As human life expectancy rises, so does the risk of developing Alzheimer’s, a chronic disease that increases exponentially after age 65. Before it was even conventional to do so, Penn researchers have been working to develop therapies to prevent and treat the disease, which causes memory loss and confusion, and has no cure.
“When Alzheimer’s disease was discovered in 1906 by Alois Alzheimer, it was a rare disorder that very few people had because very few people lived beyond age 65,” says John Trojanowski, director of Penn’s Institute on Aging and Alzheimer’s Disease Core Center. “With life expectancy extending to the late 70s and still rising, five and a half million people have Alzheimer’s just in the United States, and 30 million worldwide. The cost of Alzheimer’s care is now over $230 billion.”
It was back in 1985 when Trojanowski, with a background in pathology and neuropathology, and his wife Virginia Man-Yee Lee, who studied biochemistry and pharmacology, came up with the idea to combine their skillsets to study Alzheimer’s.
“We asked our mentors, who were senior like me now 30 years ago, ‘Is this something we should do?’” says Trojanowski. “They all said, ‘No. It’s a swamp, and you’ll ruin your careers because so little is known.’ What they saw as a swamp, we saw as a huge challenge and opportunity that has led to an engaging career.”
Over the years, Trojanowski and Lee, a professor of pathology and laboratory medicine at the Perelman School of Medicine, director of the Center for Neurodegenerative Disease Research, and co-director of the Marian S. Ware Alzheimer Drug Discovery Program, have made three major discoveries—all of which have become strong foundations for those working on Alzheimer’s disease and related disorders around the world.
Earlier findings determined that an Alzheimer’s patient’s brain progressively accumulates plaques, abnormal clusters of protein fragments called beta-amyloid, that build up between nerve cells, and tangles, which form inside dying cells.
In 1991, Lee and Trojanowski determined that tau is the building block protein of the neurofibrillary tangles.
In 1997, they found that Lewy bodies, the hallmark brain pathology of Parkinson’s disease, are formed by alpha-synuclein. Knowing what causes Lewy bodies is important to Alzheimer’s researchers because about 50 percent of Alzheimer’s patients have Lewy bodies that contribute to cognitive deficits.
In 2006, Lee and Trojanowski discovered the pathological protein deposits in amyotrophic lateral sclerosis, or ALS, and frontotemporal degeneration, or FTD, are formed by TDP-43, a multifunctional DNA- and RNA-binding protein, and these deposits are also present in a large number of Alzheimer’s patients’ brains. In addition, they contribute to cognitive deficits in affected individuals.
“Our goal has always been to understand the protein building blocks of Alzheimer’s and related disorders, develop models of the disease, and eventually come up with therapies targeting these abnormalities to stop or reverse these diseases,” says Lee. “That is a very lofty goal, but that is what we are working to do, and our most recent findings are that the pathological proteins in these disorders spread from cell-to-cell, which is likely the basis for the progression of these disorders.”
Because Alzheimer’s is a uniquely human disease, it is important researchers are able to study patient material, Lee says. That’s where Penn’s collaborative nature comes into play.
“For example, we work with people from the Departments of Neurology and Psychiatry at Penn Medicine, the Department of Chemistry in the School of Arts & Sciences, at Penn Vet, and at the Penn Memory Center, as well as [the Children’s Hospital of Philadelphia],” Lee says. “Particularly because of the proximity of the schools and centers, it really facilitates a lot of collaboration.”
“It takes a team to solve Alzheimer’s and related dementias,” Trojanowski adds. “You’re not going to do it in an individual laboratory.”
The Penn Memory Center, led by co-directors Jason Karlawish, a professor of medicine, medical ethics, and health policy and neurology, and David Wolk, an associate professor of neurology, acts as a resource for older adults seeking evaluation, diagnosis, and treatment involving progressive memory loss.
Faculty and staff at the Memory Center evaluate patients clinically, operating as the Clinical Core component of the Alzheimer’s Disease Core Center.
“Data from patients and controls, including cognitive, medical, neurological, and neuroimaging, and biofluids—blood, spinal fluid—is collected and ultimately included in a large database that encompasses the other neurodegenerative disease centers at Penn,” says Wolk, who specifically leads the Clinical Core. “These richly characterized patients facilitate research efforts across domains of inquiry, as, for example, one can match pathological or genetic data with clinical markers in these patients.”
Memory Center faculty have their own research programs, too. Wolk’s work, for instance, focuses on neuroimaging measures that differentiate normal aging from the earliest pathological changes of Alzheimer’s disease, as well as the cognitive neuroscience of memory in aging.
“Development of these tools is critical to understanding the biology of the clinical manifestations of the disease and as biomarkers for intervention studies at the earliest stages,” says Wolk.
Although working in different capacities, Wolk mirrors Lee and Trojanowski’s appreciation for collaboration at the University.
“The breadth and depth of related work in the neurodegenerative domain is outstanding,” Wolk says. “Particularly unique is our unified database with other neurodegenerative conditions, such as Parkinson’s disease and frontotemporal dementia. There are many overlaps in pathology and mechanisms in these diseases. The ability to study them at multiple levels—clinical, genetic, neuroimaging, molecular—is truly unique.”
