Alzheimer’s disease as a clinical entity first came to the attention of the public in 1976 with an editorial by Robert Katzman in Archives of Neurology,1 but disease awareness and meaningful research were slow to accumulate. This progressive, debilitating and eventually devastating illness is now much better characterised, but we are still a long way from a complete understanding of the underlying disease pathology, contributing factors and optimal treatment strategies. Importantly, awareness of Alzheimer’s disease and other causes of dementia is still limited across the world, directly inhibiting timely diagnosis, while also contributing to stigma that further delays people seeking medical attention.
Throughout World Alzheimer’s Month, the numerous societies dedicated to improving the care and treatment of patients with Alzheimer’s disease have been uniting around the need to highlight the effects of dementia and the importance of early recognition to improve outcomes. Alzheimer’s Research UK have continued asking people to ‘Share the Orange’ to highlight that Alzheimer’s disease and other causes of dementia are physical illnesses, rather than simply ‘a normal part of ageing’ – the weight of an orange being approximately equivalent to the weight of brain tissue that is lost during the course of dementia.
This loss has profound effects on people suffering with dementia. The deterioration of brain cells and connections between different areas of the brain gradually erodes their memory and cognitive ability, inhibits their ability to perform essential tasks, alters their personality, and eventually leads to death. The stories being shared by family members and carers on the Alzheimer’s Association website are extremely poignant, highlighting the deepening sense of loss experienced by relatives and friends as they observe this slow decline in their loved ones. One partner of an Alzheimer’s disease patient stated: “Over the next three to four years, Di’s memory steadily worsened. In reality, I probably lost my soul mate then,” while another highlighted the importance of talking about dementia: “If you hide it, you’ll keep suffering. But if you tell them, then some people will realise, understand and be helpful.”
These stories also demonstrate that there is an urgent need for better treatment options in Alzheimer’s disease. Until very recently, no disease-modifying therapy was available, with the last approval being for the cognition-enhancing therapy memantine in 2003.2 The need for effective therapies may be answered with the recent emergence of aducanumab, approved by the FDA in June 2021.3 Many have hailed this approval as a major landmark in the campaign to defeat Alzheimer’s disease, offering hope to millions of sufferers worldwide. Furthermore, it is hoped that this success will prove to be a catalyst for further, better-funded research, eventually leading to more treatment options.4
The decision to approve aducanumab was based on its demonstrated ability to target and cause destruction of amyloid plaques from brain areas suspected to be linked to Alzheimer’s disease.3,5 However, the approval was controversial for several reasons, principal among them being the use of an unvalidated surrogate endpoint for the approval rather than proven clinical benefit in terms of cognitive outcomes.6 Neurologists and other experts remain divided as to the likelihood of success for aducanumab,7 with some expressing concern around the potential for brain swelling caused by damage to the cerebral vasculature as a side effect of amyloid removal. Furthermore, the high price set by Biogen may delay its widespread adoption, with several payers deciding not to fund the therapy.
Amyloid plaques are one of the characteristic pathological features of Alzheimer’s disease, along with neurofibrillary tangles associated with tau protein, and are central to the ‘amyloid hypothesis’ of Alzheimer’s pathology. Aducanumab is the latest in a long line of therapies developed to address the presence of amyloid in the brain. However, it is the first to demonstrate sufficient benefit to be approved, with many other amyloid-targeting antibodies having failed at the Phase 3 hurdle.8 In fact, before the approval of aducanumab, the amyloid hypothesis was regarded by some as flawed, with experts advising that new targets should be sought.9,10 Meanwhile, manufacturers of other anti-amyloid antibodies pushed their therapies into trials in earlier stages of the disease to assess whether the high-profile trial failures were due to initiation of therapy after a threshold of amyloid build-up had been passed, rather than flaws with the mechanism itself. Two of these early trials have already reported data, which in the main were not positive,11,12 but with intriguing sub-analyses that suggest the potential for efficacy in certain circumstances.13 Several more are due to read out in 2022 and 2023 and will be watched eagerly.14
The amyloid hypothesis represents one of many pathophysiological targets that may potentially be exploited to achieve a therapeutic effect in Alzheimer’s disease. Following the initially disappointing results with anti-amyloid antibodies in the early-to-mid-2010s, researchers have renewed efforts to discover and take advantage of these additional targets. The most logical mechanism to target after amyloid is tau protein, which is associated with neurofibrillary tangles – the second key pathological feature of Alzheimer’s disease and one that has been shown to correlate more closely than amyloid with cognitive impairment.15 Many tau-targeting therapies are now in Phase 2 or Phase 3 trials. Very recently, one of these therapies, semorinemab, has shown a significant cognitive benefit in one of two Phase 2 trials.16 Interestingly, in a reverse of the situation with amyloid, the more positive data with semorinemab were observed in patients with later stages of Alzheimer’s disease. This is consistent with the observation that tau abnormalities and formation of neurofibrillary tangles often occur downstream of amyloid build up.17
The Alzheimer’s disease pipeline is now bursting with new and repurposed compounds exploiting additional approaches – indeed, tau and amyloid-targeting therapies are now the exception rather than the rule in Phase 1 trials.
