By Dr Francesca Properzi, PhD. Research Manager, Centre for Health Solutions

Since 2012, September has been celebrated as World Alzheimer’s Month, and this year’s theme is 'Let's talk about dementia'. This is clearly much needed, especially as one person is diagnosed with dementia every three seconds.¹ As a neuroscientist, I spent more than 10 years leading a research lab dedicated to finding new approaches for diagnosing and treating neurodegenerative diseases at the Italian Institute of Health in Rome. I also had first-hand experience of the disease, as I had originally accepted that position and left my job in London, to take care of my father, who was himself fighting dementia. Those years have shaped me greatly both personally and professionally and, as September coincides with my last month at the Deloitte Centre for Health Solutions, I am delighted to use this blog to provide my reflections on the challenges presented by Alzheimer’s disease and to consider what more needs to be done to expedite progress in identifying treatments and ultimately a cure.

The scale and impact of Alzheimer’s disease

Alzheimer's disease is the most common form of dementia with risk increasing with age. It causes irreversible degeneration of the brain leading to disruptions in memory, cognition, personality, and other functions and eventually death. From the age 65, the risk of Alzheimer's disease increases by an average of 23 per cent per year. The incidence among people age 85 and older is about 14 times that among people aged 65 to 69 years old.²

The World Health Organization (WHO) recognises dementia as a public health priority. Globally there are around ten million new cases of Alzheimer’s disease every year, and some 50 million people living with the disease. The global costs are more than one trillion US dollars, and are expected to reach two trillion US dollars by 2030.³ Although dementia costs more than cancer and heart disease combined, it receives a disproportionately low amount of research investment.⁴ Moreover, despite many years of intense research efforts, an effective treatment or indeed a cure has proved elusive.

Why is a cure or treatment so elusive?

Currently, despite decades of research there remains an incomplete understanding of the molecular and cellular dynamics that cause neurodegeneration. Alzheimer’s disease, along with some other forms of dementias, are characterised by two main traits:

• amyloid plaques: the accumulation of protein fragments called beta amyloid that form plaques between neurons in the brain. Beta amyloid is broken down and eliminated in a healthy brain, but in Alzheimer’s disease the fragments accumulate to form hard, insoluble plaques. Plaques are formed in a similar manner in other dementia diseases but can be made by different type of proteins.
• neurofibrillary tangles: twisted fibres inside neurons that mainly consist of a protein called tau, which forms part of structures called microtubules that transport nutrients and other molecules from one part of a neuron to another. In Alzheimer’s, tau is abnormal and microtubules collapse, affecting molecular transport.

Many recent and current drug development strategies focus on targeting either beta amyloid or tau, but with very limited results. As noted in our 2017 report The future awakens: Life sciences and health care predictions 2022, between 1998 and 2014, 123 potential medicines for Alzheimer’s were halted in clinical trials, and only four medicines were approved (in 1996, 2000, 2001 and 2003). In 2017, there were 87 potential drugs in development for Alzheimer’s in the US, including 16 in Phase III clinical trials. Since then a number of large pharma companies have halted their trials, while others continue their quest.⁵

It is likely that other molecular factors are the culprits causing neurodegeneration and that plaques and tangles are only two pieces of a much more complex puzzle. This means investigating alternative approaches is crucial.

Shifting the paradigm: new trends in diagnosis, therapy and drug delivery

There are some promising emerging lines of research focused on Alzheimer’s diagnosis, drug development and drug delivery:

• Protecting neurons and synapses at early stages - loss of synapses is an early feature in Alzheimer’s disease and is a cellular event that can trigger the death of brain cells. UK scientists have found that preventing loss of synapses and neuronal toxic responses at early stages can help the survival of brain cells and prolong life in mouse models of neurodegeneration.⁶ This innovative approach has a significant therapeutic potential, especially as it can be achieved by repurposing specific small molecules requiring shorter times for development and approvals.⁷
• Gene therapies - research published in September 2020 shows that when activating a gene called ‘p38gamma’ through a gene therapy approach restores much of the memory in Alzheimer’s animal models, blocking disease symptoms.⁸ In 2019, the UK Dementia Research Institute awarded £2 million to set up a hub of gene therapy research at King’s College London to tackle inherited forms of dementia.⁹
• Stem cells for therapy and disease modelling - stem cell therapies can also be used to repair neuronal loss in Alzheimer’s disease. It was recently shown that mice that had received neural stem cells showed an improvement in short and long-term memory and reduction in the number of amyloid plaques.¹⁰ In addition, human induced pluripotent stem cell (iPSC)-based models directly derived from patients have an outstanding potential in modelling diseases mechanism, as never achieved before. They can also be used for the screening of potential new drugs and identify unwanted side effects, crucially accelerating drug discovery.¹¹ In 2019, UK researchers utilised iPSC from patients with a genetic form of the Alzheimer’s disease and showed that common mutations have distinct effects on the processing of amyloid beta.¹²
• Exosomes for diagnosis and drug delivery – when I started my research in Rome about ten years ago, a new theory on neurodegeneration, called ‘prion-like’ theory, was just emerging. According to prion theory, amyloid proteins, which are normally present in healthy brains, can convert into toxic forms and propagate from cell to cell (similar to prion proteins which cause prion disease) and cause dementia. To travel inside the brain, they use some small lipid vesicles released by cells, called exosomes. As we found in our lab, these lipid nanoparticles contain many important molecules associated with neurodegeneration and they are a precious diagnostic tool.¹³ Exosomes are heavily involved Alzheimer’s cellular dynamics. There is evidence that they can predict Alzheimer’s diseases up to ten years before disease onset and can also be exploited as Trojan horses for the delivery of drugs in the central nervous system.¹⁴ 

