Presentation (CTI)

OBJECTIVES: To explore how the types and sources of uncertainty in Alzheimer’s disease appraisals have changed over time and how these shifts affect the evidence base and assumptions used in economic modelling, comparing early appraisals of acetylcholinesterase inhibitors (AChEIs) with recent and emerging disease-modifying therapies (DMTs).
METHODS: A comparative review of NICE technology appraisals for Alzheimer’s disease treatments was undertaken, focusing on how uncertainty in clinical and implementation evidence informs the structure and inputs of economic models. Key areas of analysis included trial design, outcome measures, time horizons, surrogate endpoints, and population definition.
RESULTS: Earlier appraisals of AChEIs were based on relatively mature evidence from late-stage trials, using established symptomatic endpoints and short- to medium-term time horizons. Uncertainty was largely confined to issues of generalisability, adherence, and caregiver impacts. In contrast, emerging DMTs present deeper uncertainties, particularly around disease staging, biomarker-based diagnosis, and the durability of treatment effect. While biomarkers such as amyloid were used to confirm biological activity, clinical benefit in appraisals relied on short-term changes in cognitive and functional scales (e.g. CDR-SB, iADRS). These outcomes introduce complexity in modelling, as long-term projections require substantial extrapolation and assumptions about the persistence of effect, disease progression, and real-world implementation pathways.
CONCLUSIONS: As Alzheimer’s treatments shift from symptomatic management to disease modification, the nature of uncertainty relevant to economic modelling is also changing. New sources of uncertainty, particularly around early-stage diagnosis, treatment timing, and long-term outcomes, require methodological adaptations to ensure that models remain robust and decision-relevant. Addressing these challenges will be critical for maintaining consistency and credibility in future Alzheimer’s disease appraisals.