What happens in Alzheimer’s disease?
To understand the different ways that AD is being treated, it is first necessary to understand what goes on in a patient when they have AD. There are three main hallmarks that AD is characterized by, namely amyloid-beta plaques, chronic neuroinflammation and tau protein tangles [1]. While both amyloid-beta and tau are proteins present in a healthy brain as well, in a diseased setting they undergo misfolding and aggregation. Along with chronic inflammation, this then leads to the progressive damage of brain cells and eventually diagnosable dementia.
It is important to note that other forms of dementia exists. Dementia is an umbrella term for diseases causing cognitive decline, affecting around 55 million patients worldwide [2, 3]. Other types of dementia include vascular dementia, frontotemporal dementia or Lewy Body Dementia.
The exact cause of Alzheimer's disease (AD) is not fully understood. It's believed to be caused by a combination of genetic, lifestyle, and environmental factors. Some research even suggests that the poor oral health may be linked to Alzheimer's disease.
Why is Alzheimer's Disease so difficult to treat?
The first problem arises from the fact that it is incredibly difficult to diagnose AD before it is too late. Indeed, while the disease begins with the build-up of amyloid-beta plaques, they do not directly cause cognitive impairments and it takes up to 30 years for the first symptoms of AD to appear – meanwhile the brain can already be swamped by amyloid-beta [4]. The onset of symptoms rather correlates with the development of tau tangles, which only appear after a considerable delay [5]. In this case, this already signifies significant neurodegeneration and widespread damage to neuronal networks. A point at which damage has been already done and the processes have proven to be almost impossible to stop at this stage.
This not only means that it is difficult to identify patients in the prodromal stage to prevent the onset of dementia, but it also means that it is incredibly difficult to design clinical trials to develop and test drugs that could potentially treat the disease.
Medicines that alleviate Alzheimer's disease symptoms
Up until 2023 [6], the only available drugs that were approved for the treatment of AD only alleviated its symptoms, but were not able to prevent, treat or cure the disease. Nonetheless, they are still in widespread use as they can successfully improve a patient’s wellbeing at a certain point in time, even if they do not slow disease progression.
Acetylcholinesterase (AChE) inhibitors
Mechanism of action
Medicines such as donepezil (Aricept), galantamine and rivastigmine all belong to a group of drugs called acetylcholinesterase (AChE) inhibitors. They work by inhibiting the activity of the AChE enzyme, thus preventing the breakdown of acetylcholine [7]. Acetylcholine is a neurotransmitter that is crucial for the communication between cells in the brain. Importantly, AD-related neurodegeneration heavily affects cholinergic neurons. AChe inhibitors are hence thought to alleviate symptoms by increasing acetylcholine concentrations in the brain despite the substantial loss of cholinergic neurons [8].
Patient use
Patients with mild to moderate AD are eligible for AChe inhibitor use. Donepezil is prescribed as an oral medicine taken once a day [7].
Glutamate receptor antagonist
Another well-known symptomatic drug is Memantine (Ebixa, Nemdatine, Valios), a drug that works by blocking N-methyl-D-aspartate receptors (NMDARs), a type of glutamatergic receptor in the brain [9]. These receptors bind glutamate, an excitatory neurotransmitter, which like acetylcholine, is responsible for communication between neurons. Importantly, it has been shown that AD is associated with excessive activity of glutamate, which can cause neuronal death from excitotoxicity [10]. By blocking NMDARs, Memantine helps to prevent excessive glutamate activity which is thought to contribute to managing AD symptoms.
Patient use
Memantine is currently prescribed to patients with moderate to severe AD as an oral formulation taken once a day [9].
Medicines that treat AD
Lecanemab
Mechanism of action
Undergoing accelerated approval by the FDA in July 2023 [6], Lecanemab is the first treatment that has been shown to slow down AD progression. Even though Lecanemab slows the disease down only by 27%, this is still an incredible improvement [11]. Sold under the brand name Leqembi®, it is a monoclonal antibody developed against soluble and toxic amyloid-beta protofibrils. This means it targets and removes amyloid-beta that has not yet aggregated into plaques and rather prevents plaque development [12].
Ultimately, this prolongs the onset of tau tangles and associated cognitive decline.
Patient use
Lecanemab is prescribed to patients with mild AD and to patients that are not diagnosable with AD yet but exhibit mild cognitive impairments. It is administered intravenously every two weeks [12].
Future of AD treatment
The next line of medicines currently in Phase III clinical trials that are awaiting potential approval includes treatments such as Donanemab [13]. Similarly, this antibody also targets soluble amyloid-beta, and current results are pointing to a significant improvement in patients’ outcomes. However, this still leaves patients with severe or late AD without a treatment of cure, and it is up for future research to identify possible drugs that potentially target tau tangles and hence deal with later stages of the disease as well.