AI and digital technologies for a future without dementia

The use of AI technologies can speed-up the identification of new therapeutic targets in areas of medicine of unmet need and design highly efficient drugs for these targets in a very short time. This is explored in detail in our Intelligent drug discovery: Powered by AI report, which highlights the unprecedented potential of AI to revolutionise our understanding of drug compounds and targets, as well as their binding affinity. Moreover, machine learning has the potential to unravel the complexities of neurodegeneration and the heterogeneity of the patient population which are the main barriers to the identification of successful diagnostic and therapeutic approaches.¹⁵ As highlighted in our report many pharma companies are already investing in the sector primarily though collaboration with dedicated start-ups.

Conclusion

My reflections, based on what I have learned over the past two years at the Centre, and looking back over my time researching neurodegeneration, is that to accelerate the process of finding of a cure for Alzheimer’s disease, new models of funding are essential. Moreover, two of the positive outcomes that have emerged over the past year, as researchers across the world have embarked on the search for a treatment for COVID-19 disease, is an improved understanding of the value of AI-enabled drug discovery and the benefits of partnerships and collaborations between the pharma industry, academia, governments and other payers. My belief is that a similar approach could finally unlock the current stalemate in the search for a cure for Alzheimer’s disease.

As we bid farewell to this year’s World Alzheimer’s month, now, more than ever, it is important and urgent to promote innovative ideas, target resources and find the intellectual and scientific courage to prioritise state-of-the-art approaches to already tested hypotheses on neurodegeneration. Paraphrasing my favourite Green Day song: ‘as my memory rests but never forgets what I have lost, wake me up when September ends’.

Dr Francesca Properzi (PhD) - Research Manager, Deloitte UK Centre for Health Solutions

Francesca is a new Research Manager for the Deloitte UK Centre for Health Solutions. She was previously a Principal Investigator at the Italian Institute of Health, supporting research on neurodegenerative diseases and on novel diagnostic and therapeutic nanotechnologies. She also worked previously at the MRC Prion Unit in London as a Senior Scientist, where she joined the team of Prof. Charles Weissmann working on cell-based assays and drug screening of prion diseases. Francesca has a PhD in neuronal regeneration from Cambridge University, and she is currently completing an executive MBA at the Imperial College Business School London focused on innovation and healthcare. 

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¹ https://www.who.int/news-room/fact-sheets/detail/dementia
² https://www.alz.org/alzheimers-dementia/what-is-alzheimers/causes-and-risk-factors
³ https://www.statista.com/statistics/471323/global-dementia-economic-impact-forecast/
⁴ https://www.dementiastatistics.org/statistics/funding-comparisons/
⁵ http://www.pharmatimes.com/web_exclusives/the_search_for_a_cure_for_alzheimers_is_far_from_over_1282807
⁶ RBM3 mediates structural plasticity and the protective effects of cooling in neurodegenerative disease. Peretti D, Bastide A, Verity N, Guerra Martin M, Molloy C, Moreno JA, Radford H, Steinert J, Dinsdale D, Willis AE and Mallucci GR. Nature 2015 518(7538):236-9. doi: 10.1038/nature14142
⁷ https://academic.oup.com/brain/article/140/6/1768/37378676?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627319310566%3Fshowall%3Dtrue
⁸ https://link.springer.com/article/10.1007/s00401-020-02191-1
⁹ https://ukdri.ac.uk/news-and-events/gene-therapy-2m-boost-for-a-core-facility-at-the-uk-dri
¹⁰ https://www.nature.com/articles/s41598-018-33017-6
¹¹ https://www.nature.com/articles/s41380-019-0468-3
¹² https://www.ucl.ac.uk/brain-sciences/news/2019/apr/cells-alzheimers-disease-patients-shed-light-disease-mechanism
¹³ https://smw.ch/article/doi/smw.2015.14204
¹⁴ https://www.jneurosci.org/content/39/47/9269.long
¹⁵ https://www.nature.com/articles/s41582-020-0377-8