Introduction

Overview of Alzheimer's aisease

Alzheimer's disease (AD), which causes between 60% and 80% of dementia cases, is a neurodegenerative disorder typically affecting people aged 65 and over, although it may occur sooner in life. When the symptoms of Alzheimer's show in those under 65, this is known as early-onset Alzheimer's (EOAD). In the UK, EOAD has been found to occur in people as young as 30 years old.

Overview of amyloid-beta

For decades, the amyloid-beta protein - and its abnormal accumulation in the brain - has captivated neuroscientists studying Alzheimer’s disease. A notorious molecule in the field, amyloid-beta suffers from a biochemical phenomenon known as protein misfolding, rendering it chemically “sticky.” With this stickiness, molecules of AB clump together over time to form stubborn deposits known as amyloid-beta plaques between brain cells. Eventually the connection between brain cells is lost, culminating in cell dysfunction and death.

AB plaques are a pathological hallmark of Alzheimer’s disease and a critical component of modern AD drug discovery.

Current non-anti-amyloid treatments for Alzheimer's disease

Currently, there are six available treatments for AD. The principal class of drugs used for the treatment of AD are cholinesterase inhibitors, which primarily function by blocking the enzyme acetylcholinesterase.

Acetylcholinesterase inhibitors

Acetylcholinesterase is an enzyme located on the edge of the post-synaptic cleft, the receptive end of the junction between a nerve and muscle cell. From there, it receives and subsequently breaks down the neurotransmitter acetylcholine, which passes through the junction via a series of biochemical reactions. Acetylcholine works as a chemical messenger. Of note, acetylcholine plays a crucial role in memory and cognition.¹ 

In people with AD, the levels of acetylcholine are exceptionally lower than those without. Decreased acetylcholine levels are associated with decreased behavioral, cognitive, and day-to-day function. Therefore, as the most common available treatment of AD, acetylcholinesterase inhibitors – which maintain stable levels of the neurotransmitter by inhibiting its structural degradation by acetylcholinesterase – are related to targeting the symptoms of the disease.^2,3

There are currently three FDA-approved acetylcholinesterase inhibitors, all of which are typically used to treat mild to moderate AD. From first to last approved, they are:

1. Donepezil (as Aricept in 1996)
2. Rivastigmine (1997)
3. Galantamine (2001)

NMDA receptor agonists

Currently only one other drug is FDA approved for the treatment of Alzheimer’s disease. Memantine, which is administered specifically in the moderate to severe stage, does not inhibit acetylcholinesterase or in fact inhibit any enzyme at all. Instead it binds to glutamate receptor N-methyl-D-aspartate (NMDA), a protein found throughout the brain particularly related to memory, causing a slowing effect on abnormal brain activity and toxicity.

In Alzheimer’s disease, high glutamate levels are indicative of neuronal loss caused by the damage to the brain cells. When there is an excessive level of glutamate, this can lead to the toxic overstimulation of the glutamate receptor, culminating in cell death. Therefore as a drug, memantine works to reduce the rate of toxicity. It also has an effect on slowing down memory loss.⁴

Newly-approved beta-amyloid targeting treatments

Of note and very recently, there have been huge leaps made in Alzheimer’s research regarding anti-amyloid treatments. Despite one prompt discontinuation, there have been two additional FDA approvals, all of which are described below.

Aducanumab

Aducanumab, an intravenous antibody treatment that removes amyloid-beta plaques from the brain, was approved for use in the US in June 2021. At the time of its approval, aducanumab was the only disease-modifying therapy of AD. Rather than providing symptom relief like acetylcholinesterase inhibitors, it targeted a fundamental physiological feature of the disease itself (the amyloid-beta plaques), slowing down the progression of AD. 

The approval was made through two time-saving approaches: “Fast Track” and “Accelerated Approval.” Typically, these are granted by the FDA when the proposed drug treats an unmet medical need of a serious illness. Despite the speed-related similarities between these approaches, they can be differentiated by the prerequisite for “accelerated approval” - a proven biological endpoint.

However, this decision to approve aducanumab was followed by a wealth of controversy, with critiques being raised regarding cost and poor clinical data results.

Following this, a perspective piece was written and published by one of the original decision makers, the then Director of the Division of Quantitative Pharmacology at the FDA, acknowledging the issues with the programme and reiterating the evidence used to support the approval.⁵ However, as of January 2024, aducanumab was ultimately discontinued in early 2024.

Lecanemeb

Before the discontinuation of aducanumab was announced, in July 2023, Lecanemeb became FDA approved as a treatment that did not just target symptom relief, but the pathology of the disease. 

This is known as a disease-modifying therapy, an exciting new approach to Alzheimer’s research. Lecanemeb is a monoclonal antibody. As a monoclonal antibody, it stimulates the immune system, forcing white blood cells to recognise and remove the amyloid. 

 The accelerated approval of Lecanemeb came alongside a satisfying set of results. According to clinical research carried out, it:

• Slowed the rate of cognitive decline by 27% 
• Slowed down the decline in quality of life by up to 56%
• Successfully reduced the levels of beta amyloid in early AD

Donanemab

Donanemab became FDA approved in July 2024. Like lecanemeb, donanemab is a monoclonal antibody, targeting a neurotoxic causative factor of Alzheimer’s disease: the plaques. 

In trials, donanemab performed excellently, calculated to slow down the progression of AD by more than 20%. Almost half of people taking the drug demonstrated 0 decline of disease severity at 1 year, and there was a 40% reduction in decline of completion of daily activities. 

Controversies and potential issues of current amyloid-beta treatments

One possible major concern with anti-amyloid treatments is side effects, in particular amyloid-related imaging abnormalities or ARIA. During their respective clinical trials, both donanemab and lecanemeb showed ARIA as a prominent adverse effect.

Additionally, whilst lecanemeb can be administered in the UK via prescription from a licensed physician, donanemab is yet to be available in the UK.

Summary

• Currently there are 6 FDA approved drugs for the treatment of Alzheimer’s disease
• Four of these are symptom-targeting drugs
• Two are disease-modifying therapies which target the pathological features of the disease to slow its progression
• They are called lecanemeb and donanemab and were approved in 2023 and 2024 respectively
• However, the first ever Alzheimer’s disease modifying therapy to be approved was called aducanumab
• Aducanumab was discontinued after a rushed approval with high associated costs was met with a great deal of controversy
• There may be some issues with the existing anti amyloid treatments, such as popularising them and adverse effects of anti amyloid treatments