Fighting dementia with precision interventions
Written by Jessica Binkley Lain
Researchers at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases use a comprehensive approach to discover new targets for personalized and precise treatments of dementia.
Cognitive decline is one of the more distressing hallmarks of aging. Losing memory and the ability to control thoughts, emotions and behavior is a devastating loss for both patients and caregivers. The Biggs Institute at UT Health Science Center San Antonio is poised to make breakthroughs in dementia prevention and treatment as one of 33 centers in the nation recognized as a National Institute on Aging-designated Alzheimer’s Disease Research Center.
professor in the Department of Neurology, and Robert R. Barker Distinguished University Professor
“Dementia affects a person’s memory and thinking, which is a core part of who we see ourselves as,” said Sudha Seshadri, MD, founding director of the Biggs Institute. Seshadri has dedicated her career to studying the brain and identifying the genetic underpinnings of dementia, as well as caring for those suffering the loss of themselves.
“It’s important to emphasize that dementia can happen in people with a lot of abilities,” Seshadri said. “We don’t want to just give this diagnosis and then say, ‘go home and withdraw from society.’ We want to help you live the best life you can. All of that is part of our responsibility.”
The dementia epidemic in South Texas
South Texas is home to a majority Hispanic population, a group of people who are 50% more likely to develop Alzheimer’s disease than non Hispanic whites and are projected to bear the largest relative increase in Alzheimer’s and related dementia cases by 2060, Seshadri explained. Factors such as poverty, inadequate access to health care, as well as the prevalence of diabetes and other vascular risk factors in this population all increase the risk.
This prevalence has a significant economic impact on the region, especially considering that each Alzheimer’s patient has an average of three caregivers. For the 400,000 Texans who have Alzheimer’s disease, there are 1.2 million Texans who are caregivers for them. Moreover, one in six of those caregivers is under the age of 35, holding them back during a time of major life milestones, such as pursuing additional education, starting families or starting new careers, Seshadri said.
However, dementia is inadequately studied in Hispanic patients, which is why many research efforts at the Biggs Institute focus on investigating dementia in people of Hispanic ancestry in all aspects of study, from genetics and environmental factors to inclusion in clinical trials.
This is important not just because Hispanics are the fastest-growing demographic in the country, but also because unraveling mysteries in one population can lead to breakthroughs that benefit everyone, Seshadri said.
“Typically, it is by studying populations that haven’t yet been studied that we find answers,” she said. Seshadri and her team are using genome sequencing, transcriptome sequencing, metabolomics and proteomics to identify why this population is prone to dementia. In addition, these studies will provide new targets to intervene in the progression of dementias.
Precision therapies for patients
Clinical trials are crucial to find new treatments and improve existing ones, and to understand what combination of therapies can benefit patients for their specific disease. One of the major barriers to identifying new treatments for dementia is that it’s not just one disease with one cause, but many diseases that can each have many etiologies.
“We know now that there are many contributions to dementia and with multiple types existing at once within a patient,” Seshadri said. “We need to understand all of these and take a precision approach to the diagnosis and treatment. It won’t be just one agent, but likely a combination of agents.”
The most common and well-known cause of dementia is Alzheimer’s, Seshadri explained, noting that 60% to 70% of dementia patients exhibit an Alzheimer’s pathology, with plaques of beta-amyloid and tangles of tau. And the number of genetic variants associated with Alzheimer’s is growing.
Seshadri is a founding principal investigator of the International Genomics of Alzheimer’s Project, a National Institute of Aging-funded study established in 2009 that conducts genome-wide association studies.
“We’ve doubled the number of genes that we know are associated with Alzheimer’s disease. We know now that there are around 90 genes,” Seshadri said. “And each of these genetic variants is a route to understanding the biology and a potential target for treatment.”
Moreover, there are other common causes of dementia beyond Alzheimer’s that very often coexist, such as dementia with Lewy bodies, vascular dementia and other rarer causes. Researchers at the Biggs Institute study all of these, Seshadri said, which is why large clinical trials and observational studies are so important to sift through the many underlying causes and identify patterns that predispose people to Alzheimer’s disease and related dementias.
“We have many trials and observational studies going on now, for all people at all different stages of dementia,” Seshadri said. “We have trials for people at risk due to family history, even if they are completely asymptomatic, and then we have trials for people with mild cognitive dementia and for those with early dementia, as well as trials for people with specific, rare diseases.”
It’s never too LATE for new discoveries
The study of one prominent and newly discovered underlying pathology, called Limbic-predominant Age-related TDP43 Encephalopathy, or LATE, has led to new insights about the complicated nature of multiple, coexisting pathology lesions in the brains of dementia patients.
Margaret Flanagan, MD, is an associate professor in the Department of Pathology and neuropathologist at the Biggs Institute. Her research investigates the role of the protein TDP43 in the development of different types of clinical dementia syndromes including LATE, which she contributed to naming.
LATE is an amnestic dementia syndrome similar to Alzheimer’s disease, but it may stem from different underlying causes and disease mechanisms. At the time of brain autopsy examination, individuals with LATE have been found to have an accumulation of a pathologic form of the protein TDP43 in their brains, Flanagan explained. The discovery of TDP43 accumulation in one form of dementia raises the possibility that it could be targeted with a protein degrader or an antibody to decrease progression of LATE.
“Not only has the pathologic form of TDP43 protein been associated with the type of amnestic dementia that’s very similar to Alzheimer’s disease dementia, but, interestingly, the accumulation of the pathologic TDP43 in these individuals has also been very strongly associated with atrophy in the hippocampus, also seen in association with the pathognomonic plaques and tangles of Alzheimer’s disease,” she said.
To make it more complicated, pathologic TDP43 also commonly coexists along with the plaques and tangles of Alzheimer’s.
