Looking for a Breakthrough in Alzheimer’s Disease
(April 6, 2023) — When the U.S. Food and Drug Administration (FDA) approved aducanumab for the treatment of Alzheimer’s disease in 2021, it had been nearly 20 years since the last medication had been approved to treat the neurodegenerative disease, which affects 6.7 million patients nationwide. Soon after, lecanemab received accelerated approval from the FDA in 2023.
After nearly two decades of clinical trials failing to deliver new treatments, Alzheimer’s disease researchers and clinicians, as well as patients and their families, have expressed cautious optimism regarding the new medications — and their implications for the future.
R. Scott Turner, MD, PhD, director of Georgetown’s Memory Disorders Program, described the approval of an effective disease-modifying treatment as “a historic moment and a true breakthrough.”
Since the discovery of Alzheimer’s disease in 1906, the condition has been characterized by two underlying pathologies visible (with a microscope) in patients’ brains. The main feature discussed by researchers studying Alzheimer’s disease is the presence of amyloid-beta plaques — clumps of protein outside of neurons. They have been shown to induce inflammation and disrupt synaptic transmission.
“Both aducanumab and lecanemab target amyloid-beta, and the working hypothesis is that the more amyloid removed from the brain, the better the clinical outcome,” Turner says.
The second pathology seen in the brains of Alzheimer’s patients are neurofibrillary or tau tangles, which are bundles of protein within a neuron. They are not as well-researched as amyloid-beta plaques, but are much better correlated with the degree of cognitive decline found in Alzheimer’s patients.
However, questions remain regarding the relationships between the development of amyloid-beta plaques, tau tangles and the onset of Alzheimer’s disease symptoms. Ultimately, the cause of Alzheimer’s disease is unclear, but the leading culprit is amyloid.
New Treatments Offer Hope
While previously approved medications for Alzheimer’s disease treat its symptoms, both aducanumab and lecanemab are the first drugs to treat the underlying causes of the disease, potentially slowing its progression.
Aducanumab (Aduhelm®) is the first FDA-approved treatment for Alzheimer’s disease that addresses one of the pathologies. Aducanumab is a monoclonal antibody, a laboratory-made protein engineered to bind to amyloid-beta and facilitate its clearance from the brain.
While research on aducanumab showed that it can bind to amyloid-beta and facilitate its clearance, it is not the breakthrough that researchers had been hoping for. Aducanumab showed conflicting effects in slowing the progression of cognitive decline, as well as potentially serious side effects, including swelling and bleeding in the brain.
“Its clinical effectiveness remains unclear,” Turner says. “Thus, Medicare decided not to reimburse the costs of Aduhelm treatment outside of a new clinical trial, which is now underway.”
Luckily, aducanumab was a prelude towards the next FDA-approved drug for Alzheimer’s: lecanemab.
Lecanemab (Leqembi™) is also an anti-amyloid-beta antibody with better clinical outcomes than its predecessor. During the 18 months of the trial, those who took lecanemab experienced a significantly slower rate of cognitive and functional decline compared to those who took the placebo. Medicare will rule on reimbursement of costs of lecanemab treatment in 2023 or early 2024.
Understanding the Impact of Amyloid Accumulation
There is a long-standing debate among researchers on the importance of amyloid-beta plaques on cognitive decline in individuals with Alzheimer’s disease. Genetic mutations that cause familial, early onset Alzheimer’s promote amyloid plaque formation.
However, individuals without cognitive impairments can have amyloid-beta accumulation in the brain. In fact, amyloid accumulates in the brain long before it causes memory problems. In a study looking at the role of amyloid-beta plaques and tau on cognitive function, completely removing tau rescues cognitive function while having no effect on the amyloid-beta plaques. This suggests that tau, rather than amyloid-beta plaques, drives cognitive decline. Some investigators suggest that “amyloid fills the car’s tank, but tau floors the pedal.”
The success of lecanemab suggests that clearance of amyloid-beta slows the rate of cognitive decline seen in Alzheimer’s. However, tau levels in the brain also decreased with the treatment. “We think that amyloid [accumulation] drives the tau/tangles and over time, the tangles drive progressive cognitive and functional decline (dementia),” Turner says. “This is the overall working hypothesis, which is supported by these lecanemab results”.
Another potential treatment strategy studied at Georgetown is a drug that induces autophagy, which is a process that breaks down abnormal proteins and removes them from the cell. “Promoting autophagy gets rid of all of neuronal aggregates, whether it’s amyloid, tau, [or other pathological aggregates],” Turner describes. This study showed promising results, but more research is needed to test safety and efficacy in Alzheimer’s patients.
Turning from Treatment to Prevention
Currently, a clinical trial underway at Georgetown is examining lecanemab as a preventive measure. “We’re finding people who are cognitively normal, but have amyloid in the brain and then treating them with lecanemab to remove amyloid,” Turner says. “If the trials work and we can prevent Alzheimer’s, that may be more effective than treating after the disease begins.”
Turner says lecanemab promises to be only the beginning of anti-amyloid treatments for Alzheimer’s as there are other anti-amyloid antibodies in clinical trials. He says there may be even more effective antibodies and other drugs in the research pipeline that will clear amyloid in the brain.
Ultimately, Turner is inspired by a possibility of eradicating Alzheimer’s altogether through active immunization – the Alzheimer’s vaccine.
“Could we inject people with amyloid that would trigger their body to make their own antibodies?” Turner says. “I think eventually we could move more to the active strategy and give everyone an Alzheimer’s vaccine when they turn 50 or 55 — before they have a lot of amyloid accumulation in the brain — to prevent Alzheimer’s.”
But for now, Turner feels a renewed spirit about the future. “Lecanemab is the first effective disease-modifying treatment — our foot in the door,” he says.
Lara Stefansson is a PhD student in neuroscience and a trainee in Georgetown’s Pharmacological Sciences Training Program.