Defining Alzheimer’s by biomarkers could improve clinical trials

Incorporating biomarkers into the research definition of Alzheimer’s disease should lead to delayed progression, better treatment and new criteria for clinical trials.

When we think about getting older, one of the things many people fear is developing dementia or Alzheimer’s, with the associated loss of brain function, often devastating effects on lifespan and healthspan and increased burden on family, healthcare providers and the economy.

Longevity.Technology: When people think about Alzheimer’s, they think about memory loss. It is the most prevalent cause of dementia – understood to contribute to around 60 or 70% of cases of dementia globally – and as well as affecting memory, it impacts on other cognitive functions, hugely affecting daily functions and social ability. As the disease progresses, full-time care is often needed. As the world’s population ages, there is a focus on preventing and curing Alzheimer’s, and this definition change could help optimise research and clinical trials .

In Alzheimer’s memory problems can be the first set of symptoms that occur; the sufferer may also show waning interest in previously-enjoyed activities, and, as time progresses, the person may develop more serious symptoms such as confusion and disorientation, difficulty making decisions, problems with speech and language, difficulty moving around and performing self-care tasks, personality changes, hallucinations, delusions and low mood or anxiety [1].

Now, The National Institute on Aging and the Alzheimer’s Association are suggesting changes to the research definition of Alzheimer’s disease. Although a doctor’s diagnosis would still be based on symptoms such as memory loss and changes in thinking and cognition, the criteria for defining what Alzheimer’s disease actually is for use in clinical trials and research would change to being defined by the presence of biomarkers.

A biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention [2].”

Biomarkers are big news; they have become critical tools in drug development R&D moves away from broad spectrum approaches and towards personalised healthcare and targeted therapies. Aging clocks that use machine-learning crunched data, advancements in omics datasets and next-generational sequencing mean that researchers have been able to incorporate analytics data into their clinical trials earlier and on a much wider scale. This scalability means targeted clinical trials as biomarkers streamline the development process and identify specific patient populations.

The biomarkers that would make up the proposed new research definition of Alzheimer’s are the build-up of plaques and tangles in the brain; these can be identified by imaging scans of the brain and samples of cerebrospinal fluid.

Biomarkers that are ideal for clinical trials are those that are easy to measure, consistent across different groups of people and modifiable with treatment.

The biomarkers that would make up the proposed new research definition of Alzheimer’s are the build-up of plaques and tangles in the brain; these can be identified by imaging scans of the brain and samples of cerebrospinal fluid (CSF). This change would, the proponents say, allow researchers to better design clinical trials, target the most appropriate participants and learn more about the disease in its earlier stages.

The symptoms of Alzheimer’s disease with which we are familiar don’t actually define it; rather they result from the changes in the brain, the plaques and tangles, that define the disease. Plaques are abnormal clusters of beta-amyloid protein fragments that build up between nerve cells, blocking cell-to-cell signalling at synapses and thought to activate the immune system cells that trigger inflammation. Neurofibrillary tangles are formed when the tau protein, which usually keeps a vital cell transport system made of proteins in neat, orderly lines, collapses into twisted, matted strands; this causes the transport network to disintegrate and the cell to die.

Plagues and tangles are identifiable long before outward symptoms of Alzheimer’s are expressed; using these biomarkers to define Alzheimer’s would mean that sensitive clinical and neuropsychological assessments to help detect and track the early stage of the disease could be developed and refined and a model of Alzheimer’s disease progression over decades, from its earliest, pre-symptomatic stage right through to crippling dementia could be built.

Biogen’s aducanumab is moving a step forward to FDA approval, but has had a chequered history; although it is the first drug to have been found to slow the decline of Alzheimer’s disease rather than only ameliorate the symptoms, the external panel found the lack of biomarker data a factor in their non-recommendation.


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