“We’re finding more and more that multiple coexisting types of pathology lesions in the brain are much more common than having purely one type,” she said. “It’s the norm and not the exception.”
Thus, many forms of dementia overlap, with multiple distinct causes contributing to a given patient’s cognitive decline, making it even more difficult to identify new therapies.
Eye exams for early detection
Flanagan has worked with a new technology that has possibilities for early detection of specific combinations of pathology lesions and providing patients with personalized diagnostic protein profiles underlying their clinical dementia. Collaborating with researchers at the University of Minnesota and RetiSpec, a private company based in Toronto, Canada, Flanagan’s work has helped validate a noninvasive retinal scanner that can take a picture of an individual’s retina to identify each patient’s unique hyperspectral signature based on the individual’s distinctive combination of proteins accumulated in the back of the eye.
“These abnormal proteins appear to accumulate earlier in the eye than in the brain, and the hope is that routine eye exams using this noninvasive technology will ultimately reliably identify different combinations of coexisting pathology in the retina before symptoms develop in patients,” Flanagan said. “Once the combination of coexisting pathology lesions is determined, then combination therapies specific to each patient’s unique profile can be initiated before memory problems begin for effective, personalized dementia prevention.”
This is especially important given that the new anti-amyloid antibodies for preventing cognitive decline in Alzheimer’s disease are more successful when given early in the course of dementia, she said.
Stimulation to slow decline
A novel surgery to slow cognitive decline and memory loss from Alzheimer’s disease is being tested at UT Health Science Center San Antonio. The procedure, called deep brain stimulation, or DBS, is an established treatment for movement disorders such as Parkinson’s disease.
Gabriel de Erausquin, MD, PhD, professor of neurology in the Long School of Medicine and researcher at the Biggs Institute, has experience in overseeing more than 200 DBS cases for movement disorders.
De Erausquin has a long career treating both Alzheimer’s and Parkinson’s patients. Upon moving to the university, he began focusing on the application of deep brain stimulation and other neuromodulation techniques to combat memory loss. He currently serves as principal site investigator for a global study, across 27 sites worldwide, evaluating the effectiveness of DBS in treating patients with early, mild Alzheimer’s disease.
Deep brain stimulation for Alzheimer’s involves the placement of electrodes in the fornix, hippocampus and amygdala — areas of the brain associated with memory. The electrodes are connected to a battery-operated generator in the chest, similar to a pacemaker. A small impulse of electricity moves from the generator to the electrodes to stimulate specific areas of the brain. The surgery is minimally invasive for a quick recovery with the least amount of pain, blood loss and hospital time. The small electrical stimulus promotes memory retention in the brain, potentially preventing the decline of memory in most dementias.
In 2021, a San Antonio woman in her 70s underwent South Texas’s first DBS surgery for Alzheimer’s at University Hospital, clinical partner of UT Health Science Center San Antonio, with great success, De Erausquin said.
“The usual course of illness for people with early Alzheimer’s disease is a progressive loss of function that is very steady and doesn’t slow down,” De Erausquin said. And while DBS cannot reverse disease progression, “being able to slow symptoms from progressing might mean that a patient could continue to drive to the store, to church or to another family member’s home. That ability is quickly lost if symptoms advance.”
Trial testing for DBS surgery has now closed, but a second part of the trial testing multisensory neurostimulation is currently underway. This method stimulates the brain without surgical implants, using outside sources such as light and sound. The results aren’t yet in, but so far, De Erausquin has seen “promising results” in slowing disease progression using these techniques.
An unwelcome opportunity for discovery
Another project De Erausquin leads is the Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection, a World Health Organization initiative of research and clinical teams from around the world to track the long-term impact of COVID-19 on the brain.
“When the pandemic hit, this created a very unwelcome, but great scientific opportunity,” De Erausquin said. “We had a unique time-locked, very well-defined environmental challenge that we thought could be a risk factor for cognitive decline. One of the things that has become apparent from the cooperative work around the world is that COVID does, in fact, increase the risk of cognitive decline, particularly in older adults.”
Younger people suffering from long COVID tend to have difficulty maintaining attention and concentration and have some trouble with executive function, but their memory isn’t particularly affected, De Erausquin explained. Older adults over 60, however, seem to have much more prominent impairment to recent memory and language, failing at simple tasks, forgetting appointments and losing the ability to recall words — a profile that is “much more consistent with what you expect to see in somebody with Alzheimer’s,” he said.
“The link between Alzheimer’s disease and environmental factors has been discussed for the better part of the past 100 years,” De Erausquin explained. There is a definitive link between gum disease and Alzheimer’s, for example. This links the microbiome of the mouth to the function of the brain over time, opening a new area of potential intervention to prevent dementia. And it’s been found that if an individual has had to receive antiviral drugs administered intravenously at some time in their life, their risk of having Alzheimer’s disease later is decreased by half, he said.
“The exact nature of these infections in relation to the process of Alzheimer’s remains to be proven or studied, but that’s exactly what the pandemic gave us — a very specific opportunity to address an environmental trigger as a possible pathological process underlying Alzheimer’s disease.”
Study researchers are looking at large samples of whole genome sequencing data to understand if there is a particular genetic risk that makes someone more likely to have a cognitive decline following COVID and if that risk would also lead to developing Alzheimer’s disease later in life, De Erausquin said. So far, he reports that researchers have found that there is a definitive genetic component in the form of heritability, but which particular genes are to blame for this interaction remains unknown.
Seshadri, Flanagan and De Erausquin share a passion for making neurodegenerative disease a mere memory for South Texas. Together, they and their research colleagues at UT Health Science Center San Antonio are on the cusp of revolutionizing the prevention and treatment of dementia.
