Image Courtesy of Sophia Zhao.
Alzheimer’s disease (AD) is a progressive and devastating disease that affects more than six million Americans. This neurodegenerative disease is characterized by the deterioration of memory, cognition, and behavior to a greater extent than the memory loss typically associated with aging. AD involves the buildup of abnormal protein in the brain, forming beta-amyloid plaques and tau tangles. These protein aggregates are believed to cause the malfunctioning of neurons and the loss of neural connections that ultimately result in AD.
In Alzheimer’s, the first areas of the brain to be affected are usually the hippocampus and the entorhinal cortex, both of which are crucial to memory formation. Over time, neuronal death can affect additional parts of the brain, causing brain tissue to shrink. Symptoms of the disease at different stages can vary, ranging from difficulty handling money to not recognizing loved ones or even forgetting how to eat, eventually progressing to total body shutdown. Given the immense toll of Alzheimer’s on both patients and their loved ones, research focused on treating AD has the potential to transform the lives of millions.
Scientists do not fully understand what exactly causes neurodegeneration and cognitive decline. Thus, it is unlikely that a single drug could successfully treat all patients living with Alzheimer’s. Based on current knowledge that the brain produces less acetylcholine—an important brain chemical for memory and thinking—as the disease progresses, several cholinesterase inhibitors have been approved by the US Food and Drug Administration (FDA) to help manage symptoms in patients. These drugs, such as galantamine, rivastigmine, and donepezil, prevent the breakdown of acetylcholine and temporarily improve a patient’s quality of life. These drugs were the only available treatments until recently, in 2021, when the FDA approved the first AD drug—aducanumab—that targeted the underlying cause of the disease.
With this development, scientists are now advancing the landscape of Alzheimer’s disease treatment with this new class of drugs that attack the disease at its source rather than just ameliorating symptoms. Recent clinical trials at Yale are studying monoclonal antibodies that target amyloid plaques.
Drug Contender #1: Aducanemab
Anita Huttner, director of the Yale Alzheimer’s Disease Neuropathology Core, obtained the first pathological evidence substantiating the impact of aducanumab to reduce amyloid plaque neuropathology in an AD patient. Aducanumab is a human antibody, or immunotherapy, that targets the protein beta-amyloid. Currently, aducanumab is sold under the brand name Aduhelm to treat patients with early-stage AD or mild cognitive impairment. The researchers hypothesized that healthy donors with no cognitive effects likely possessed immune systems that could successfully resist AD, so they used a process known as ‘reverse translational medicine’ to harvest antibodies from healthy donors and turn them into therapeutic antibodies.
In a recent study published in Acta Neuropathologica, Huttner analyzed an eighty-four-year-old woman with moderate dementia who received thirty-two monthly doses of aducanumab before passing away in hospice. The patient was included in a multicenter trial of aducanumab organized by Huttner’s colleague Christopher van Dyck at the Alzheimer’s Disease Research Unit at Yale, which enrolled patients with early-stage Alzheimer’s disease and tracked their disease progression over time with amyloid positron emission tomography (PET) scans and cognitive tests. To determine the effects of aducanumab, Huttner analyzed the data collected over the course of the patient’s time in the study and from their final autopsy.
Huttner’s autopsy of the patient who recently passed confirmed that aducanumab successfully reduced the size of amyloid plaques in the patient’s brain. “The results were very surprising,” Huttner said. “The effects were very significant. The antibody ate away at the fluffy periphery of the amyloid plaques, leaving a dense core behind.” This data corroborated the amyloid PET scans collected over the course of the patient’s treatment and provided substantial evidence supporting the therapeutic effects of aducanumab. As aducanumab has completed a phase three study in early AD patients, Huttner’s studies are a reason for optimism.
However, Huttner cautions that there is still much work to do. “Keep in mind that the ultimate goal is not just to remove plaques, but also to prevent cognitive decline,” she said. The autopsy results show that amyloid plaques were decreased in the recently deceased patient, but they do not reveal the mechanism of the antibody’s action or why amyloid plaques lead to cognitive decline. Still, Huttner is enthusiastic about this first stepping stone towards better understanding AD pathology and developing an effective treatment.
