Alzheimer’s disease is a relentlessly progressive degenerative brain condition characterised predominantly by the failure of short-term memory, followed by difficulty with problem-solving, visuospatial orientation, language and other cognitive skills, all of which interfere with a person’s ability to perform day-to-day activities. This is often accompanied by changes in mood and behaviour.
Alzheimer’s disease is the most common form of dementia in the elderly, affecting approximately 50 million people worldwide. The main pathological hallmark of Alzheimer’s disease is the accumulation of extracellular aggregates of a protein called amyloid (amyloid plaques) and intracellular aggregates called neurofibrillary tangles inside the brain.
For any disease, there are two types of treatment: one is to treat the symptoms which is like treating the effect of the disease and the other is to treat the disease itself which is called disease-modifying therapy (DMT). While symptomatic therapies improve symptoms and quality of life, they are ineffective in preventing the progression of the disease. They are typically effective in the early stages of the disease. In contrast, disease-modifying therapies are capable of slowing or halting the progression of the disease and are the most sought-after treatment for chronic disabling diseases like Alzheimer’s.
Symptom-relieving medications such as Donepezil, Memantine, Galantamine and Rivastigmine have been the mainstay of treatment of Alzheimer’s for the last several decades. Disease-modifying therapies that target amyloid plaques and prevent their accumulation in the brain have been the focus of extensive research for the last few decades.
Two types of disease-modifying therapies have been explored: active immunisation and passive immunisation. In passive immunisation techniques, highly specific antibodies that target beta-amyloid called monoclonal antibodies are synthesised in the laboratory. When administered, these monoclonal antibodies bind to amyloid and result in disintegration of the plaques and potentially prevent further accumulation in the brain. Active immunisation is like vaccines, which stimulate the formation of antibodies by the body’s immune system following exposure to the administered antigen. These antibodies synthesised within the body could destroy the amyloid plaques.
While both approaches have been actively pursued, it’s the field of monoclonal antibodies that have produced the most promising results. There are numerous monoclonal antibodies under trials, each targeting a specific aspect of pathways of amyloid formation. The first disease-modifying therapy approved by the US FDA for early Alzheimer’s disease was Aducanumab in June 2021. It is a second-generation anti-amyloid beta monoclonal antibody administered every four weeks as a slow intravenous infusion in a hospital setting. The most common and worrisome adverse effect is Aria (amyloid-related imaging abnormalities) in the form of brain swelling, micro-
bleeds and superficial siderosis, which can be minimised by monitoring the patients on a regular basis.
The approval of this therapy was mired in controversy because of claims of inadequate benefit, inadequate peer review and accelerated approval. Other second-generation monoclonal antibodies like Lecanemab and Donanemab have produced even better results in trials, with Lecanemab already having obtained FDA approval and Donanemab expected to obtain approval later this year.
The emergence of these therapies is a path-breaking moment in the treatment of Alzheimer’s disease as for the first time ever, doctors and patients have access to means to slow down the disease.
However, these treatments are currently approved only for use in the early stages of the disease. This requires very early diagnosis using advanced techniques like an amyloid PET scan of the brain which is currently unavailable in India, or highly specific CSF-based amyloid and tau assays that are currently available only in a few centres like Manipal Hospital. Early diagnosis of a disease whose symptoms are frequently overlooked as normal aging-related changes and in a society with very little awareness is going to be a perennial challenge. Another huge obstacle is the prohibitive cost of these medicines that puts them out of the reach of a majority of Alzheimer’s patients.
There is, however, hope and promise that eventually, these therapies and the necessary investigations will become mainstream and will be accessible to the growing numbers of Alzheimer’s disease patients across the world. And a defining chapter in the treatment of a disabling degenerative disease will truly be underway.
The writer is a neurologist with a private hospital