Additional targets being explored for disease-modifying treatments include neuroinflammation, cerebral vasculature, glucose metabolism/insulin sensitivity, the neuroendocrine system and synaptic plasticity. In addition, delivery of neuroprotective proteins via gene therapy19 and the application of stem cells for neuronal repair20 are also being investigated.
World Alzheimer’s Month offers the opportunity to reflect on the current status of Alzheimer’s disease globally. While it continues to be a devastating disease, recent developments offer plenty of hope, potentially providing a glimpse of an optimistic future for patients and their families. Until then, a renewed focus on increasing awareness of Alzheimer’s disease is crucial to improve care for patients.
- Katzman R. Editorial: The prevalence and malignancy of Alzheimer disease. A major killer. Archives of neurology 1976; 33(4): 217-8.
- FDA. NAMENDA (memantine HCl) tablets, for oral use. NAMENDA (memantine HCl) solution, for oral use. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021487s010s012s014,021627s008lbl.pdf.
- FDA. ADUHELM™ (aducanumab-avwa) injection, for intravenous use. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s003lbl.pdf.
- Mullard A. Landmark Alzheimer’s drug approval confounds research community. Nature 2021; 594(7863): 309-10.
- Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537(7618): 50-6.
- Mullard A. Controversial Alzheimer’s drug approval could affect other diseases. Nature 2021; 595(7866): 162-3.
- Rabinovici GD. Controversy and Progress in Alzheimer’s Disease – FDA Approval of Aducanumab. The New England journal of medicine 2021; 385(9): 771-4.
- Ceyzériat K, Zilli T, Millet P, Frisoni GB, Garibotto V, Tournier BB. Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer’s Disease. Current Alzheimer research 2020; 17(2): 112-25.
- Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimerdisease. Nature reviews Neurology 2019; 15(2): 73-88.
- Morris GP, Clark IA, Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta neuropathologica communications 2014; 2: 135.
- AlzForum. Topline result for first DIAN-TU clinical trial: negative on primary. 2020. https://www.alzforum.org/news/research-news/topline-result-first-dian-tu-clinical-trial-negative-primary.
- Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. The New England journal of medicine 2021; 384(18): 1691-704.
- AlzForum. Confused about the DIAN-TU trial data? Experts discuss. 2020. https://www.alzforum.org/news/conference-coverage/confused-about-dian-tu-trial-data-experts-discuss.
- Armstrong M, Fagg J, Evaluate Pharma. Anti-amyloid approaches come back from the dead. 2020. https://www.evaluate.com/vantage/articles/analysis/spotlight/anti-amyloid-approaches-come-back-dead.
- Soeda Y, Takashima A. New Insights Into Drug Discovery Targeting Tau Protein. Frontiers in molecular neuroscience 2020; 13: 590896.
- AlzForum. First cognitive signal that tau immunotherapy works? 2021. https://www.alzforum.org/news/research-news/first-cognitive-signal-tau-immunotherapy-works.
- Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology 2014; 71(4): 505-8.
- Cummings J, Lee G, Zhong K, Fonseca J, Taghva K. Alzheimer’s disease drug development pipeline: 2021. Alzheimer’s & dementia (New York, N Y) 2021; 7(1): e12179.
- Forbes. Clinical trial begins for gene therapy to treat Alzheimer’s disease. 2021. https://www.forbes.com/sites/carolineseydel/2021/03/12/clinical-trial-begins-for-gene-therapy-to-treat-alzheimers-disease/?sh=2ded25ca7171.
- Han F, Bi J, Qiao L, Arancio O. Stem Cell Therapy for Alzheimer’s Disease. Advances in experimental medicine and biology 2020; 1266: 39-55.