Challenging memory tests in early Alzheimer's disease: From research to clinical practice

Alzheimer's disease (AD) diagnosis is undergoing rapid change with the advent of disease-modifying therapies, highlighting the need for earlier and more accurate identification of disease-related cognitive changes, particularly in preclinical stages. In response, several challenging memory paradigms have been introduced to more directly target encoding and storage processes affected in early AD. Building on these paradigms, novel experimental methods based on memory binding, cognitive stress testing, and accelerated long-term forgetting have been proposed to target cognitive processes not captured by traditional episodic memory measures. However, their clinical relevance and applicability remain uncertain. This narrative review summarizes current evidence on the clinical utility of these novel methods. It examines construct validity based on associations with AD biomarkers; discriminative validity to distinguish early pathological cognitive decline from normal aging, and to differentiate AD-related impairment from non-AD etiologies; and predictive validity for future cognitive decline and clinical progression. Particular attention is given to their readiness for individual-level interpretation. Although several methods show promise, particularly for detecting subtle cognitive vulnerability in preclinical AD, none currently fulfills the criteria for routine clinical implementation. The strongest evidence is available for the Memory Binding Test and the Loewenstein-Acevedo Scales of Semantic Interference and Learning, followed by the Face-Name Associative Memory Exam. This review discusses key barriers to clinical translation across the reviewed methods, as well as the evolving requirements for validation of neuropsychological tools in the biomarker-driven era, where cognitive testing is increasingly intended for use in preclinical and early prodromal disease stages.