For over three decades, Dennis Selkoe, MD, co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, has studied protein abnormalities that occur in Alzheimer’s disease (AD). In the mid-1980s, he and his colleagues at the Brigham were among the first scientists to discover that neurofibrillary tangles associated with AD were made of the tau protein. In the early 1990s, he was instrumental in developing the amyloid hypothesis, which links excess amyloid β (Aβ) in the brain to the initiation of AD, and his lab made several discoveries supporting the concept.
Recently, Dr. Selkoe’s amyloid hypothesis was put to the test in two widely discussed, breakthrough clinical trials that resulted in the June 2021 FDA approval of aducanumab, the first disease-modifying treatment for slowing the progression of AD. In the two trials, the monoclonal antibody was found to effectively bind to Aβ in the brain and clear it; other advanced trials of similar antibodies are underway and have also shown this. Dr. Selkoe discussed his support for aducanumab and other anti-amyloid immunotherapies in a perspective published in Science.
“The approval of aducanumab may provide a proof of concept that can be rapidly improved upon,” Dr. Selkoe wrote in Science. “It may also enable combination treatments, as is typical in chronic diseases.”
Correcting Faulty Genes
In Dr. Selkoe’s clinical practice, he treats patients with AD as well as some other neurological disorders like Parkinson’s disease. In his research work, he spends his time analyzing and trying to correct the faulty genes that cause AD. These include the parent gene of Aβ called amyloid precursor protein (APP) and presenilin, mutations in either of which cause early-onset, familial AD.
Dr. Selkoe’s lab discovered that APP makes Aβ throughout our lives and that presenilin is an enzyme that “cuts” APP to release the Aβ peptide — a discovery at the heart of the amyloid hypothesis. He noted that other AD genetic risk factors, such as the APOE4 protein, are also linked to enhanced Aβ deposition.
“APOE4 is critical for clearing amyloid out of the brain and is a far more common genetic cause than other identified genes linked to AD,” he said. “This is another piece of the puzzle that helps us understand how genes and the proteins they encode do their ‘dirty work’ to cause Alzheimer’s.”
Addressing the Aducanumab Controversy
The FDA approval of aducanumab has not been without controversy. In both trials sponsored by the drug’s manufacturer, Aβ was effectively cleared from the brain. However, one trial resulted in less decline of cognitive function, while the other did not. This led an FDA advisory panel to recommend against conventional approval until a third trial was conducted. However, the FDA chose to approve the drug on a special “accelerated approval” basis, a decision that Dr. Selkoe supports.
“Waiting several years for a third trial to be conducted leaves thousands or even millions of patients unable to access a therapy proven to change the biology of the disease,” he said.
Dr. Selkoe also addressed reported brain swelling and bleeding in patients who took part in the aducanumab clinical trial. He noted that those adverse effects have also been seen in the other Phase 3 antibody trials currently underway — all of which, he said, remove amyloid plaques and have clearer data on their efficacy in preventing cognitive decline.
“Those terms make headlines, but they are a bit misleading,” he said. “The ‘swelling’ is actually a focal transient edema that is asymptomatic in about 75 percent of the patients and usually goes away without treatment in four to 14 weeks. The ‘bleeding’ is the same type of micro-hemorrhage that is not uncommon in Alzheimer’s patients and is also largely asymptomatic. Clinicians treating patients with aducanumab should certainly be on the lookout for adverse symptoms and can pause treatment for a month or more if they occur.”
Pioneers in Alzheimer’s Disease
Dr. Selkoe praised the Brigham for supporting the complex research he and his colleagues have done to pioneer the prevention and treatment of previously untreatable AD.
“From our well-equipped labs to our huge cadre of scientists doing basic and translational research, the Brigham is one of the world’s leading centers for Alzheimer’s,” he said. “It’s a great environment in which to conduct groundbreaking research on complex diseases.”