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Early diagnosis and treatment of Alzheimer’s disease: progress, challenges and opportunities

Many of us can now expect to live into our 10th decade. However, with almost half the population over 90 being diagnosed with dementia, the societal and economic costs of cognitive decline are expected to worsen.

 

PLOS ONE recently launched a call for papers on the early diagnosis and treatment of Alzheimer’s disease, the most frequent cause of dementia. In this blog post PLOS ONE staff editor George Vousden interviews Michael Weiner, one of the Guest Editors for the call. Professor Weiner explains the progress that’s been made in this area and how data sharing can aid in the search for new treatments for Alzheimer’s disease.

 

How are the goals of early diagnosis and treatment of Alzheimer’s disease related? What progress has been made in the diagnosis of the disease?

Alzheimer’s disease is associated with the formation of amyloid beta plaques and tau tangles inside nerve cells, resulting in neurodegeneration. Whilst removal of these classic symptomologies may slow cognitive decline and prevent dementia, to do so would require intervention at an early stage of the disease.

Detection of Alzheimer’s pathology was traditionally only possible in post-mortem specimens. However, over the last 10 to 20 years technology has improved to a point where we can detect the presence of Alzheimer’s biomarkers at a much earlier stage. Plasma assays are now able to detect proteins known to be associated with the disease such as amyloid beta, neurofilament light and tau. As a result of these advances, blood tests are being developed that can be used to inform clinicians of the levels of these proteins in the brain. Progress is also being made at identifying individuals with an increased risk of developing the disease. Polygenic risk scores, which look at multiple variants within the genome, are increasingly being used to identify individuals susceptible to the disease. This information that will likely prove vital in preventing the development of Alzheimer’s.

 
Why has this disease proved so difficult to treat?

Recent trials in this have indeed been disappointing. The pharmaceutical company Biogen recently terminated a clinical trial with the antibody aducanumab.Whilst this drug removed amyloid from the brain, the trial was terminated for “futility”. Although some investors may have been discouraged by these and similar results, there is hope amongst scientists and clinicians a cure will be found. Government funding in this area remains strong, with the National Institute for Aging recently increasing their funding in this area.

It is important to acknowledge that it is only recently that we have been testing potentially disease modifying treatments for Alzheimer’s disease. Many treatments currently being developed utilise immunotherapy, a concept that has only existed for 20 years or so. In addition, it is only in the last 4-5 years that it has been possible to accurately diagnose patients with Alzheimer’s without taking pathological samples. This may have resulted in considerable heterogeneity in specific pathologies in the patients taking part in previous clinical trials making significant effects harder to detect.

One of the additional challenges in developing new treatments in this area is the slow and varied progression of symptoms of patients with Alzheimer’s disease. This means large and extended treatment trials are required to test the efficacy of novel treatments. This is in stark contrast to other diseases which, historically, have been much easier to treat. For example, prior to the introduction of penicillin in the 1940s, patients with Streptococcus pneumoniae could die within 5 days.

 

What challenges do you think the field will need to overcome in the next 20 years?

We first need to identify biomarkers and risk factors for Alzheimer’s disease so we can identify those at risk of the disease before symptoms develop. This will create opportunities to prevent the disease in these individuals. The development of effective treatments will require an understanding of which biological effects, which may include removal of amyloid or tau, influence the disease. These treatments must also be scalable – this is an issue with the infusion-based treatments currently under development

 

You are the principal investigator on the Alzheimer’s Disease Neuroimaging Initiative. What is this and what are its aims?

The overall goal of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer’s disease clinical trials. It’s an observational, naturalistic study and has received over $200m in since its launch in 2004. We’ve enrolled over 2,000 people, which includes healthy individuals (including Michael Weiner), individuals with mild-cognitive impairment and those with Alzheimer’s disease. As part of the study participants are extensively phenotyped and undergo neuropsychological tests, PET and MRI scans and lumbar punctures each year. This rich dataset is available to freely download.

 

Over 2000 publications have arisen from ADNI (over 100 of which are in PLOS journals). Why has ADNI been so successful?

The wonderful thing about ADNI is that all the data are available online at no cost. Access to these data can be used by interested individuals conducting research in multiple domains, including the design of studies developing novel interventions for Alzheimer’s. The data can be used to forecast disease progression in a sample population of a clinical trial, allowing researchers to optimise their study design to maximise statistical power.

A second accomplishment of ADNI was the demonstration that amyloid phenotyping can be done on a mass scale in a multisite study. ADNI is one of the few studies to measure amyloid levels in cerebrospinal fluid and through PET imaging – it’s the only large-scale study to do so and make the data freely available. These data have been instrumental in demonstrating the associations between increased levels of amyloid in the brain and Alzheimer’s disease.

 

Users of the ADNI dataset are encouraged to submit their work to the PLOS ONE call for papers, Early diagnosis and treatment of Alzheimer’s disease.

About Michael Weiner:

Michael (Mike) W. Weiner has been doing research for over 50 years. After a B.S. degree from Johns Hopkins University, he received his M.D. from Upstate Medical Center, completed a Residency in Internal Medicine at Mt. Sinai Hospital and Yale University and was Board Certified in Internal Medicine and Nephrology. After a postdoctoral fellowship in Biochemistry at the University of Wisconsin he moved to Stanford University where he won the Young Investigator Award of the American College of Cardiology.  In 1980 he performed one of the first whole-animal NMR experiments and began a new career using NMR (which became MRI) for clinical research. He began studying Alzheimer’s Disease with MRI/MRS in 1989. He is the Principle Investigator of the Alzheimer’s Disease Neuroimaging Initiative and the Brain Health Registry. He has been awarded the VA Middleton Award, the Nancy and Ronald Reagan Award from the Alzheimer’s Association and the Potemkin Prize from the American Association of Neurology.

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