Targeting Alzheimer's Disease in the Preclinical Stage

With an improved understanding of the pathological progression of Alzheimer’s disease (AD), the field has coalesced around the idea that intervening in the earliest stages of the disease process may prevent progression to dementia. This concept — secondary prevention — has already spawned several large clinical trials, yet there remains uncertainty about how best to identify people in the preclinical stage of disease and the optimal way to conduct secondary prevention studies. Preclinical AD thus was chosen as the focus of the Alzheimer’s Association Research Roundtable (AARR) fall 2018 meeting, which brought together experts from academia, the pharmaceutical and diagnostics industries, and regulatory agencies to explore the pathophysiology, signs, and symptoms of preclinical AD and how to translate that knowledge into methods that will support and accelerate secondary prevention clinical trials. In 2010, Jack and colleagues published a hypothetical model of how AD biomarkers change over the disease continuum [1]. Since then, this model has been supported and updated by real data from multiple populations [2,3] and led to the now widely accepted notion that biomarkers of AD can be detected decades before clinical symptoms appear [4]. It is this stage — the preclinical stage — that is targeted in secondary prevention trials. Yet while imaging and cerebrospinal fluid (CSF) biomarkers have shown great promise in detecting preclinical AD, less invasive and less expensive methods will be needed to screen large populations and identify candidates for secondary prevention trials. In addition, there is a need to discover and further validate biomarkers that can predict or correlate with clinical response to therapies being investigated. Plasma biomarkers offer one promising solution. Other screening tools discussed at the AARR that may provide even earlier markers of neurodegeneration included sensitive cognitive measures, assessments of subjective cognitive decline (SCD) and mild behavioral impairment (MBI), and objective measures of sleep quality. Secondary prevention trials that are underway in preclinical populations have provided important learnings for future trials, especially on the value of collaboration and data sharing. They have also had an impact on clinical care by informing clinicians about the nature of the preclinical experience, noted Jason Karlawish of the University of Pennsylvania. Clinicians should think carefully about how biomarker results are conveyed to patients, he said, since this can shape the experience of people with preclinical AD. The AARR also addressed the topic of primary prevention, which involves intervening even earlier in at-risk individuals before pathology becomes evident. Among the tools discussed with the potential to identify those at risk for AD were polygenic risk scores and digital biomarkers that enable the capture of continuous, objective, multidimensional data on function and behavior [5]. Patient registries such as the Brain Health Registry and the Alzheimer’s Prevention Registry are crucial recruiting tools for all AD clinical trials, but especially for primary and secondary prevention trials. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) and the Alzheimer’s Prevention Initiative (API) already have primary prevention trials underway in people with genetic mutations that confer a nearly 100 percent likelihood of developing AD. Reisa Sperling of Brigham and Women’s Hospital and the Harvard Aging Brain Study and John Sims of Eli Lilly and Company McDade and Hake are co-first authors. *Corresponding author. Tel.: 312-335-5722. E-mail address: mcarrillo@alz.org