Jericó, Antioquia, Colombia (Credit: Melissa Sanchez A.)
The Colombian region of Antioquia is a 12-hour drive from the border of Panama, but it is in some ways the center of the world of Alzheimer’s disease research.
Antioquia is “genetically isolated” and has a large population carrying a rare gene that increases their risk of developing Alzheimer’s disease. This makes its residents ideal human models for Alzheimer’s disease, but researchers must first weigh the legal, ethical, and social implications of working with this cohort.
Such was the focus of a presentation made by Penn Memory Center Co-Director Jason Karlawish at Columbia University March 27.
“Right now, to be diagnosed with Alzheimer’s disease, I have to say that you’re demented and that the cause of your dementia is Alzheimer’s,” Karlawish said. “Someday, you will not have to be demented to have Alzheimer’s disease. Instead some test or tests will identify you with the disease.”
Karlawish mapped out the path of research needed to achieve this. He explained how clinical trials like the Colombian Alzheimer Prevention Initiative (CAPI) are a key part of this research. The CAPI is testing a drug that targets amyloid, one of the pathologic hallmarks of AD.
The study’s key innovation is that its subjects are persons who have the uncommon gene that causes a person to develop Alzheimer’s disease some two decades earlier than the usual age of onset. This uncommon form of Alzheimer’s disease is called autosomal dominant Alzheimer’s disease.
“If the drug works, we will have discovered a way to slow the natural history of decline,” Karlawish said. “It will be proof of concept for a therapy for these patients but as well for the far larger population of patients at risk for Alzheimer’s later in life. With this kind of result, we need to begin to imagine a future when an amyloid test diagnoses Alzheimer’s disease and, in turn, a prescription for a drug that targets amyloid.”
As promising as this study is, the investigators faced a substantial ethical challenge. The Antioquia population has a high prevalence of ADAD but does not have genetic counselors.
“The standard is not to know,” Karlawish said. “This presents a dilemma. The custom is not to learn your gene result. How can you perform a clinical trial testing a drug in persons who have the gene?”
Dr. Jason Karlawish (Credit: Damari McBride)
In his talk, Karlawish explained the unique study design he and his colleagues developed to fit with current community standards while recognizing that the study is going to change those standards. A registry and associated study is recruiting both carriers and non-carriers of the gene, so volunteers could participate in the study without learning their genotype. The clinical trial, with targets amyloid in the brain, is currently active and will run until 2022.
Additionally, researchers provided healthcare to all participants, and implemented a social plan that will remain post-trial, providing education and care strategies and support.
Finally, Colombia is working with research to make the plan sustainable after 2022 by providing access to therapy and bringing genetic testing and counseling to the nation.
Even if the clinical trial is ineffective, researchers will have raised awareness. What Colombians call “Lo Bobera” — “the idiocy” — will become “Alzheimer Familiar.”
If the therapy is effective, “Lo Bobera” could become “pre-clinica Alzheimer Familiar,” in which a carrier of the ADAD gene mutation could receive an intervention before signs of dementia are present.
Karlawish’s talk was part of the 2017 Annual CEER Conference at Columbia University Medical Center. Other key speakers at the conference included Dr. Ira Shoulson, Director of the Program for Regulatory Science and Medicine at Georgetown University; Dr. Janet Williams, a genetics nurse specialist at the University of Iowa, and Dr. Claudia Chiriboga, a neurologist at Columbia University.