In his teen years, Andrew Saykin spent his summers delivering sofas and dressers to customers of his family’s Massachusetts furniture store, but his mind was often on other matters—those deep within the human psyche.
“I got interested in psychology and read a lot of books about schizophrenia and other psychoses—strange, delusional thinking—I was interested in everything from personality theory to social systems,” said Saykin, PsyD, director of the Indiana Alzheimer’s Disease Research Center (IADRC) at Indiana University School of Medicine. “Early on, I was reading psychological theories and not thinking about the underlying organ that supports thought processes.”
That would come later.
Today, Saykin is a multidisciplinary expert in neuropsychology, neuroimaging and medical genetics. In addition to leading the IADRC, he is director of the Center for Neuroimaging and is the Raymond C. Beeler Professor of Radiology, as well as professor of psychiatry, neurology, and medical and molecular genetics at IU School of Medicine.
“Dr. Saykin has made many significant contributions to our understanding of Alzheimer’s disease,” said Tatiana Foroud, PhD, executive associate dean for research affairs. “He was one of the early founders of the area of imaging genetics–that is identifying the genetic factors contributing to the variation we see in brain imaging. This was important because the work of Dr. Saykin and others has shown that genetics plays an important role in the brain imaging changes we see in those with mild cognitive impairment and Alzheimer’s disease.”
More than 6 million Americans have Alzheimer’s or related dementias, and the number is growing fast. Known by his colleagues as a strong, collaborative leader, Saykin’s research is driven by one overarching goal—to develop new diagnostic and treatment approaches to eliminate the suffering of people living with Alzheimer’s and other brain diseases.
In 2006, Saykin founded the scholarly journal Brain Imaging and Behavior, and he has authored or co-authored over 550 publications. Nationally, he leads the Genetics Core of the National Institute on Aging Alzheimer’s Disease Neuroimaging Initiative (ADNI) and participates in multiple research consortia sponsored by the National Institutes of Health (NIH).
“Dr. Saykin is a highly collaborative leader and researcher and a very strong advocate for team science that involves members across a wide variety of disciplines,” said Bruce Lamb, PhD, executive director of the Stark Neurosciences Research Institute at IU School of Medicine. “He is a national and international leader in the Alzheimer’s disease research community.”
Since joining IU School of Medicine in 2006, Saykin has received $53.6 million in NIH funding for research spearheaded by IU and work done in collaboration with other institutions. Lamb calls him a “truly visionary leader in the field.”
“Andy has been a key partner in the incredible growth of the Alzheimer’s disease research programs we have seen over the past 7-8 years,” Lamb said. “I’m convinced that we wouldn’t have seen this level of growth without his strong and steady leadership.”
From psychology to brain sciences
Saykin grew up in western Massachusetts. A favorite aunt, who later developed Alzheimer’s disease, sparked his initial interest in medical science when she gave him a book on genetics.
As an undergrad student at the University of Massachusetts, Saykin started with dual interests in psychology and music. He worked his way through school by playing string bass and electric bass for weddings, jazz concerts and other gigs. He also volunteered at the state psychiatric facility, Northampton State Hospital, which has since closed.
“I started spending time there with people who were my age but were floridly psychotic and delusional—one thought they were Jesus Christ, another thought they were a famous rock star, those kinds of things—the severity is so compelling. You wonder, what is causing this?” Saykin said. “Not much was known. So, I started studying schizophrenia.”
Saykin continued his studies in clinical psychology at Hahnemann Medical College (now Drexel University College of Medicine) in Philadelphia. There, he and two other graduate students were given the opportunity to pilot a visionary three-year training program in neuropsychology within the medical school developed by Sandra Koffler, PhD.
“I took neuroanatomy and physiology courses with the medical students, which was challenging given my background focused in psychology,” Saykin said. Then we participated in the care of people in the hospital and neurologic clinics with a range of brain disorders. It was a fantastic learning experience.”
