The University of South Florida and healthy older adult volunteers from the Sarasota area will play an increasingly crucial role in the landmark Preventing Alzheimer’s with Cognitive Training (PACT) study. This study, funded by the National Institute on Aging, part of the National Institutes of Health, examines whether computerized brain training exercises can reduce the risk of cognitive impairment and dementia such as Alzheimer’s disease. Additional funding awarded earlier this year will provide PACT study participants with an option to provide blood samples that will be used to develop tests for early detection of Alzheimer’s disease. This is the largest study of its kind to date, investigating not only how to possibly prevent dementia but also how to detect it earlier.

USF’s PACT study expansion to Sarasota will increase our expected study enrollment from 2,354 to 3,567 over the next two years. To qualify, participants must be 65 or older with no signs of cognitive impairment or dementia. There is an emphasis on the need for African-American/Black and Hispanic study volunteers. According to the Alzheimer’s Association, these populations are at the highest risk for Alzheimer’s disease and other dementias.

“We are excited for the opportunity to launch PACT in Sarasota. We are seeking another 1,213 healthy older adults to volunteer for this important study. We are grateful for the 2,354 volunteers in the Tampa Bay region and beyond who have already joined our fight against Alzheimer’s disease by enrolling in PACT. The scientific contributions made possible by our PACT volunteers have the potential to positively impact our lives and the lives of future generations,” said Brianne Stanback, PhD, research assistant professor in the USF Health Morsani College of Medicine and director of Community Engagement for PACT.

Those interested in the study may participate at USF Sarasota-Manatee, Tampa, or St. Petersburg campuses or at Reliance Medical in Lakeland or Winter Haven. Participants may also join the study at University of Florida in Gainesville or Jacksonville, University of North Florida, Clemson University in Seneca or Greenville, SC, or Duke University in Durham, NC.

PACT participants will be asked to initially come to two in-person study visits. They will then complete 45 computerized training exercises in their own home or they may choose to complete activities at a study site. Participants will be asked to return about three years later for a third study visit.

More information is available at the PACT study website, pactstudy.org, or by calling (941) 500-4447.

The PACT study is supported by the National Institute on Aging, part of the National Institutes of Health (NIH), grant number R01AG070349. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Tampa FL (June 8, 2022) – The University of South Florida received $3.2 million from the National Institute on Aging to investigate if Alzheimer’s disease can be detected early through simple blood tests.

The new funding dovetails with a $44.4 million, five-year NIH grant awarded to USF last year testing whether computerized braining training can reduce dementia risk in older adults. Called the Preventing Alzheimer’s with Cognitive Training (PACT) study, it is the largest primary prevention trial to date designed to rigorously test the effectiveness of computer-based training to protect against MCI and dementias.

Participants enrolling in the PACT study can also enroll in the study investigating whether a simple blood test can detect dementia. The PACT study will work with the National Centralized Repository for Alzheimer’s Disease and Related Dementias to analyze blood samples collected from study participants.

“We need another 2000 healthy older adults to volunteer for the PACT study. We are very grateful to the 1800 volunteers from Tampa Bay who have already joined our fight against Alzheimer’s disease by enrolling in PACT.” said principal investigator Jerri Edwards, PhD, a professor of psychiatry and behavioral neurosciences in the USF Health Morsani College of Medicine. “Participants will now not only be contributing to our work on how to possibly prevent dementia, but also advancing efforts to develop blood tests for early detection of the disease.”

Jerri Edwards, PhD, professor of psychiatry and behavioral neurosciences at the USF Health Morsani College of Medicine, is USF site principal investigator for the PACT study.

Currently, diagnosing dementia such as Alzheimer’s disease requires expensive PET scans or invasive cerebrospinal fluid samples. This new study will contribute to research working toward developing simple blood tests to improve existing methods.

Launched last year, the PACT study continues to recruit participants, seeking healthy older adults to volunteer for the landmark study examining whether computerized brain training exercises can reduce the risk of cognitive impairment and dementia such as Alzheimer’s disease. PACT study volunteers should be age 65 or older with no signs of cognitive impairment or dementia. Those accepted into the study will participate in initial testing at a PACT location at the USF Tampa or St. Petersburg campuses or at Reliance Medical in Lakeland. The PACT study is also being conducted by partner sites at Clemson University, University of Florida, University of North Florida, and Duke University.

The USF PACT study concentrates on the effectiveness of computerized programs, or brain games, for preventing dementia such as Alzheimer’s disease. These computerized training exercises are designed to potentially enhance mental quickness and visual attention. At the end of the trial, the scientists will examine the blood samples from willing participants and determine which specific blood-based biomarkers predict Alzheimer’s disease, the severity of the disease, and/or responsiveness to treatment.

The PACT study is supported by the National Institute on Aging, part of the National Institutes of Health (NIH), grant number R01AG070349. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

More information is available at the PACT study website, pactstudy.org, or by calling 813-974-6703.

The new research may help identify measures to prevent or delay mild cognitive impairment and dementia

Can what you eat influence the health of your brain now and in the future?

That is a key question that USF Health Morsani College of Medicine researchers hope to answer with the help of a noninvasive Microbiome in the Aging Gut and Brain (MiaGB) study.

The new clinical study expects to enroll 400 adults ages 60 and older in the Tampa Bay region and beyond — both those who are cognitively healthy as well as those diagnosed with mild cognitive impairment and early-stage dementia.

The researchers will analyze the composition of bacteria in stool samples and saliva samples (oral swabs) donated by study participants one time at the beginning of the study and then once a year for at least five years. They will track alterations over time in the populations of oral and gut microorganisms, collectively known as the microbiome. Using an interactive mobile app, study participants will complete a daily dietary recall questionnaire and yearly tests of their memory, speed of thinking, and other cognitive abilities.

“We want to know, based on changes in the microbiome ‘signature’ from the saliva and stool samples, if we can predict an older person’s risk of developing cognitive decline or dementia. And can we do that early enough to delay or prevent those age-related diseases – either by modifying the individual’s diet or the microbiome itself,” said Hariom Yadav, PhD, an associate professor of neurosurgery and brain repair at the Morsani College of Medicine and director of the USF Center for Microbiome Research.

