging (DECCAR), is working closely with Curtis Johnson, an associate professor of biomedical engineering in the College of Engineering and leader of the neuroimaging biomarker core within DECCAR, on research funded by a nearly $4 million grant from the National Institute on Aging (NIA), a division of the National Institutes of Health (NIH).  

“A lot happens as we age, so we’re aiming to pinpoint the timing and exact mechanisms that cause these changes in midlife adults,” Martens said. 

This latest grant extends DECCAR’s ongoing Delaware Longitudinal Study for Alzheimer’s Prevention (DeLSAP), which seeks to study how risk and protective factors for dementia are related and change over time. Those eligible for DeLSAP could also meet the criteria for participating in the new study. 

In his Neurovascular Aging Laboratory, Martens studies mechanisms leading to the stiffening of arteries, while Johnson is specifically interested in measuring the stiffness of the brain.

“As a person ages, the brain gets softer and breaks down, and we’re looking to see whether changes in arterial stiffness and patterns of blood flow in the brain cause this decline,” Johnson said. 

Changes in blood flow to the brain come from controllable factors. Smoking, cardiovascular health, diet and exercise all impact blood flow positively and negatively. 

“A lot of aging research is done at the end of life,” Johnson said. “We want to look at midlife and try to predict what happens later in life so we can prevent it.” 

While the brain gets softer with age, arteries get stiffer.

“We hypothesize that midlife increases in stiffness in blood vessels cause damaging pulsatile pressure to enter the brain,” Martens said. “We believe this is one of the reasons we start to develop cognitive issues at an older age because the brain is exposed to increased pressure; that pressure is likely inflicting damage on surrounding brain tissue.” 

In Johnson’s Mechanical Neuroimaging Lab, researchers will use high-resolution magnetic resonance elastography (MRE) to determine where brain damage occurs and what specific brain structures may be affected. 

“From an MRI perspective, most researchers look at AD and other neurodegenerative diseases like multiple sclerosis with an emphasis on detection in a hospital setting,” Johnson said. “Using highly specialized techniques we’ve developed, we focus on the earlier side and how these changes progress into disease from the neuroscience side, emphasizing prevention.” 

Together, they’ll seek to learn whether arterial stiffness causes the kind of cognitive impairment seen in AD or whether the decline is associated with a loss in the integrity of brain tissue. 

“If we can prove arterial stiffness is playing a causal role in cognitive aging, that would provide further support for focusing on blood vessel health as an intervention for delaying AD or other forms of dementia versus solely focusing on the brain,” Martens said.

Biomedical engineering doctoral candidate Mary Kramer came to UD to study alongside Johnson and learn about his novel MRE technique. 

“Correlating blood-based biomarkers of Alzheimer’s with our MRI measures could have enormous implications for non-invasive imaging and to track disease progression,” Kramer said. 

For her, this research has a personal impact. Her grandmother had Alzheimer’s, and her father recently developed mild cognitive impairment. 

“The fear of losing your memory is ubiquitous, and what are we if not a collection of memories?” she asked. “I want to make a difference and help people not suffer the same fate as my relatives.” 

Shifting the narrative

Johnson and Martens met by chance on UD’s Science, Technology and Advanced Research (STAR) campus, where their offices were two doors down.

“If not for the interdisciplinary nature of the STAR campus, we may have never interacted,” Martens said.

But after a conversation about each other’s research, they’ve now collaborated on several grants. They hope this research shows students in physiology and biomedical engineering the kinds of collaborations that are possible.

“This is what interdisciplinary research looks like,” Martens said. “You can think outside the box and work with people in other fields to answer important questions in their field.” 

Current therapies aimed at slowing the progression of AD include removing amyloid plaque build-up in the brain. 

“While that’s worthwhile, it’s a later signal in the progression of the disease. Amyloid may be more like a smoke signal, but we must go after the fire,” Martens said. “Vascular changes happening outside the brain in midlife may be one of the earliest events that ultimately leads to amyloid in the brain several decades later due to the damage that the pressure waves cause to brain tissue.” 

Once elasticity is lost from arteries, it can’t be regained, underscoring the importance of adopting healthy lifestyle habits that can prevent arterial stiffening and slow AD progression.  

“Lifestyle factors play a role in blood vessel health and are critically important for brain health,” Martens said. “The relationship between blood vessel health and the brain might be why those healthy lifestyles are so protective.” 

Martens and Johnson hope this research raises awareness and shifts the public narrative on the root causes of AD. 

“Alzheimer’s is a devastating disease, but there are steps a person can take through diet and exercise, and taking those steps in midlife isn’t too late to slow or significantly delay the disease,” Martens said.

He also hopes students gain an appreciation for studying AD through a prevention lens. 

“This disease starts decades before symptoms show, and that’s when we can have the biggest impact in preventing or delaying the disease,” Martens said. “Studying midlife adults is a pathway to ultimately curing AD.”