New FDA-Approved Drug Could Be the Much-Awaited Panacea for Alzheimer’s

Alzheimer's disease, the most common form of degenerative dementia, first affects the parts of the brain involved in learning and memory. As the disease progresses, neurons and their connections are lost, causing the brain to atrophy. Although people in the early stages of the disease have little trouble in performing everyday tasks, such as driving, working or household chores, these activities become increasingly difficult as more neurons die, and brain tissue is irreversibly lost. At the center of the pathology of the disease are two proteins of interest – beta-amyloid and tau. While beta-amyloid clumps up surrounding nerve cells forming plaques, tau proteins form neurofibrillary tangles and accumulate within neurons. In the pre-symptomatic stage of the disease, individuals show beta-amyloid plaques but do not have symptoms. However, when patients start showing signs of cognitive decline, the density of beta-amyloid plaques may reach its maximum and plateau. But at this stage tau begins to deposit in the brain., and the amount of tau tangles increases with disease severity. Recent evidence suggests that excessive beta-amyloid can trigger a series of pathological biochemical processes that eventually become independent of the amyloid that initially started the cascade. In summary, Alzheimer's is now postulated to have an amyloid-dependent phase, when the disease can be stopped by lowering amyloid, and an amyloid-independent phase, when lowering amyloid has no change in the progression of the disease. This second phase is characterized by tau tangles, nerve and nerve connection loss, among other disruptions of brain tissue. "Think of beta-amyloid as smoking and the tau protein as lung cancer. You can prevent lung cancer by avoiding smoking, but once you have lung cancer, avoiding smoking does not have much bearing on cancer,” said Masdeu. “Similar idea with beta-amyloid and tau, you cannot fix tau by changing beta-amyloid, but tau can be prevented by changing amyloid." Masdeu added that the failure of drugs like aducanumab, an anti-amyloid medication, in Phase III trials could have been because patients were given drug infusions during the amyloid-independent stage of the disease. Hence, in the Houston Methodist clinical trial, lecanemab, another anti-amyloid drug, is administered during the amyloid-dependent phase, when individuals are pre-symptomatic. Patients included in the study are women and men between 55-80 years old, who have had a positive plasma biomarker for elevated brain beta-amyloid and have elevated beta-amyloid in PET scans. They receive a lower dose of lecanemab every four weeks for the first four weeks and then a higher dose every four weeks up to 216 weeks. Although the clinical trial is still ongoing, the drug has been reported to slow cognitive decline compared to placebo even in patients in the early stages of Alzheimer’s disease. These promising results have prompted the Food and Drug Administration to grant accelerated approval for Alzheimer's treatment in early 2023. “The brain is like a very complex orchestra piece, where brain cells fire at the appropriate time because they are amazingly wired,” said Masdeu. “We want to intervene early to preserve neurons and their rich connections; we want to prevent Alzheimer’s.”