Several studies have correlated healthy guts, characterized by a well-balanced diversity of microorganisms, with healthy aging. Alzheimer’s disease and other dementias are among the growing number of medical conditions linked to an imbalance of microorganisms (more bad bugs than good bugs) within the intestines. Emerging evidence also suggests that oral health and brain health are interconnected, including a large National Institute on Aging study last year linking gum disease with dementia.

Hariom Yadav, PhD, (standing) and Shalini Jain, PhD, are faculty members at the USF Center for Microbiome Research, based in the USF Health Morsani College of Medicine. Their research focuses on the gut-brain connection (gut-brain axis) in relation to cognitive function.  — Photo by Allison Long, USF Health Communications and Marketing

The daily food intake logged by study participants will indicate any deficiencies in their usual diets, said Shalini Jain, PhD, the MiaGB study’s IRB principal investigator and USF Health assistant professor of neurosurgery and brain repair. “We’ll be able to evaluate the effects that certain types of foods (i.e, protein, fruits, vegetables, dairy, carbohydrates, fermented foods, and junk food) have on the growth of certain types of bacteria and see how the mix of bacteria changes if the diet is modified.”

Study participants may benefit by learning more about the calories and nutritional balance (or imbalance) in their diets, Dr. Jain added. Based on the dietary information reported, the mobile app suggests healthy habits that can be incorporated into the individual’s lifestyle.

Ronald Day and his wife Ardell, both 74, were among the first to enroll in the MiaGB study after attending a presentation about the USF Health microbiome research. Day, a retired pastor and volunteer chaplain at his Tampa continuing care retirement community, said he was intrigued by the idea that populations of microorganisms in the gut may affect cognitive skills controlled by the brain.

“On a practical level, I’m hoping to learn something about my eating habits from the food diaries we keep that might indicate what foods I should add to my diet, or which to avoid,” Day said. “And in the future, I’m hoping researchers learn enough from studies like this to suggest individualized diets (or other interventions) tailored to our own microbiomes.”

As someone in “the last third of life,” Day added, he’s keenly aware of the need to prevent or delay cognitive decline. “One of our neighbors is in the early stages of Alzheimer’s disease, and it’s been difficult for the family… Anything that can help maintain mental acuity as we age is so important.”

Photo by Allison Long, USF Health Communications and Marketing

Aging is not a disease, Dr. Yadav emphasized, but as people age it’s particularly important to keep a healthy balance of intestinal microbes so that a potentially harmful strain of bacteria does not overgrow and monopolize the food source of beneficial bacteria. “A healthy gut allows you to adequately absorb the healthier nutrients and keep a check on the stimulation of inflammation, which is a root cause of several age-related conditions, including abnormal cognitive function,” he said.

For more information about the MiaGB study, please email jains10@usf.edu or call (813) 974-6281.

Hariom Yadav focuses on microbiome’s role in the gut-brain axis, including creating fermented foods, probiotic mixtures, and modified diets to regulate gut “leakiness”

Hariom Yadav, PhD, is on the frontier of exploring the connection between the microbes in our gut and our brain health – including the impact on age-related cognitive decline and moods.

Dr. Yadav, an associate professor of neurosurgery and brain repair, was recruited to the USF Health Morsani College of Medicine to direct the Center for Microbiome Research, a key component of the newly launched USF Institute for Microbiomes. When he joined USF Health this April from Wake Forest School of Medicine in North Carolina, he brought more than $4 million in research awards from the National Institutes of Health and the U.S. Department of Defense.

“The major focus of our laboratory is investigating whether and how a leaky gut caused by disturbances in the gut microbiome contributes to the risk of dementia and other age-related chronic diseases such as diabetes, cardiovascular disease, and cancer,” Dr. Yadav said. “We also work to develop evidence-based products — probiotics, prebiotics, fermented foods, modified ketogenic diets — that can modulate the microbiome to help prevent bad effects of abnormal leakiness in the gut.”

The human body’s largest population of microorganisms lives in the intestinal tract, numbering in the trillions. These communities of microbes, mainly various strains of bacteria and to a lesser extent fungi and protozoa, are collectively called the gut microbiome. Unique to each individual, the gut microbiome performs various functions, including helping to digest food, control glucose metabolism and nutrient storage, boost the immune system, and moderate inflammatory responses.

Some gut microbes are beneficial, and others can be harmful. If the bugs coexist in harmony – for instance, without a potentially disease-causing strain of bacteria overgrowing and monopolizing the food of useful bacteria – then the digestive tract functions normally, Dr. Yadav said. “A healthy gut microbiome is characterized by a diverse, balanced collection of microorganisms.”

Hariom Yadav, PhD, associate professor of neurosurgery and brain repair at USF Health, stands in front of the anerobic chamber used to grow bacteria under oxygen-free conditions that mimic the gut. He was recently recruited to direct the USF Center for Microbiome Research | Photo by Allison Long, USF Health Communications

Our diet plays the predominant role in determining gut health. Lifestyle factors like exercise, sleep, stress, or the use of antibiotics and other medications, can also alter the gut microbiome’s composition.

Using modern genetic sequencing to precisely characterize the genetic makeup of microbes, scientists like Dr. Yadav have begun to unlock how the gut microbiome works and its massive implications for health and disease.

What does a “leaky gut” mean?

A “leaky gut,” also known as increased intestinal permeability, happens when the mucosal barrier lining the intestines becomes structurally and functionally damaged. That impairs this natural barrier’s ability to prevent infection and maintain general health.

As people age, Dr. Yadav explained, the mucus barrier of the bowel walls thins and becomes more porous than usual, making it easier for harmful bacteria and other toxins to pass from the intestines into the blood and circulate to other organs, including the brain. The microbiome of older guts also has diminished capacity to remove undigested food particles and to clear dead epithelial cells shed from the gut lining to make way for new ones, which contributes to leakiness, he said.

Dr. Yadav and assistant professor Shalini Jain, PhD, (front right) with members of their  research team. | Photo by Allison Long

Alzheimer’s disease and other dementias are among the growing number of medical conditions linked to imbalance in the gut bacteria, known as gut dysbiosis.

