Validation status of cognitive digital assessments by the FDA BEST framework and context of use in preclinical AD studies: A systematic review

Abstract

Digital cognitive assessments have rapidly expanded in Alzheimer's disease (AD) research, offering a sensitive, scalable, and cost-effective alternative to traditional neuropsychological tests. This systematic review examines the validation and utility of digital cognitive assessments in cognitively normal (CN) individuals and explores their potential classification within the US Food and Drug Administration's Biomarkers, Endpoints, and other Tools (FDA BEST) framework. Additionally, we provide recommendations to consider for their implementation. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched PubMed for studies validating digital cognitive tools against paper-based tests and standard AD biomarkers, including measures of amyloid beta and tau in fluid and neuroimaging biomarkers. Our findings suggest potential use as risk or monitoring biomarkers, though further longitudinal validation is needed. This review highlights the latest advancements in digital cognitive assessments, their role as novel AD biomarkers, and essential considerations for their effective use in AD. HIGHLIGHTS: Digital cognitive assessments for preclinical Alzheimer's disease (AD) are associated with established biomarkers, including paper-based neuropsychological tests and amyloid beta and tau measures in both fluid and neuroimaging techniques. These assessments have the potential to serve as novel AD biomarkers classified within the US Food and Drug Administration's Biomarkers, Endpoints, and other Tools framework and context of use, but long-term studies spanning different disease stages are needed to fully establish their validity for some of the biomarker categories. Several biases may be present when conducting digital cognitive assessments; their optimal use should follow specific recommendations to minimize them.

Keywords: Alzheimer's disease; amyloid beta; biomarkers; digital biomarkers; digital cognitive assessments; preclinical Alzheimer's disease.