The costs of Alzheimer’s disease – to economies, health services, families, and above all, individuals with this devastating disease – are truly awful. Even in this period, with a pandemic sweeping the world, it is sobering to realise that in many countries, deaths due to Alzheimer’s rival those due to COVID-19, and indeed a large proportion of those dying in the first wave of the virus also had dementia. The response to SARS-CoV-2 has been extraordinarily rapid and successful, and as this gradually brings the pandemic under control, Alzheimer’s disease and its related disorders will again become one of humanity’s greatest unmet medical needs.

After many frustrating years of failed clinical trials, it is exciting to see progress being made in the development of therapeutics designed to modify the disease process in Alzheimer’s. Most late-stage clinical trials to date have focused on amyloid as a target – whether by reducing generation of the A-beta peptide with small molecules or using monoclonal antibodies to reduce the various pools of aggregated amyloid in the brain. Recently, the first such compound received a conditional approval from the United States Food & Drug Administration (FDA). Whatever the final outcome of post-approval investigations now initiating, and whatever the impact of this approval on the provision of therapies to people with or at risk of getting Alzheimer’s disease, this approval marks an important stage in the history of the disease from its first description by Alois Alzheimer over 100 years ago.

The Alzheimer’s disease field is experiencing three very substantial shifts, which might even be thought of as paradigm shifts. These shifts in research and development and in the acceleration to find a truly transformative treatment – in our understanding of disease heterogeneity, in the development of biomarkers, and most importantly in the diversification of target development – are set to impact substantially on drug development and increase the likelihood of a treatment, potentially a preventative treatment, for the disease.

The description by Alzheimer of the plaque and tangle lesions in the brain of his patient, Auguste Dieter, was masterful given the limited investigational tools at his disposal. For the following century, the presence of plaques made from aggregated amyloid and intracellular tangles, composed of aggregates of truncated and phosphorylated tau, were the hallmarks of diagnosis, a determination that could only be made definitively at post-mortem. The clinical syndrome he described was refined over the years and is moderately good at predicting the post-mortem clinical findings, especially when taking into account the transition or staging of pathology that was so carefully documented by Braak and Braak.

However, in recent years, the limitations of this long established clinical and pathological syndromic description have become more apparent. While amyloid and tau pathologies are indisputably part of a pathological process, increasing data suggested that their relationship to neurodegeneration is not equal – the amount of tau pathology appears more closely correlated to current cognitive deficit, although both amyloid and tau pathology predict future decline. Most data, whether from post-mortem pathology studies, or from studies in life using biomarkers, and above all from genetics, suggest some process associated with amyloid generation is the trigger that initiates the disease process, but that it is tau pathology that is the ultimate driver of neuronal degeneration and hence the symptoms of the clinical syndrome.

However, it has become increasingly clear that pathologies beyond either amyloid or tau also contribute to the clinical syndrome. A considerable amount of evidence suggests that vascular damage to the brain is the most common coincident pathology associated with dementia and might be an area where behavioural or systemic interventions could reduce risk. Whether or not the tried and tested clinical syndromes are eventually superseded by a more pathology/target-based description of disease, there is little question that drug development is driven by our understanding of mechanism and target.

At Janssen, we have embraced this diversification of targets and refinement of the classification of neurodegenerative syndromes based on their pathology. As a result, we have a pipeline that looks very different from the amyloid-centric approach of the past; all of these pathologies are in our sights either directly or through related targets. Looking ahead, a new world becomes possible where the ethos of precision medicine – right drug, right patient, right time – drives not only drug development but clinical practice too.

A pipeline diversified around different pathologies demands biomarkers to identify the right patient for the right drug. Progress in delivering such biomarkers has been remarkable.
PET tracers to identify and monitor the pathologies of Alzheimer’s disease have become widely effective; however, plasma biomarkers represent a significant advance in the category. Combined analysis of plasma markers for A-beta, tau and neurofilament light chain (a marker for neurodegeneration) have allowed for new, more specific, classification of the disease. The addition of markers for other pathologies of neurodegeneration, such as synucleinopathy and TDP-43 pathology, could further hone ability to classify and/or differentiate patients. And before long, patients entering trials may be selected by specific pathological load.

The importance of having biomarkers for early decision-making in clinical trials cannot be underestimated. Again, at Janssen, we have embraced the importance of biomarkers not only in recruiting the right patient at the right time to clinical trials but in making outcome decisions in early development clinical trials wherever possible. And where not possible, because the appropriate biomarkers are not yet available, we are working hard internally and with partners to ensure that they are.

These are promising times for neurodegeneration research. The first disease modification therapy has had conditional approval, large pharma companies that had previously decreased their activities in neuroscience have come back to the field, and small company biotech and biopharma are blossoming with a significant increase in funding.

These changes are reflected in the rapidly growing diversification of therapeutic targets with compounds in clinical development, and for every clinical compound, there are many more in preclinical phases.

This diversification could not be more welcome. Accompanied by our growing understanding of pathological processes and a parallel development in biomarkers, the promise of precision medicine in neurodegeneration is close to being realised. Janssen is leaning into these developments with a portfolio diversified in its approach but focused on pathologies with biomarkers for inclusion and outcome. But despite the accelerating science and our growing confidence, there is little doubt that neurodegeneration continues to be a difficult category, and until there are fully approved compounds reaching patients, we cannot risk complacency. For these reasons, we are not only driving our internal efforts, but in key, strategically important areas, we are working with others to share data and samples and to speed the development of biomarkers.

Today, we are perhaps where oncology was a decade or two ago. Where therapies were once few in number and discovered largely by serendipity, today, precision medicine and therapeutics by design are the norm. Patients have benefited beyond measure, and in oncology, survival has become commonplace, and survivorship has become a thing. That too is coming to Alzheimer’s disease and its related disorders, and Janssen’s pipeline is set to make a major contribution.

‘Alzheimer’s disease, and its related disorders, is one of humanity’s greatest unmet medical needs, and deaths due to Alzheimer’s rival those due to COVID-19 in many countries’