A preclinical study by Dr. Yadav and colleagues, published in JCI Insight, showed that the gut microbiomes of older mice were associated with chronic inflammation stimulated by increased gut leakiness via disruption of the intestine’s mucus barrier. The same study indicated that a human-derived probiotic “cocktail” mixing strains of bacteria isolated from healthy infant guts could suppress gut leakiness and improve both the metabolic and physical functions in older mice.

Probiotics are usually live bacteria that, when consumed in appropriate amounts, interact beneficially with other bacteria present in the human gut. Another study by Dr. Yadav’s team, published in GeroScience, found that a probiotic does not need to be alive to confer health benefits. The researchers discovered that a probiotic strain of Lactobacillus paracasei D3.5, even in its heat-killed or inactive form, decreased leaky gut and inflammation and improved cognitive function in older mice. This technology is under commercial development with the Postbiotics Inc., a N.C. biotechnology company cofounded by Dr. Yadav.

Brandi Miller (right), a PhD student, with Dr. Yadav and Dr. Jain. | Photo by Allison Long

Emerging research defining how gut microbiome abnormalities lead to leaky gut and harmful inflammation holds great promise for treating a growing number of age-related diseases. But interactions between the gut microbiome, its human host, and the outside environment are very complex.

The science is in its early stages, Dr. Yadav emphasized. “We still need to prove whether the long-term inflammation triggered by a leaky gut (causally) contributes to Alzheimer disease, cognitive decline or other age-related conditions in people at high risk.”

The gut-brain connection

The human gut contains as many nerve cells as the brain, and in some ways serves as a “second brain,” Dr. Yadav said. That’s because the intestines and the brain can send neuronal signals back and forth directly through a circuit known as the gut-brain axis.

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This bidirectional gut-brain communication can affect processes like how hungry we feel, how much food we eat, how individual food tastes differ, and whether certain foods upset our stomach. Studies have also begun to unravel how the gut microbiome may affect executive brain function, including its influence on depression, anxiety and cognition.

Several gut bacteria make neurotransmitters, including serotonin and dopamine – two chemical messengers linked to mood and mental health. The “gut neurons” can shoot these neurotransmitters to the brain through the gut-brain axis and the mood-modifying chemicals can also be released into circulating blood, Dr. Yadav said.

Research in mice and humans indicates that the high-fat, low carbohydrate ketogenic diet is a powerful regulator of brain function, improves Alzheimer’s disease pathology, and alters the gut microbiome.

With that in mind, an earlier pilot study led by Dr. Yadav and colleagues reported that specific harmful fungi interacting with bacteria in the guts of older patients with mild cognitive impairment (which increases the Alzheimer’s disease risk) can be beneficially changed by eating a modified ketogenic diet. The research appeared last year in the Lancet journal EBioMedicine.

PCR-amplified DNA used to study microbiome-sensing mechanisms. | Photo by Allison Long

Supported by a National Institute on Aging grant, Dr. Yadav’s team is now working to distinguish the gut microbiomes of those who respond to a modified ketogenic diet, versus the microbiomes of non-responders. The researchers want to determine exactly how the gut microbiome promotes the metabolic action of the modified ketogenic diet to possibly reduce age-related cognitive decline and Alzheimer’s disease.

“Our goal is to identify alternatives that can either supplement this ketogenic diet or mimic the diet’s effect on the gut microbiome (in non-responders) to improve brain health,” Dr. Yadav said.

Dr. Yadav’s laboratory plans to launch a Microbiome in Aging Gut and Brain (MiAGB) clinical study led by assistant professor Shalini Jain, PhD. The investigators will collect clinical samples (stool, blood, cerebrospinal fluid) from people age 60 and older with no age-related cognitive decline as well as those diagnosed with mild cognitive impairment (MCI) and dementia. They will track alterations in the gut microbiomes of healthy older adults over time to see if certain biomarkers can accurately predict, early in the disease process, which individual are most likely to develop MCI or dementia.

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Baby poop: A source of beneficial probiotics?

With a project he calls “Foods for Mood,” Dr. Yadav aims to identify microbial therapies to create a more balanced, varied gut microbiome — both to help maintain overall health as we age and to prevent or delay Alzheimer’s disease and other forms of dementia.

The probiotic strains his laboratory tests and refines as potential biotherapeutics come from a readily available source: baby poop. “Babies are usually pretty healthy and clearly do not suffer from age-related diseases,” Dr. Yadav said.

Using fecal samples from the diapers of infants, his team follows a rigorous protocol to isolate, purify and validate the safety of those strains of microbes most promising for promoting gut health. These probiotics (health-promoting bacteria), prebiotics (primarily fiber substances that the beneficial bacteria eat) or synbiotics (combinations of prebiotics and probiotics) are being incorporated into prototype high-fiber or fermented foods like yogurts, milk, or butter. The laboratory-grown strains need to be tested in clinical trials and follow the regulatory path to be commercialized as food products before they appear on supermarket shelves.

The “Foods for Moods” project led  by Dr. Yadav includes incorporating probotics, prebiotics and synbiotics into high-fiber and fermented food products. | Photo by Allison Long

The bacterial strains in baby feces are particularly good at helping produce short-chain fatty acids (SCFAs), a byproduct of gut microbe digestion that reduces inflammation, Dr. Yadav said. People with diabetes, cancers and age-related illnesses often have fewer SCFAs, and accumulating evidence indicates that the neuropathology underlying Alzheimer’s disease may be partly regulated by SCFAs.

“We are interested in targeting the source of (harmful) inflammation, which we think is the leaky gut. If we can fix that early enough, perhaps we can reduce the risk of chronic inflammatory response-mediated diseases, which mainly develop later in life,” Dr. Yadav said. “A healthy gut absorbs the nutrients we need from foods and supplies them to the body to help prevent age-related diseases and conditions, or to improve their management.”