Brain imaging was an emerging field at the time, and Saykin recalls the excitement when Hahnemann purchased its first computed tomography (CT) scanner. Then Saykin read a paper on something even more advanced, the positron emission tomography (PET) scanner.
“It was very new at the time—there were only a few in the country,” he said. “A researcher in New York had shown that brain metabolism was reduced in the frontal lobes in a patient with schizophrenia. That, for me, was a transformative moment—you could actually see something in the brain that helps explain this extreme behavior.”
Saykin wanted to see this new technology for himself and was delighted to discover one existed just down the road, at the University of Pennsylvania. Soon he was working with Penn researchers Ruben and Raquel Gur, who were using novel imaging techniques to study brain changes in schizophrenia patients. After completing his doctorate in clinical psychology at Hahnemann with a neuropsychology specialization, Saykin joined the faculty at Penn, working on a variety of brain disorders including schizophrenia, Alzheimer’s disease, epilepsy and traumatic brain injury. A theme connecting all these conditions is their impact on memory and learning. His first grant from the NIH was to study the outcome of brain surgery for epilepsy, looking for ways to avoid complications affecting memory.
In 1992, Saykin took a faculty position with Dartmouth College just as the field of human genomics was taking off. He remembers the impact when Bernardino Ghetti, MD, IU distinguished professor and founder of the IADRC, discovered the first prion-related hereditary dementia in 1989.
“Today we get the sequence of all 3 billion base pairs in the human genome through one blood sample, but back then, only one marker at a time could be analyzed,” Saykin said. “Then a new technology came along where you could build a gene chip, so that was really transformative. The genetic and imaging tools have gotten better and better over the years, but the concept is the same—to relate cognition to structural, functional and molecular changes in the brain and to understand the role of genetic variation.”
Neuroimaging tools also rapidly progressed. Functional magnetic resonance imaging (fMRI) was developed soon after Saykin moved to Dartmouth.
“We began administering cognitive tests to patients with Alzheimer’s and other conditions while they were in the scanner enabling us to watch brain circuits activate during memory and other tasks,” he said. “This was another huge development in the field.”
Saykin has been recognized by the Radiological Society of North America with the New Horizons Lecture for his work in advanced neuroimaging.
Earlier detection of dementia
Today, one of the many advancements exciting Saykin is the possibility of detecting early signs of Alzheimer’s disease through a simple blood test. He is one of the principal investigators on a new $41 million collaborative study jointly led by Mayo Clinic in Florida and IU called CLEAR-AD that will connect more than 40 experts and 13 institutions across the nation seeking to better understand the biological pathways underlying Alzheimer’s disease so it can be identified earlier—and more easily—leading to personalized care plans.
“A lot of what I think about is precision medicine, and that’s the theme of our research center,” Saykin said. “How do we tailor treatment? Everyone is not the same, and Alzheimer’s disease might not be driven by the same underlying biology in every individual.”
Adding to IU’s efforts in this area, Saykin helped recruit Jeffrey Dage, PhD, from Eli Lilly and Co. Dage, a senior research professor of neurology and investigator with Stark Neurosciences Research Institute and the IADRC, is leading research for blood-based biomarker development.
“Imagine, in the near future, you could go to your primary care office, get a blood test done and see signatures in the blood chemistry that relate to what’s happening in the brain—to detect amyloid and tau and a range of other markers in the blood sample,” Saykin said.
Showing additional promise for personalized medicine, a global research team, including Saykin and Foroud, recently identified 75 genes which could indicate a risk for Alzheimer’s and related dementias; their findings were published in the scientific journal Nature Genetics.
“Dr. Saykin has played a significant role in recognizing the importance of studying the very earliest changes that may be preludes or precursors to the development of Alzheimer’s disease,” Foroud said. “His focus on mild cognitive impairment and subjective cognitive complaints is essential if we are to develop treatments that can stop the progression to Alzheimer’s disease as early as possible in the disease course.”
