Alzheimer’s disease is often referred to as one of the final frontiers in drug discovery. It represents one of the most complex, elusive and high stakes areas in medical research. It is one of the most formidable challenges in neuroscience and drug development due to the complexity of the brain, the long pre-clinical phase of the disease and the difficulty in measuring outcomes.
The stakes are high
Alzheimer’s disease and other forms of dementia are unfortunately common; many readers will likely know someone affected by these conditions. Alzheimer’s disease is a progressive neurological disorder that unfolds gradually, impacting memory, cognitive functions and daily activities.
The preclinical stage involves brain changes occurring years before any symptoms emerge. This is followed by mild cognitive impairment, characterized by subtle memory issues while maintaining independence. In the early stage of mild dementia, noticeable memory lapses may occur, such as difficulty in word-finding or becoming disoriented. The middle stage, or moderate dementia, sees increased confusion, mood fluctuations, challenges with daily tasks and behavioural changes. The late stage, or severe dementia, results in individuals losing the ability to communicate, recognize loved ones or control movements, necessitating full-time care.
Beyond the significant emotional and personal toll, the economic cost of Alzheimer’s disease and other dementias is substantial. Annually, unpaid care, social care and healthcare costs amount to an estimated $1.3 trillion, with this figure projected to more than double by 2030.
The amyloid hypothesis
Until recent advancements, most treatments focused on managing the disease’s symptoms rather than addressing its root cause. The amyloid hypothesis proposes that Alzheim
er’s disease is caused by an accumulation of amyloid beta protein fragments in the brain. These fragments clump together, disrupting communication between brain cells and eventually causing cell death. This hypothesis has guided research since the early 1990s, following the pioneering work of Professor John Hardy and his team at University College London (UCL). They first identified genetic mutations associated with certain types of Alzheimer’s and then observed the build-up of amyloid beta plaques in patients. The key question is whether eliminating this build-up of amyloid will stop the disease’s progress?
Major breakthroughs?
There have been several advancements in anti-amyloid treatments, with new medications such as Eisai’s Lecanemab and Eli Lilly’s Donanemab demonstrating effectiveness in clearing amyloid from the brain and decelerating the progression of the disease by up to 35% in clinical trials. However, the real-world results have been less impressive. In the US, physicians have been reluctant to prescribe these medications, and many health systems globally have refused to cover the costs.
The recent decision by National Institute for Health and Care Excellence (NICE), one of the primary decision-making bodies for the NHS in the UK, not to cover the estimated $30,000 annual cost highlights the issues, concluding that these drugs offer only modest benefits and require significant resources to administer via intravenous infusion and the necessary scans for diagnosis and monitoring.
Does this disprove the amyloid hypothesis? A significant challenge is that by the time patients typically exhibit symptoms and become eligible for these treatments, the brain damage incurred during the long, multi-decade pre-clinical stage is irreversible. By focusing trials on symptomatic patients or those already at an advanced stage of the disease, the best achievable outcome is a deceleration of decline. However, if we can diagnose the disease earlier in its course, when patients are still cognitively normal, the outcomes could be substantially different.
A new hope
There are several imminent developments poised to significantly alter the landscape. Blood-based diagnostics developed by companies such as Sysmex are on the verge of receiving regulatory approval. These diagnostics can detect specific proteins in the blood many years before symptoms manifest, offering a simpler and more cost-effective alternative to brain scans and lumbar punctures.
The next generation of treatments, such as Eli Lilly’s Remternetug, currently in phase 3 trials, will be administered subcutaneously, like insulin pens.
Looking further ahead, primary prevention trials are exploring the administration of anti-amyloid drugs to individuals genetically at risk, up to 25 years before the expected onset of symptoms. Additionally, combination treatments that address both amyloid beta accumulation and associated Tau tangles are under investigation. These have the potential to transform Alzheimer’s disease into a manageable chronic condition, akin to the advancements in HIV treatments during the 1990s.
What about the cost?
The recent decision by NICE primarily focused on quantifiable costs to the NHS and observable benefits, but it did not consider the quality of life and financial implications for patients and their families. A more holistic analysis could potentially lead to different conclusions. The cost of housing a dementia patient in a care home with specialist nursing care exceeds $100,000 a year and is increasing. Additionally, the benefits of having patients and their caregivers remain in the workforce for longer are likely to be substantial.
Tackling Alzheimer’s disease is a significant challenge, but recent advancements in diagnostics and treatments offer hope. Early diagnosis and innovative therapies are paving the way for better management of the condition, potentially improving patients’ quality of life to a degree where the benefits will far exceed the costs. While obstacles remain, the progress made signifies a crucial step forward.
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