The synbiotic yogurt developed at USF Health combines strains of prebiotics and probiotics that have been isolated, purified and preclinically validated for safety and effectiveness in promoting gut health. | Photo by Allison Long

Advancing technologies for microbiome research

Dr. Yadav received a PhD in biochemistry from the National Dairy Research Institute, India, in 2006. He conducted postdoctoral training in cell biology and metabolic diseases at the NIH’s National Institute of Diabetes and Digestive and Kidney Disease in Bethesda, Maryland.

Dr. Yadav has published more than 130 peer-reviewed papers and serves on the editorial boards and as a reviewer for several high-impact journals. He speaks frequently to scientific audiences and the media about the role of the gut microbiome and its modulators in age-related disorders, the gut-brain axis, probiotics and other biotherapeutics.

As director of the university-wide Center for Microbiome Research based at USF Health, he organizes technologies to advance microbial studies, including human microbiome/probiotics biorepositories, tools to grow bacteria and perform fecal microbiome transplantation, machines to sequence the genomes of microbes, and bioinformatics pipelines to robustly analyze massive volumes of sequencing data.

The image on the computer monitor depicts the movement of food through mice intestines labeled with a fluorescent dye. | Photo by Allision Long

Something you might not know about Dr. Yadav

Dr. Yadav attributes his interest in gut microbiome research in part to his mother’s severe gastrointestinal reactions to the widely prescribed type 2 diabetes medication metformin. Years later, he discovered that metformin and other drugs interact with microbes in an individual’s gut to influence medication effectiveness and the patient’s drug tolerance.

While metformin does not work for every diabetes patient, Dr. Yadav’s team recently presented findings at the American Physiological Association (APS) Experimental Biology 2021 meeting showing that metformin inhibited the spread of Clostridioides difficile or C. diff — a potentially life-threatening infection commonly acquired during hospital stays.

Dr. Yadav describes himself as a “grower” who enjoys growing flowers, plants and vegetables in his family’s backyard, growing bacteria in the laboratory, and helping his students grow in their scientific proficiency. A vegetarian, he makes his own probiotic-fortified yogurt and smoothies.

The USF Health Byrd Alzheimer’s Center contributed to a new international study in Nature Medicine suggesting there is reason to reevaluate the concept of “typical” Alzheimer’s disease. The study examined the largest and most diverse population in the world to date using tau-positron emission tomography scans (tau-PET scans), an advanced neuroimaging technique.

Amanda Smith, MD, professor of psychiatry and behavioral neurosciences and clinical research director at the Byrd Alzheimer’s Center, USF Health Morsani College of Medicine, was among the Alzheimer’s Disease Neuroimaging Initiative (ADNI) coauthors for the Nature Medicine paper. As one of more than 60 ADNI sites across the U.S. and Canada, the Byrd Alzheimer’s Center shares PET and MRI images, cognitive tests, blood biomarkers and other research data used by scientists worldwide to improve the understanding of Alzheimer’s disease.

Amanda Smith, MD, is director of clinical research at the USF Health Byrd Alzheimer’s Center.

Alzheimer’s disease is characterized by toxic accumulation of the protein tau (as well as abnormal amyloid protein deposits), leading to the death of nerve cells in the brain.

The recent study, led by researchers from McGill University and Lund University, delineates four distinct patterns (subtypes) of tau pathology in Alzheimer’s disease — each distinguished by where in the brain toxic tau deposits originate and spread. The researchers showed that over time each pattern of tau accumulation correlates to different clusters of symptoms with different prognoses for the affected individuals.

For the past 30 years, many researchers have described the development of tau pathology in Alzheimer’s using a single model, despite recurring cases that do not fit that model.

The current findings help explain why different patients may develop different symptoms, Dr. Smith said.

“In the clinic where we assess hundreds of patients with Alzheimer’s disease, we know that not everyone presents with the same symptoms. Many people present with typical short-term memory loss. Some can remember but exhibit very prominent language problems. Others may have visual difficulties that cause them to not see, or to misinterpret, what is front of them,” she said. “Although advanced Alzheimer’s tends to look the same, individuals don’t necessarily fit neatly into one category (of symptoms) earlier in the disease process.”

The recent tau-PET scan findings have implications for how disease progression is staged, and ultimately helping with the discovery of individualized treatments.

Byrd neuroscientists are working to develop both anti-amyloid and anti-tau antibodies – drugs to stop or delay Alzheimer’s disease, which yet has no disease-modifying therapies. In addition to more precisely detecting the early presence of disease and monitoring its progression, the latest neuroimaging techniques help researchers see whether their investigational drugs can remove the damaging Alzheimer’s-associated proteins from the brain.

PET scans of the brains of Alzheimer’s patients, showing patterns of both amyloid and tau. CREDIT: Dean Wong, MD, PhD, Ayon Nandi, MS, and Hiroto Kuwabara, MD, PhD | Johns Hopkins Medicine

“The increasing degree of specificity provided by neuroimaging studies may advance our ability to accurately target treatments for individuals with abnormal tau in the brain – and that’s not just limited to Alzheimer’s disease,” Dr. Smith said. “While amyloid is unique to Alzheimer’s, toxic tau is found in other cognitive disorders, including certain frontotemporal dementias and chronic traumatic encephalopathy.” (CTE is brain degeneration linked to repeated head trauma, including concussions in athletes.)

Dr. Smith leads clinical trials at the USF Health Byrd Alzheimer’s Center that involve brain imaging of a wide range of older adults – from study participants with no symptoms (presymtomatic) or very minor memory difficulties, to those diagnosed with mild cognitive impairment or various stages of Alzheimer’s dementia.

Current trials include Alzheimer’s Disease Initiative 3, the AHEAD Study, and the Trial-Ready Cohort for the Prevention of Alzheimer’s Dementia (TRC-PAD).  For information on these and other clinical studies, please visit health.usf.edu/medicine/byrd/clinical-trials, or call 813-974-4904.

TAMPA, Fla. (April 6, 2021) — The National Institutes of Health (NIH) has awarded the University of South Florida (USF) total expected funds of $44.4 million over the next five years to study whether computerized brain training exercises can reduce the risk of mild cognitive impairment (MCI), and dementias like Alzheimer’s disease, in older adults.