Drug Contender #2: Lecanemab
van Dyck, director and founder of Yale’s Alzheimer’s Disease Research Unit, has been researching the ability of another drug, lecanemab, to slow cognitive decline in patients with early-stage Alzheimer’s disease. Following the recent publication of the phase III clinical trial results in the New England Journal of Medicine, the FDA granted the treatment accelerated approval.
Lecanemab is an antibody that works by binding to amyloid beta protofibrils, which are small soluble protein strands that come together to form the larger insoluble protein fibers that form harmful beta-amyloid plaques. Lecanemab is thought to clear protofibrils from the brain, slowing the progression of Alzheimer’s disease. By reducing toxic forms of amyloid plaque buildup, lecanemab also decreases the number of abnormal tau tangles in the brain. “The difference between this and the originally approved drugs [for Alzheimer’s] back in the ʼ90s is that those were symptomatic therapies,” van Dyck said. “They were compensating for neurodegeneration rather than slowing it.”
In a trial consisting of 1,795 participants, van Dyck and other investigators found that lecanemab reduced amyloid plaque in the brains of patients with early-stage AD, as well as led to significantly less cognitive and functional decline than a placebo for the eighteen months that the treatment was taken.
When looking towards the future for lecanemab, van Dyck is excited to research the efficacy of lecanemab when given to participants with elevated brain amyloid who don’t yet have symptoms in the AHEAD Phase III clinical trial funded by the National Institutes of Health. “It’s all about going earlier,” van Dyck said. “Imagine how much time we might save somebody [with Alzheimer’s] with intervention before symptoms begin that then continues for several years of treatment. That’s very much the hope.”
van Dyck credits a mixture of personal and intellectual motivating factors for his involvement in Alzheimer’s research. “I remember going to my grandparents’ fiftieth wedding anniversary when I was in college. I hadn’t seen them for two or three years, and when I said, ‘Hey, grandad!’ he responded, ‘Who are you?’” van Dyck recalled. van Dyck has spent his career studying degenerative diseases like Alzheimer’s from a patient-oriented standpoint. “I trained initially in psychiatry and really gravitated towards older patients with these cognitive disorders that were like a puzzle to diagnose,” van Dyck said. “Right out of residency and fellowship, I founded Yale’s Alzheimer’s Research Unit. At that time, no other researchers were interested in Alzheimer’s disease, so we had to build it from the ground up.”
Fast forward to the present, van Dyck is now leading a massive research unit with studies ranging from neuroimaging investigations of AD to therapeutics trials, as has been the case with lecanemab. Pharmaceutical company Eisai is partnering with Biogen Inc. for the manufacture and sale of lecanemab as Leqembi™, a drug delivered via intravenous infusion once every two weeks.
Aducanumab and lecanemab are both antibodies targeting toxic aggregated forms of beta-amyloid proteins in the brains of patients with AD. Both exhibit promising results in their ability to reduce amyloid plaques in their clinical trials, but some patients in both drug trials have experienced side effects such as brain swelling and bleeding. Since amyloid protein is also deposited in vessel walls, its clearance by antibodies may compromise the blood-brain barrier, leading to temporary swelling. Sometimes, the swelling can cause small vessels to rupture leading to microhemorrhages in the brain. Larger hemorrhages are rare and unusual, and considering the fact that there are no existing treatments for patients with AD that actively target the disease itself rather than just managing symptoms, the benefit-to-risk ratio may be favorable.
van Dyck emphasized that—based on the success of these trials—both aducanumab and particularly lecanemab are currently being used as treatments for AD on a limited basis by patients paying out of pocket or those in patient assistance programs. “Most experts view lecanemab as the first unequivocally positive disease-modifying therapy for AD,” van Dyck said. He described lecanemab’s development as relatively smooth, contrasting it against that of aducanamab. “Its trials were fraught with complications and unfortunate circumstances,” van Dyck said. These issues included having to adjust dosages mid-study and having to prematurely halt the trials for presumed futility.
Although the last decade of AD research has largely focused on the amyloid beta protein, the disease is much more complicated than plaques accumulating in the brain—there are many types of dementia and causes of cognitive decline. “The amyloid story is just one aspect of understanding Alzheimer’s disease,” Huttner said. It remains uncertain whether focusing on amyloid beta plaques is the best trajectory due to the complexity of the disease. Regardless, we are at the point where we can start analyzing the effects of aducanumab and lecanemab. The information from these trials has the potential to inform a new class of drugs and a new way of understanding Alzheimer’s disease pathology.