Anticipating Trial Design Challenges Across The Alzheimer's Disease Severity Continuum

By Paul O’Donohue Senior Director, eCOA Product and Science at Medidata Solutions; and Kaycee Sink MD, MAS, Chief Medical Officer at Cogstate

Alzheimer’s disease (AD) unfolds along a broad and complex continuum of severity, ranging from the earliest biological changes in the brain — often occurring years before any observable symptoms — to the profound cognitive, functional, and behavioral impairments characteristic of mid- to late-stage dementia. At the earliest stages, individuals may remain entirely asymptomatic or experience only subtle changes that are difficult to detect clinically, while those at later stages face significant loss of independence and increasing reliance on caregivers.

Given this wide spectrum of disease manifestation, clinical trial teams must approach each stage of Alzheimer’s disease almost as a distinct condition. Trial objectives, endpoints, and methodologies must be carefully aligned with the specific characteristics of the disease stage under investigation, as well as with the lived experiences of patients and caregivers at that stage. Measures that are sensitive and meaningful in early AD may be inappropriate or infeasible in later stages, and vice versa, underscoring the importance of stage-specific trial design.

In this whitepaper, we examine the key clinical trial design challenges encountered across the Alzheimer’s disease severity continuum. We explore how thoughtful endpoint selection, targeted and ongoing rater training, and the strategic implementation of electronic clinical outcome assessments (eCOA) can help address the unique scientific, operational, and human considerations at each stage of the disease. By adopting a participant- and rater-centric approach to trial design, sponsors can improve data quality, reduce variability, and enhance the overall trial experience. Ultimately, these strategies support more informed drug development decisions, accelerate the path to new treatments, and help ensure that patients and caregivers are supported throughout their journey with this devastating disease.