The grant from the NIH’s National Institute on Aging, supported under Award Number R01AG070349, expands USF’s Preventing Alzheimer’s with Cognitive Training (PACT) study. PACT will be the largest primary prevention trial to date designed to rigorously test the effectiveness of computer-based training to protect against MCI and dementias. Dementia such as Alzheimer’s disease leads to a loss in thinking, reasoning, memory, and everyday functional abilities.

“We are grateful for the willingness of the Tampa Bay community to support our efforts to prevent Alzheimer’s disease and dementia by participating in the PACT trial,” said USF site principal investigator Jerri Edwards, PhD, a professor of psychiatry and behavioral neurosciences at the USF Health Morsani College of Medicine. “Because of their willingness to join us in the fight against Alzheimer’s disease, we can now expand this trial across the U.S. with hope of ultimately reducing dementia incidence.”

No proven treatments yet exist to cure or stop the progression of Alzheimer’s disease, the most common form of dementia. Dementia prevention research like that done by Dr. Edwards and her team takes on increased urgency, because the few Alzheimer’s medications currently on the market primarily provide short-term management of symptoms for those who already have dementia. Alzheimer’s disease afflicts 5.8 million Americans, including one in every 10 people age 65 and older, according to the Alzheimer’s Association. Without effective interventions, the human and economic costs for those living with dementia, their caregivers, and the health care system will continue to rise as the population ages.

“If we can reduce the chances of progressing to Alzheimer’s disease and related dementias with a cognitive training regimen – an inexpensive and safe non-drug intervention – that would be a huge public health advance,” Dr. Edwards said. “Research suggests that delaying the onset of dementia by even one year would result in millions of fewer cases over the next 30 years.”

Jerri Edwards, PhD, professor of psychiatry and behavioral neurosciences at the USF Health Morsani College of Medicine, is  USF site principal investigator for the PACT study.

The multisite trial is expected to expand the study to enroll 7,600 healthy adults at various US locations who are ages 65 and older with no signs of cognitive impairment or dementia. People with mild cognitive impairment experience more memory problems than expected for those the same age. MCI can increase the risk for dementia. Within two years, Dr. Edwards said, about 15% of people with MCI progress to dementia with more serious cognitive decline that interferes with everyday tasks, such as preparing a meal, doing laundry, or driving.

Published research by Dr. Edwards and others indicates that targeted computerized training can help maintain mental and physical function. In the breakthrough Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, healthy older adults randomized to receive such training had a 29% lower risk of dementia after 10 years than the untreated control group. Those completing additional training benefited even more; they were 48% less likely to show signs of dementia 10 years later.

“As an academic medical center with a growing Neuroscience Institute and well-established Byrd Alzheimer’s Center, USF Health is at the forefront of the latest research attacking Alzheimer’s disease and related dementias on multiple fronts,” said Charles J. Lockwood, MD, senior vice president of USF Health and dean of the USF Health Morsani College of Medicine. “This pivotal study, based on compelling preliminary evidence, moves us one step closer to answering a critical question: Can computer-based cognitive training prevent dementia and help keep our brains healthy as we age?”

With the PACT study, Dr. Edwards’ team seeks more conclusive evidence about whether and how computerized training can protect against age-related cognitive impairment and dementia. The researchers will identify through comprehensive medical evaluation any study participants who develop MCI or dementia three years after enrollment in the PACT study. They will use brain scans to diagnose dementia such as Alzheimer’s disease and to see if those with amyloid protein in the brain (a hallmark protein of the neurodegenerative disease) benefit from the training.

Dr. Edwards emphasizes the need for more African-American and Hispanic/Latino study volunteers as the Alzheimer’s Association reports they are populations at highest risk for Alzheimer’s disease and other dementias.

USF Health expects to continue enrolling participants across the Tampa Bay region in the PACT study over the next three years. Study participants cannot have dementia or other neurological disorders, but a family history of Alzheimer’s disease does not disqualify an otherwise healthy person. Two initial supervised training sessions will be conducted onsite (with strict adherence to CDC guidelines for COVID-19), and study participants will complete the remaining brain training sessions independently at home over the next two years.

For more information, please visit the PACT study website at pactstudy.org or call (813) 974-6703.

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USF Health Research Day 2020 keynote speaker Allan Levey, MD, PhD, spoke about some of his work with national collaborators from various disciplines. He directs Emory University School of Medicine’s Goizueta Alzheimer’s Disease Research Center, one of 32 NIH-funded ADRCs in the U.S.

Alzheimer’s disease, affecting as many as one out of every two people over age 85, is an impending epidemic in the U.S., where the rate of people living into their 80s and beyond continues to rise.

Despite the failure of pharmaceutical trials to yield any treatments to halt or delay the devastating brain degeneration of this complex, chronic disease, Allan Levey, MD, PhD, this year’s Research Day keynote speaker, encouraged the audience of experienced and emerging USF Health scientists to remain optimistic.

“Now more than ever is the time to invest in research. We have powerful new tools and interdisciplinary approaches that are helping us discover more about the root causes of Alzheimer’s disease and related dementias,” said Dr. Levey, professor and chairman of neurology at Emory University School of Medicine and director of Emory’s Alzheimer’s Disease Research Center. “So, there is great reason for hope, but we need to wake up the country about the looming crisis.”

Dr. Levey, a practicing neurologist and widely respected neuroscientist, shared his perspectives on the race to cure Alzheimer’s disease as well some data from his own work at Emory and with national collaborators. He co-leads a National Institutes of Health-funded, multi-institutional Open Drug Discovery Center for Alzheimer’s Disease dedicated to advancing and diversifying the pipeline for innovative therapeutics. He also co-chairs an advisory council of the U.S. Department of Health and Human Services’ National Alzheimer’s Project Act Plan, which ambitiously lists as its top goal to “prevent and effectively treat Alzheimer’s disease and related dementia by 2025.”

Deanna Chan, Department of Molecular Pharmacology and Physiology, discusses her neuroscience research poster with Dr. Levey.

Dr. Levy commended the work of USF Health faculty and trainees at the Byrd Alzheimer’s Center, who are embracing new approaches to better understand the underlying causes of Alzheimer’s disease and related neurodegenerative disorders, and to translate those discoveries into urgently needed, effective treatments.