Saykin is principal investigator on two of IU School of Medicine’s largest NIH grants for 2022—$3 million for the IADRC’s ongoing mission to accelerate research toward prevention and effective treatment of Alzheimer’s, and $2.53 million for the Korean Brain Aging Study, a multidisciplinary, international collaborative project to collect multi-ethnic genomic data.
To develop precision medicine for Alzheimer’s disease and related dementias, studies need to include people of all races. According to the Alzheimer’s Association, older Black Americans are twice as likely to develop Alzheimer’s as their white peers, and Hispanics are 1½ times as likely to have Alzheimer’s.
“We’re focusing on bringing diversity to Alzheimer’s disease research, which is something that I consider extremely important,” Saykin said. “We are working with the African American community here in Indianapolis. The IADRC has a community advisory board of local pastors, health professionals, attorneys and other leaders who are helping guide us. We’re beginning to find ways to work with the Hispanic community as well and hope to develop bilingual capacity soon.”
‘Big picture’ collaborations to end Alzheimer’s
The IADRC and Center for Neuroimaging support several large consortium grants including ADNI, the Alzheimer’s disease neuroimaging study launched in 2004. IU is one of 60 sites nationwide following study participants longitudinally all the way through end of life.
“I am especially proud of ADNI’s open science leadership role in Alzheimer’s research. We make all the deidentified data available to the scientific community immediately with no embargo, which has been transformative,” Saykin said. “We put all the genomic data, imaging data, cognitive data, fluid biomarkers—all of it—in scientists’ hands, and it has led to over 5,000 publications.”
After more than 500 failed clinical trials for drugs to slow the progression of Alzheimer’s, two drugs have shown positive results; the first disease-modifying drug received full FDA approval earlier this month. Both are anti-amyloid drugs that help clear the plaques in the brain associated with Alzheimer’s disease. While not a cure, both have been shown to slow progression.
“It’s transformative for the field and has a lot of important implications,” Saykin said. “It’s wonderful news, but what we need to understand is what causes the plaques and the tangles in the first place. And that is still a mystery. Just like for many cancers, combination therapies tailored to the individual will likely be most effective in slowing progression and, ultimately, to prevent the disease.”
Artificial intelligence (AI) is helping accelerate the potential for a cure. A $17.8 million NIH grant for a project known as AI4AD will enable Saykin and four other primary investigators, along with 40 co-investigators at 11 research centers, to use AI to analyze cognitive, imaging and genomic data collected from more than 70,000 individuals with Alzheimer’s disease.
“Data science, network science and advanced bioinformatics will be really important for taking all of this information and finding what’s sometimes referred to as ‘20 needles in 20 haystacks’ to get the clues to understand the fundamental mechanisms driving this disease process,” Saykin said.
Shannon Risacher, PhD, associate professor of radiology and imaging sciences, calls Saykin “one of the most collaborative and supportive researchers that I have encountered.”
Saykin has been her primary mentor since her first days as a graduate student in 2007. She now co-leads the Neuroimaging Core of the IADRC with Saykin and Yu-Chien Wu, MD, PhD. “He is a great leader and inspires curiosity and excellence in his co-workers, collaborators, students and trainees,” Risacher said.
Lauren Hirschfeld, PhD, also began working with Saykin during her first year of graduate school and was impressed with the number of projects and possibilities his lab offered.
“Much like his ideas, Andy’s passion for Alzheimer’s disease research is boundless,” said Hirschfeld, a 2023 IU School of Medicine graduate who has learned from Saykin how to approach problems from multiple angles to make the greatest scientific impact. “He’s an excellent leader, especially when faced with the difficult task of connecting so many interdisciplinary fields under one common goal.”
Saykin keeps the big picture in mind while also focusing on the intricacies of each puzzle piece as he assembles a team of investigators with diverse areas of expertise.
“He is incredibly supportive of collaborative research and has built an open environment that promotes physicians and scientists from many different fields, all working together to improve diagnosis and treatment for Alzheimer’s disease and related dementias,” Risacher said. “His ability to see a bigger picture that lays out how seemingly unrelated things fit together is truly one-of-a-kind.”