The number of people with dementia worldwide is forecast to rise to 115.4 million – or one in 85 people – by 2050. Improved techniques and technologies are being developed with the aim of early diagnosis of Alzheimer’s disease (AD), the most common form of dementia. Today, increasing numbers of AD clinical trials are mandating the use of biomarkers, in particular neuroimaging markers and cerebrospinal fluid biomarkers tracked via lumbar punctures. This review examined 12 AD trials conducted / monitored by Quintiles that involved potentially disease-modifying drugs that had a significant biomarker component. These trials have enrolled 7,583 patients at 524 unique sites across 31 countries since 2007.
The study confirmed that lumbar punctures still represent the biggest challenge for subjects participating in these trials and for their caregivers. Changes in brain extracellular fluid are reflected in the cerebrospinal fluid (CSF) such that measurements of AD markers in CSF should reflect brain-related pathological changes and could be useful, not only for diagnostic stratification and as predictive markers, but also for monitoring the biochemical effects of drugs in clinical trials. ELISA measurement of monomeric A®42 (or A®42/ A®40 ratios), total tau and phosphorylated tau protein levels in CSF is very common in AD trials. Measurement of other A®forms, as well as efforts to characterise a number of other potential AD biomarkers in CSF, continues to be explored in preclinical and clinical studies.
The majority of subjects and/or their caregivers decline to participate in this procedure as it is invasive and can be seen as painful and / or distressing for the subject and caregiver alike. However, this procedure provides invaluable data with regards of the progression of the subjects’ disease and thus, by way of assessment of these biomarkers, offers some understanding of the mechanism of action of the investigational product on the disease and its progression. However, compliance with biomarker assessments can be enhanced in several ways, including mandating the procedure in the protocol rather than providing it as a separate set of addenda, utilising sites with on-site imaging facilities, and utilising a tool box of techniques (e.g., provision of DVDs of the procedure for subjects to take home and share with their families and caregivers) to improve lumbar puncture compliance. As a result of adopting these strategies, Quintiles’ lumbar puncture compliance rate, i.e. the number of trial subjects who consent to at least two lumbar punctures during the trial period (at the beginning and end of a trial) has risen from 8% in 2005 to more than 50% at present.
Listen to Lynne Hughes and Roza Hayduk talk about clinical trials and their role in early diagnosis of Alzheimer's disease.