“If you have a foundation of outstanding clinical care like you have here, that becomes a basis for a number of (regional and national) collaborative research opportunities,” he said. “There are huge opportunities for you to make a difference.”

Some highlights from Dr. Levey’s presentation follow:

• Alzheimer’s disease and related disorders belong to a broad family of overlapping neurodegenerative diseases including Lewy body, vascular, and frontotemporal dementias. Studies of postmortem brains show that it’s “extraordinarily rare” for an individual with Alzheimer’s disease to have only the hallmark features of amyloid plaques and neurofibrillary tau tangles, Dr. Levey said. “Alzheimer’s is almost always accompanied by other co-existing pathologies.”  Some brain changes shared with Alzheimer’s include alpha-synuclein pathology (present in Lewy body dementia and Parkinson’s disease) and TDP-43 (also found in frontotemporal dementia and ALS).
• Underlying damage to the brain typically builds for 15-20 years before the first symptoms of cognitive decline, like problems with thinking and memory, appear. That presents a major challenge requiring low-cost, noninvasive biomarkers (substances that indicate the presence of disease) to better understand specifically how Alzheimer’s progresses and to help predict the disease’s onset early and what type of treatments are more likely to work. Dr. Levey works with a company developing a simple eye test to visualize accumulating amyloid protein deposits in the retina. And, currently under review is the first potential blood test to measure very low levels of amyloid in the circulation. “We need to intervene before the (brain) degeneration occurs,” he said. “I’m very confident that we’re going to have dramatic advances in detection and diagnosis capabilities over the next year or two, and that would be a game changer.”
• For nearly 20 years, clinical trials mostly focused on developing Alzheimer’s medications and vaccines to block or destroy amyloid plaque formation – without clear success. “What we’ve learned, slowly and painfully, is that we can remove amyloid from the brains of individuals with mild-to-moderate Alzheimer’s disease without changing the progression of dementia,” he said. Now, armed with new genomic and proteomic technologies, researchers are looking for additional molecular and cellular pathways (implicated in inflammation, membrane trafficking, synaptic trafficking, to name a few), which may identify new treatment targets, beside amyloid and tau.
• Some people with genetic risk factors never get Alzheimer’s disease. So, researchers have begun to amass and analyze large amounts of data on modifiable environmental/lifestyle factors — including diet, physical and mental exercise, and cardiovascular risk factors like cholesterol, high blood pressure, and diabetes. What they learn could help keep the brain healthy and stave off cognitive decline in high-risk individuals as they age. Identifying and treating even a third of the (modifiable) risk factors “could have a huge public health impact,” Dr. Levey said.
• Over 200 proteins have been nominated as potential new treatment targets through the NIH’s Accelerating Medicines Partnership-Alzheimer’s Disease. Levey leads one AMD-AD multi-institutional project focused on discovering and validating novel proteomic targets. The researchers apply the latest systems and network biology approaches to integrate proteomic data from donated postmortem human brains (healthy and at various stages of disease). They’ve identified groups of proteins associated with inflammation, and expressed at higher levels in people as cognitive impairment increases, which appear promising as targets for treating early-stage Alzheimer’s disease.

Dr. Levey with Stephen Liggett, MD, USF Health associate vice president for research and senior vice president for research at the Morsani College of Medicine

Dr. Levey also described a clinical trial he recently completed at Emory to test in patients with mild cognitive impairment the effects of atomoxetine, a selective norepinephrine transport inhibitor FDA approved to treat attention deficit disorder. The study results proved encouraging enough to begin designing a larger multiphase drug trial, he said.

-Photos by Freddie Coleman, USF Health Communications and Marketing

His team searches beyond the hallmark Alzheimer’s disease proteins for alternative treatments

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In his laboratory at the USF Health Byrd Alzheimer’s Center, neuroscientist David Kang, PhD, focuses on how different types of proteins damage the brain when they accumulate there. In the case of Alzheimer’s disease, decades of good science has zeroed in on amyloid and tau, as the two types of hallmark proteins driving the disease process that ultimately kills brain cells.

Dr. Kang and his team investigate molecular pathways leading to the formation large, sticky amyloid plaques between brain cells, and to the tau neurofibrillary tangles inside brain cells –including the interplay between the two proteins. But, he is quick to point out that amyloid and tau are “not the full story” in the quest to understand how normally aging brains go bad.

“Our goal is to understand as much of the entire Alzheimer’s disease process as possible and then target specific molecules that are either overactive or underactive, which is part of the drug discovery program we’re working on,” said Dr. Kang, professor of molecular medicine and director of basic research for the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Neuroscientist David Kang, PhD, (third from left)  stands with his team in his laboratory at the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Attacking dementia from different angles 

Dr. Kang’s group takes a multifaceted approach to studying the biological brain changes that impair thinking and memory in people with Alzheimer’s, the most common type of dementia, as well as Lewy body, vascular and frontotemporal dementias.

That includes examining how damaged mitochondria, the energy-producing power plants of the cell, contribute to pathology in all neurodegenerative diseases. “Sick mitochondria leak a lot of toxins that do widespread damage to neurons and other cells,” Dr. Kang said.

Dr. Kang’s team was the first to identify how mutations of a gene, called CHCHD10, which contributes to both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), cause both mitochondrial dysfunction and protein pathology called TDP-43. Their findings on the newly identified mitochondrial link to both neurodegenerative diseases were published in Nature Communications in 2017.

The role of selective degradation in ridding cells of abnormal proteins, old or damaged organelles (including mitochondria) and other debris is another key line of research pursued by Dr. Kang and colleagues.

A single stained nerve cell | Microscopic image courtesy of Kang lab

“We believe something more fundamental is going wrong in the brain during the aging process to tip the balance toward Alzheimer’s disease – beyond what we call proteinopathy” or deposits of malformed proteins like toxic amyloid and tau, said Dr. Kang, whose work is bolstered by nearly $8 million in grant funding from the National Institutes of Health (NIH), the Veterans Administration (VA merit awards) and the Florida Department of Health.

“I think one of the fundamental things happening is that the (cellular) plumbing system isn’t working to clear out all the accumulating junk,” he said. “That’s why we’re looking at the protective clearance mechanisms (autophagy and mitophagy) that would normally quickly remove misfolded proteins and dysfunctional mitochondria.”

Unfortunately, pharmaceutical trials to date have yielded no effective treatments for Alzheimer’s disease, the sixth leading cause of death in the U.S.  Most clinical studies have centered on developing medications to block or destroy the amyloid protein plaque formation, and a few have targeted the tau-containing neurofibrillary tangles. The five Alzheimer’s drugs currently available may provide temporary relief of symptoms, such as memory loss and confusion. But, they do not prevent or delay the mind-robbing disease as toxic proteins continue to build up and dismantle the brain’s communication network.

Lesson learned: The critical importance of intervening earlier

Some scientists argue that the “amyloid hypothesis” approach is not working. Dr. Kang is among those who maintain that amyloid plays a key role in initiating the disease process that leads to brain atrophy in Alzheimer’s – but that amyloid accumulation happens very early, as much as 10 to 20 years before people experience memory problems or other signs of dementia.

Early detection and treatment are key, Dr. Kang says, because as protein plaques and other lesions continue to accumulate in the brain, reversing the damage may not be possible.

“One reason we’ve been disappointed in the clinical trials is because so far they have primarily targeted patients who are already symptomatic,” Dr. Kang said. “Over the last decade we’ve learned that by the time someone is diagnosed with early Alzheimer’s disease, or even mild cognitive impairment, the brain has degenerated a lot. And once those nerve cells are gone they do not, for the most part, regenerate… The amyloid cascade has run its course.”

As protein plaques and other lesions continue to accumulate, becoming apparent with MRI imaging, reversing the damage may not be possible.  So, for anti-amyloid therapies – or even those targeting downstream tau – to work, patients at risk of Alzheimer’s need to be identified and treated very early, Dr. Kang said.

USF Health is recruiting healthy older adults with no signs of memory problems for a few prevention trials. A pair of Generation Program studies will test the effectiveness of investigational anti-Alzheimer’s drugs on those at high genetic risk for the disease before symptoms start. And, the NIH-sponsored Preventing Alzheimer’s with Cognitive Training (PACT) study is examining whether a specific type of computerized brain training can reduce the risk of mild cognitive impairment and dementias like Alzheimer’s disease in those age 65 and older.

To accelerate early intervention initiatives, more definitive tests are needed to pinpoint biomarkers that will predict Alzheimer’s disease development in genetically susceptible people. Dr. Kang is hopeful about the prospects.  His own team investigates how exosomes, in particular the lipid vesicles that shuttle proteins and other molecules from the brain into the circulating bloodstream, might be isolated and used to detect people at risk of proteinopathy.

“I think within the next five years, some type of diagnostic blood test will be available that can accurately identify people with early Alzheimer’s brain pathology, but not yet experiencing symptoms,” he said.

Graduate research assistant Yan Yan, a member of Dr. Kang’s research team, works at a cell culture hood.

Searching for alternative treatment targets

Meanwhile, Dr. Kang’s laboratory continues searching for other treatment targets in addition to amyloid and tau — including the enzyme SSH1, which regulates the internal infrastructure of nerve cells, called the actin cytoskeleton. SSHI, also known as slingshot, is needed for amyloid activation of cofilin, a protein identified by the USF Health neuroscientists in a recent study published in Communications Biology as a possible early culprit in the tauopathy process.

“Cofilin is overactive in the brains of Alzheimer’s patients so if we can inhibit cofilin by targeting slingshot, it may lead to a promising treatment,” Dr. Kang said.

Ultimately, as with other complex chronic diseases, Alzheimer’s may not be eliminated by a single silver-bullet cure.  Rather, Dr. Kang said, a combination of approaches will likely be needed to successfully combat the neurodegenerative disorder, which afflicts 5.8 million Americans.

“I think prevention through healthy living is definitely key, because brain aging is modifiable based on things like your diet as well as physical activity and brain exercises,” he said.  “Also, we need to focus on earlier diagnosis, before people become symptomatic, and develop next-generation drugs that can attack the disease on multiple fronts.”

Xingyu Zhao, PhD, a research associate in the Department of Molecular Medicine, is among the scientists in Dr. Kang’s laboratory studying the basic biology of the aging brain.

Fascinated by how the brain works — and malfunctions

Dr. Kang came to USF Health in 2012 after nearly 20 years as a brain researcher at the University of California San Diego, where he earned M.S. and PhD degrees in neurosciences and completed NIH National Research Service Award fellowships in the neuroplasticity of aging.

As an undergraduate Dr. Kang switched from studying engineering to a dual major in science/psychology. He began focusing on neurosciences in graduate school, he said, because tackling how the brain works and malfunctions was fascinating and always challenged him.

“With every small step forward, we learn something else about the basic biology of the aging brain,” said Dr. Kang, “It’s not just helpful in discovering what therapeutic approaches may work best against Alzheimer’s disease – we’re also learning more about other neurodegenerative conditions affecting the brain.”

In addition to leading day-to-day research operations at the Byrd Center and helping to recruit new Alzheimer’s investigators, Dr. Kang holds the Mary and Louis Fleming Endowed Chair in Alzheimer’s Research and serves as a research neurobiologist at the James A. Haley Veterans Haley Veterans’ Hospital.

He has authored more than 50 peer-reviewed journal articles on brain aging and Alzheimer’s disease research. A member of the NIH Clinical Neuroscience and Neurodegeneration Study Section since 2016, he has served on multiple national and international editorial boards, scientific panels and advisory boards.

Dr. Kang sits next to a computer monitor depicting stained microscopic images — a single neuron (far left) and the two hallmark pathological proteins for Alzheimer’s disease, tau tangles (center) and amyloid plaques (right).

Some things you may not know about Dr. Kang

• His parents were Presbyterian missionaries in Africa, so he spent nine years of his early life (third through 10^th grade) in Nigeria.
• Dr. Kang practices intermittent fasting, often forgoing breakfast and eating only within an 8-hour window. Animal studies indicate the practice may contribute to lifespan and brain health by improving cellular repair through the process of autophagy, he said. “Autophagy really kicks your cells’ plumbing system into gear to clear out all the waste.”

-Video and photos by Allison Long, USF Health Communications and Marketing

An antagonist that blocks a specific interaction between the protein apoE and amyloid precursor protein appears promising in a preclinical study led by USF Health

TAMPA, Fla. (June 12, 2019) — Apolipoproten E (apoeE) is a major genetic risk factor for the development of Alzheimer’s disease, yet the protein tends to be understudied as a potential druggable target for the mind-robbing neurodegenerative disease.

Study lead author Darrell Sawmiller, PhD (left), and senior author Jun Tan, PhD, MD

Now a research team led by the University of South Florida Health (USF Health) Morsani College of Medicine reports that a novel apoE antagonist blocks apoE interaction with N-terminal amyloid precursor protein (APP). Moreover, this peptide antagonist, known as 6KApoEp, was shown to reduce Alzheimer’s-associated beta amyloid (β-amyloid) accumulation and tau pathologies in the brain, as well as improving learning and memory in mice genetically engineered to mimic symptoms of Alzheimer’s disease.

Many failed anti-amyloid therapies for Alzheimer’s disease have been directed against various forms of the protein β-amyloid, which ultimately forms clumps of sticky plaques in the brain. The presence of these amyloid plaques is one of the major hallmarks of Alzheimer’s disease.

The USF Health research findings suggests that disrupting apoE physical interaction with N-terminal APP may be a new disease-modifying therapeutic strategy for this most common type of dementia.

The preclinical study was published online May 2 in Biological Psychiatry, a journal of Psychiatric Neuroscience and Therapeutics.

Microscopic image shows the merging of APP (red) and apoE (green) in brain cells.  This co-localization (yellow) suggests an age-associated increase in apoE-N-terminal APP interaction and higher production of the toxic amyloid-β (Aβ) protein characteristic of Alzheimer’s disease.

“For the first time, we have direct evidence that the N-terminal section of apoE itself acts as an essential molecule (ligand) to promote the binding of apoeE to the N-terminal region of APP outside the nerve cell,” said the study’s lead author Darrell Sawmiller, PhD, an assistant professor in the USF Health Department of Psychiatry & Behavioral Neurosciences. “This receptor-mediated mechanism plays a role in the development of Alzheimer’s disease. Overstimulation of APP by apoE may be an earlier, upstream event that signals other neurodegenerative processes contributing to the amyloid cascade.”

“Initially we wanted to better understand how apoE pathologically interacts with APP, which leads to the formation of β-amyloid plaques and neuronal loss,” said study senior author Jun Tan, PhD, MD, a professor in the USF Health Department of Psychiatry & Behavioral Neurosciences.  “Our work further discovered an apoE derivative that can modulate structural and functional neuropathology in Alzheimer’s disease mouse models.”

Microscopic image depicts the merging of APP and apoE in cell cultures (above).  Depleting the N-terminal region of apoE reduces APP and apoE physical interaction (below).

Alzheimer’s disease is a global epidemic, afflicting an estimated 50 million people worldwide and 5.8 million in the U.S, according to the Alzheimer’s Association.  With the aging of the Baby Boomer generation, the prevalence of the debilitating disease is expected to increase dramatically in the coming years.  Currently, no treatments exist to prevent, reverse or halt the progression of Alzheimer’s disease, and current medications may only relieve dementia symptoms for a short time.

Dr. Sawmiller, Ahsan Habib, PhD, and Lucy (Hauyan) Hou, MD, of the USF Health Department of Psychiatry and Behavioral Neurosciences (all lead authors) collaborated with colleagues from the Laboratory of Neurosciences at the National Institute on Aging (NIA), the Department of Neuroscience at Johns Hopkins University School of Medicine, the USF Center for Neurosurgery and Brain Repair, and Saitama Medical University in Japan.  Other study authors included Takashi Mori, PhD; Anran Fan, PhD; Jun Tian, BS; Brian Giunta, MD, PhD; Paul R. Sanberg, PhD; and Mark P. Mattson, PhD.

The research was supported by an NIA grant from the National Institutes of Health.

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-Photos by Torie M. Doll, USF Health Communications and Marketing
-Microscopic images courtesy of Drs. Darrell Sawmiller and Jun Tan

USF Health’s Jerri Edwards, PhD, recently ranked #8 among National Institute of Health-funded principal investigators in Psychiatry by the 2018 Blue Ridge Institute for Medical Research Rankings, with funding of $4,602,776.

Dr. Edwards, a professor of psychiatry and behavioral neurosciences at the USF Health Morsani College of Medicine, was ranked among 1,170 principal investigators in Departments of Psychiatry nationwide.  She is nationally recognized for her research examining the effectiveness of computerized cognitive training in preventing or delaying Alzheimer’s disease and related dementias, as well as normal age-related cognitive decline. She also studies how music training may improve cognitive abilities — such as thinking, remembering and reasoning — in older adults who are non-musicians.

Jerri Edwards, PhD

Dr. Edwards is the co-principal investigator for a new $2.7 million randomized controlled clinical trial known as Preventing Alzheimer’s with Cognitive Training, or the PACT study, which is funded by the NIH’s National Institute on Aging.  USF is conducting this first-of-its kind, large primary prevention trial with Michigan State University (David Morgan, PhD, co-principal investigator).  The researchers are examining whether a specific regimen of computer brain exercises can significantly reduce the risk of cognitive decline, or dementias like Alzheimer’s disease, in a healthy, diverse population of adults age 65 or older.

The PACT study builds upon previously published research by Dr. Edwards and others indicating that computerized brain training targeting specific cognitive functions and challenging older adults to adapt their performance over time can help maintain mental and physical function. In the case of the 2017 Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, such training even reduced the risk of dementia. Conclusive evidence about whether and how brain training can protect against Alzheimer’s-related cognitive impairment is still needed.

Prevention research takes on increased urgency in the wake of recent failures of investigational Alzheimer’s drugs from major pharmaceutical companies to halt brain degeneration.

For more information on the PACT study go to www.pactstudy.org or call the USF Cognitive Aging Lab at (813) 974-6703.